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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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Brain-penetrating neurotrophic factor mimetics: HER-096 as a disease-modifying therapy for Parkinson’s disease

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Neural Regeneration Research 2025年第4期20卷 1094-1095页

作者： Natalia Kulesskaya Kira m.Holmström Henri j.Huttunen Herantis Pharma Plc EspooFinland

Neurotrophic factors as a therapeutic approach in neurodegenerative diseases:A major unmet need in the field of central nervous system diseases is disease-modifying *** for decades there have been various symptomatic treatments available to alleviate the symptoms of the disease,disease-modification,*** that stop,significantly delay,or reverse the progression of the disease,has been turned out to a difficult goal to achieve.

关键词： diseases treatment therapeutic

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Sleep as a window to understand and regulate Alzheimer's disease:emerging roles of thalamic reticular nucleus

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Neural Regeneration Research 2025年第6期20卷 1711-1712页

作者： Haoqi Sun Shiqian Shen Robert j.Thomas m.Brandon Westover Can Zhang Department of Neurology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Center for Translational Pain Research Department of AnesthesiaCritical Care and Pain MedicineMassachusetis General HospitalHarvard Medical SchoolBostonMAUSA Division of Pulmonary Critical Care and Sleep MedicineDepartment of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Genetics and Aging Research Unit McCance Center for Brain HealthMass General Institute for Neurodegenerative DiseaseDepartment of NeurologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA

Introduction:Alzheimer 's disease(AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β(Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism,showing slowed clinical decline(van Dyck et al.,2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches(Zhang, 2023).

关键词： Alzheimer inflammation hypothesis

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Ribozymes and the mechanisms that underlie RNA catalysis

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Frontiers of Chemical Science and Engineering 2016年第2期10卷 178-185页

作者： Timothy j. wilson Yijin Liu David m. j. Lilley Cancer Research UK Nucleic Acid Structure Research Group MSI/WTB Complex The University of Dundee Dundee DD1 5EH UK

Ribozymes are widespread, and catalyze some extremely important reactions in the cell. mechanistically most fall into one of two classes, using either metal ions or general acid-base catalysis. The nucleolytic ribozymes fall into the latter class, mostly using nucleobases. A sub-set of these use a combination of guanine base plus adenine acid to catalyze the cleavage reaction. New ribozymes are still being discovered at regular intervals and we can speculate on the potential existence of ribozymes that catalyze chemistry beyond phosphoryl transfer reactions, perhaps using small-molecule coenzymes.

关键词： RNA catalysis RNA structure catalytic mechanism

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Emerging role of A-kinase anchoring protein 5 signaling in reward circuit function

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Neural Regeneration Research 2025年第10期20卷 2913-2914页

作者： William j.Flerlage mark L.Dell’Acqua Brian m.Cox Fereshteh S.Nugent Uniformed Services University of the Health Sciences Department of Pharmacology and Molecular TherapeuticsBethesdaMDUSA Department of Pharmacology University of Colorado School of MedicineAnschutz Medical CampusAuroraCOUSA

There is a strong evidence supporting the hypothesis of synaptic dysfunction as a major contributor to neural circuit and network disruption underlying emotional and mood dysregulation in psychiatric disorders(Simmons et al.,2024).Diverse sets of distinct molecular signaling pathways converge on the synapse to regulate synaptogenesis,synaptic function,and synaptic plasticity in brain regions and circuits through complex interactions organized by numerous multivalent protein scaffolds,including the family of proteins known as A-kinase anchoring proteins(AKAPs).

关键词： function supporting

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Simulation and calibration of granules using the discrete element method

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Particuology 2014年第1期12卷 40-43页

作者： peter müller jürgen Tomas Institute of Process Engineering Mechanical Process EngineeringOtto-von-Guericke University MagdeburgUniversitätsplatz 239106 MagdeburgGermany

The discrete element method （DEm）, developed by Cundall and 5track to solve geomecnamcai problems, is used to simulate the mechanical behavior of granules. According to the DEm, an individ ual granule can be modeled as a realistic mechanical system consisting of primary particles bonded by interaction forces. Cranulometric properties of the model material, zeolite 4A, have been measured to determine their macro properties. To investigate the compression behavior, a compression test was performed using a strength tester on single granules between two pistons. A modeled granule consisting of more than 22,000 primary particles was generated. The micro properties of the modeled granule have been precisely set to allow its macro properties to be equivalent to the macro properties of zeolite 4A granules. To calibrate the mechanical properties, diametrical compression was simulated using two rigid walls stressed at a constant stressing velocity, The force-displacement curve of the modeled granule at compression has been calibrated by the experimental curve of zeolite 4A.

关键词： Discrete element method material behavior Granulation

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Iron Oxides and Their Relations to Colors in Some Soilsof Southern China

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Pedosphere 1998年第1期8卷 53-58页

作者： ZHANGmINGKUI m．j．wilson 等 DepartmentofSoilScienceandWaterResource ZhejiangAgriculturalUniversityHangzhou310029（CHina） Soilsand

Iron oxides from 33 samples of 25 soils derived from various parent materials in the southern China were studied using NaOH selective dissolution technique and X-ray diffraction (XRD). Goethite and hematite were the only two crystalline Fe oxides occurring in a significant quantity. The goethite / (goethite + hematie )ratios ranged from 0 to 1, being the highest in yellow soil, some yellow-red soils and saprolite samples and the lowest in soils derived from purple sandstone where only hematite was present. Al substitution in goethite ranged from 6.6 to 29.9 mol % with a mean value of 16.7 mol %, while substitution of Al in hematite ranged from 0 to 12.1 mol %. The values of Al substitution of hematite in coexisting goethite and hematite were closely related with corresponding values of goethite (r=0.7292, Pmount of hematite (r=0.8109, Pmate hematite contents of soils.

关键词： Al substitution color iron oxides southern China

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Delirium after emergency hip surgery-common and serious, but rarely consented for

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World journal of Orthopedics 2019年第6期10卷 228-234页

作者： Louis j Koizia Faye wilson peter Reilly michael B Fertleman Geriatric medicine Imperial College NHS TrustLondon W2 1NYUnited Kingdom Geriatric medicine City Hospitals SunderlandSunderland SR4 7TPUnited Kingdom Department of Trauma and Orthopaedics Imperial College Healthcare NHS TrustLondon W2 1NYUnited Kingdom

A quarter of patients admitted with a proximal femoral fracture suffer from an acute episode of delirium during their hospital *** it is often unrecognised,poorly managed,and rarely discussed by *** is important not only to the affected individuals and their families,but also socioeconomically to the broader *** increases mortality and morbidity,leads to lasting cognitive and functional decline,and increases both length of stay and dependence on *** should be routinely and openly discussed by all members of the clinical team,including surgeons when gaining *** to do so may expose surgeons to claims of *** we present a concise review of the literature and discuss the epidemiology,causative factors,potential consequences and preventative strategies in the perioperative period.

关键词： Delirium Proximal femoral fractures Consent Hip surgery montgomery medicolegal

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Those amazing dinoflagellate chromosomes

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Cell Research 2003年第4期13卷 215-217页

作者： peter j RIZZO Department of Biology Texas A & m University College Station TX 77843 USA

Dinoflagellates are a very large and diverse group of eukaryotic algae that play a major role in aquatic food webs of both fresh water and marine habitats. moreover, the toxic members of this group pose a health threat in the form of red tides. Finally, dinoflagellates are of great evolutionary importance, because of their taxonomic position, and their unusual chromosome structure and composition. While the cytoplasm of dinoflagellates is typically eukaryotic, the nucleus is unique when compared to the nucleus of other eukaryotes. more specifically, while the chromosomes of all other eukaryotes contain histones, dinoflagellate chromosomes lack histones completely. There are no known exceptions to this observation: all dinoflagellates lack histones, and all other eukaryotes contain histones. Nevertheless, dinoflagellates remain a relatively unstudied group of eukaryotes.

关键词： dinofiagellates chromosomes histones histone-like proteins.

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mechanistic action of gibberellins in legume nodulation

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journal of Integrative Plant Biology 2014年第10期56卷 971-978页

作者： Satomi Hayashi peter m.Gresshoff Brett j.Ferguson Centre for Integrative Legume Research The University of Queensland

Legume plants are capable of entering into a symbiotic relationship with rhizobia *** results in the formation of novel organs on their roots,called nodules,in which the bacteria capture atmospheric nitrogen and provide it as ammonium to the host *** molecular and physiological changes are involved in the formation and establishment of such *** phytohormones are known to play key roles in this ***（gibberellic acids;GAs）,a class of phytohormones known to be involved in a wide range of biological processes（i.e.,cell elongation,germination）are reported to be involved in the formation and maturation of legume nodules,highlighted by recent transcriptional analyses of early soybean symbiotic ***,we summarize what is currently known about GAs in legume nodulation and propose a model of GA action during nodule *** from a wide range of studies,including GA application,mutant phenotyping,and gene expression studies,indicate that GAs are required at different stages,with an optimum,tightly regulated level being key to achieve successful *** acids appear to be required at two distinct stages of nodulation：（i）early stages of rhizobia infection and nodule primordium establishment;and（ii）later stages of nodule maturation.

关键词： Gibberellic acid legume nodulation phytohormone plant development rhizobia symbiosis

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