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Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration

World Journal of Gastroenterology 2014年第47期20卷 17851-17862页

作者： Katharine m Irvine Richard Skoien Nilesh J Bokil michelle melino Gethin P Thomas Dorothy Loo Brian Gabrielli michelle m hill matthew J Sweet Andrew D Clouston Elizabeth E Powell Centre for Liver Disease Research School of MedicineThe University of QueenslandTranslational Research InstituteBrisbane 4102Australia Institute for molecular Bio-science The University of QueenslandBrisbane 4067Australia The University of Queensland Diamantina Institute The University of Queensland Translational Research InstituteBrisbane 4102Australia Department of Gastroenterology and Hepatology Princess Alexandra HospitalBrisbane 4102Australia

AIm:To develop a model of stress-induced senescence to study the hepatocyte senescence associated secretory phenotype(SASP).mETHODS:Hydrogen peroxide treatment was used to induce senescence in the human Hep G2 hepatocyte cell *** was confirmed by cytochemical staining for a panel of markers including Ki67,p21,heterochromatin protein 1β,and senescence-associated-β-galactosidase *** hepatocytes were characterised by gene expression arrays and quantitative polymerase chain reaction(q PCR),and conditioned media was used in proteomic analyses,a human chemokine protein array,and cell migration assays to characterise the composition and function of the hepatocyte ***:Senescent hepatocytes induced classical markers of senescence(p21,heterochromatin protein1β,and senescence-associated-β-galactosidase activity);and downregulated the proliferation marker,*** senescence induced a 4.6-fold increase in total secreted protein(P=0.06)without major alterations in the protein ***-induced genes were identified by microarray(Benjamini Hochbergcorrected Pment of secreted proteins among inducible *** hepatocyte SASP included characteristic factors such as interleukin(IL)-8 and IL-6,as well as novel components such as SAA4,IL-32and Fibrinogen,which were validated by q PCR and/or chemokine protein *** hepatocyteconditioned medium elicited migration of inflammatory(granulocyte-macrophage colony stimulating factor,Gm-CSF-derived),but not non-inflammatory(CSF-1-derived)human macrophages(P=0.022),which could contribute to a pro-inflammatory microenvironment in vivo,or facilitate the clearance of senescent ***:Our novel model of hepatocyte senescence provides insights into mechanisms by which senescent hepatocytes may promote chronic liver disease pathogenesis.

关键词： Cell aging Chemokines Hepatocytes Inflammation Liv

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Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin:Creation of an unnatural analogue with improved anticancer properties

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Acta Pharmaceutica Sinica B 2024年第1期14卷 421-432页

作者： Dexiu Yan Jemma Arakelyan Teng Wan Ritvik Raina Tsz Ki Chan Dohyun Ahn Vladimir Kushnarev Tsz Kiu Cheung Ho Ching Chan Inseo Choi Pui Yi Ho Feijun Hu Yujeong Kim hill Lam Lau Ying Lo Law Chi Seng Leung Chun Yin Tong Kai Kap Wong Wing Lam Yim Nikolay S.Karnaukhov Richard Y.C.Kong maria V.Babak Yudai matsuda Department of Chemistry City University of Hong KongHong Kong SARChina iGEm Team“VarieCure” City University of Hong KongHong Kong SARChina Department of Biomedical Engineering City University of Hong KongHong Kong SARChina moscow Clinical Research Center Named After A.S.Loginov Moscow 111123Russian Federation

A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin(1)and variecolactone(2)was identified in Aspergillus aculeatus ATCC *** production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 ***,the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues(5-7).Analysis of the compounds’anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities,5 was associated with significantly reduced toxic side effects in cancer-bearing mice,indicating its potentially broader therapeutic *** study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

关键词： Animal studies Anticancer properties Biosynthesis Natural products Sesterterpenoids Synthetic biology Terpene synthases Variecolin

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A multi-parametric Programming Based Analytic method to Compute Consumer Offer Curve for Reserves

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Journal of modern Power Systems and Clean Energy 2022年第2期10卷 542-546页

作者： Weiye Zheng David J.hill Wenchuan Wu the School of Electrical Power Engineering South China University of TechnologyGuangzhouChina the Department of Electrical and Electronic Engineering The University of Hong KongHong KongChina the Department of Electrical Engineering Tsinghua UniversityBeijingChina

Abstract-An analytic method is proposed to compute the price-reserve offer curve at the consumer level in hierarchical direct load *** convexification of the consumer reserve provision is examined,and the analytic expression of the optimal solution within each critical region is ***,based on multi-parametric programming,a combinatorial enumeration method in conjunction with efficient reduction and pruning strategy is proposed to compute the optimal response of consumers in the whole price *** tests along with an application example in the bi-level aggregator pricing problem demonstrate the merit of this method.

关键词： Direct load control multi-parametric programming price-reserve offer curve analytic solution

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Porous solid inspired hyper-crosslinked polymer liquids with highly efficient regeneration for gas purification

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Science China materials 2022年第7期65卷 1937-1942页

作者： Stefan J.D.Smith Colin D.Wood Paul H.m.Feron Hamidreza mahdavi Roger J.mulder Cara m.Doherty matthew R.hill Xavier mulet CSIRO manufacturing Private Bag 10Clayton SouthVIC 3169Australia Department of Chemical Engineering Monash UniversityClaytonVIC 3800Australia Australian Resources Research Centre KensingtonWA 6155Australia CSIRO Energy P.O.Box 330NewcastleNSW 2300Australia

Separation media that combine the desired material properties within a single material for a given process remain an ongoing challenge for the gas separations in *** integration of porous solid adsorbents is difficult due to their limited volumetric capacity,whereas issues of volatility and high regeneration temperatures exist for liquid amines and physical ***,we report a family of polymer liquids inspired by hyper-crosslinked polymers(HCPs),a class of highly swellable network *** with a chemically similar porous solid,the HCP-liquids demonstrate good volumetric capacity and improved selectivity of carbon dioxide over *** appears to be enhanced by intramolecular swelling of the HCP-liquids at elevated pressures,while guests are strongly rejected from the HCP-liquids at slightly elevated temperatures,leading to highly efficient *** of adsorption and specific heat capacity of the HCP-liquids are also low,further suggesting favourable process *** being easily prepared at scale,the presented HCP-liquids represent a promising step towards a material with the requisite properties to replace conventional scrubbing solvents to drastically reduce the footprint and energy needs of gas separations.

关键词： hyper-crosslinked polymers swellable network efficient regeneration porous liquids gas sorption

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Underlying solvent-based factors that influence permanent porosity in porous liquids

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Nano Research 2022年第4期15卷 3533-3538页

作者： Hamidreza mahdavi Huacheng Zhang Lauren K.macreadie Cara m.Doherty Durga Acharya Stefan J.DSmith Xavier mulet matthew R.hill Department of Chemical Engineering Monash UniversityClaytonVIC 3800Australia CSIRO manufacturing Private Bag 10Clayton SouthVIC 3169Australia School of Chemistry University of SydneySydney 2006Australia

Porous liquids(PLs)offer the potential to combine the ready handling and mature industry status of liquid absorbents,with the high permanent porosity of metal organic *** be functional,these nanocomposites need to satisfy a number of performance parameters,such as stability and viscosity of the porogen-solvent combination,avoiding solvent penetration into metal organic framework(mOF)pores,suitable capacities,and kinetics for gas *** this work,we systematically investigate the component materials to elucidate the parametric space where stable photoluminescence(PL)can be *** this situation,deeper conclusions were able to be drawn with regard to the influence of hydrophobicity/philicity on the properties of the resulting *** imidazolate frameworks(ZIFs)were combined with a range of solvents varying in steric bulk,to deliver CO_(2)sorption capacities as high as 4.2 mmol·g^(-1)at 10 *** findings may have broader implications for future investigations of this tantalising field of nanocomposites.

关键词： zeolitic imidazolate frameworks porous liquids permanent porosity gas sorption

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The mechanisms of color production in black skin versus red skin on the heads of New World vultures

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Avian Research 2023年第1期14卷 86-92页

作者： Nicholas m.Justyn matthew J.Powers Geoffrey E.hill Kayla Alexander Adrián Naveda-Rodríguez Scott A.Rush Department of Biological Sciences Auburn UniversityAuburnALUSA College of Veterinary medicine Mississippi State UniversityMississippiStateMSUSA Department of Wildlife Fisheriesand AquacultureMississippi State UniversityMississippi StateMSUSA

A determination of how the color of animal integument is produced is a starting point for investigations into the function and evolution of *** mechanisms that give rise to the color of bare skin of New World vultures are largely ***,we investigate the source of color production in the bare skin of Turkey Vultures(Cathartes aura)and Black Vultures(Coragyps atratus).Using UV-vis reflectance spectroscopy,we found evidence that hemoglobin is the primary pigment responsible for the red coloration of the bare skin on the heads of Turkey Vultures,and that eumelanin is responsible for the black coloration of the bare skin on the heads of Black *** microscopy of incisional skin samples further supported these mechanisms of color production by revealing the presence of numerous blood vessels near the surface of the Turkey Vulture skin,and a high concentration of melanosomes in the skin of Black *** high performance liquid chromatography(HPLC),we detected carotenoids within the skin of both species with significantly higher total concentrations of carotenoids in the skin of Turkey Vultures compared to the skin of Black *** carotenoids detected were dietary carotenoids that typically produce yellow coloration when accumulated in integument and were present in low *** hypothesize that the dietary carotenoids present do not contribute to the color of the skin,but rather help to compensate for the lack of melanosomes found in Turkey Vulture *** presence of additional carotenoids may act as an antioxidant to minimize UV damage when the bare Turkey Vulture head skin is exposed to direct sunlight for prolonged periods of time when soaring and scavenging for food.

关键词： Carotenoids Cathartes aura Coragyps atratus Hemoglobin High performance liquid chromatography melanosomes Skin biopsies

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Lesion-symptom mapping with NIHSS sub-scores in ischemic stroke patients

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Stroke & Vascular Neurology 2022年第2期7卷 124-131页

作者： Deepthi Rajashekar matthias Wilms m Ethan macDonald Serena Schimert michael D hill Andrew Demchuk mayank Goyal Sean P Dukelow Nils Daniel Forkert Biomedical Engineering Graduate Program Hotchkiss Brain InstituteUniversity of CalgaryCalgaryAlbertaCanada Department of Radiology Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada Hotchkiss Brain Institute University of CalgaryCalgaryAlbertaCanada Department of Clinical Neurosciences University of CalgaryCalgaryAlbertaCanada Department of Electrical and Computer Engineering University of CalgaryCalgaryAlbertaCanada Department of Community Health Sciences Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada Department of medicine Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada Alberta Children's Hospital Research Institute University of CalgaryCalgaryABCanada

Background Lesion-symptom mapping(LSm)is a statistical technique to investigate the population-specific relationship between structural integrity and post-stroke clinical *** clinical practice,patients are commonly evaluated using the National Institutes of Health Stroke Scale(NIHSS),an 11-domain clinical score to quantitate neurological deficits due to *** far,LSm studies have mostly used the total NIHSS score for analysis,which might not uncover subtle structure–function relationships associated with the specific sub-domains of the NIHSS ***,the aim of this work was to investigate the feasibility to perform LSm analyses with sub-score information to reveal category-specific structure–function relationships that a total score may not *** Employing a multivariate technique,LSm analyses were conducted using a sample of 180 patients with NIHSS assessment at 48-hour post-stroke from the ESCAPE *** NIHSS domains were grouped into six categories using two *** was conducted for each category of the two groupings and the total NIHSS *** Sub-score LSms not only identify most of the brain regions that are identified as critical by the total NIHSS score but also reveal additional brain regions critical to each function category of the NIHSS assessment without requiring extensive,specialised *** These findings show that widely available sub-scores of clinical outcome assessments can be used to investigate more specific structure–function relationships,which may improve predictive modelling of stroke outcomes in the context of modern clinical stroke assessments and neuroimaging.

关键词： patients score category

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基于超声波实验研究压力及流体对致密岩石横波衰减特征的影响

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Applied Geophysics 2024年第2期21卷 246-264,419页

作者：潘旭铭巴晶马汝鹏刘卫华程卫 Josém.Carcione 河海大学地球科学与工程学院南京211100 东北石油大学三亚海洋油气研究院三亚572000 中石化石油物探技术研究院有限公司南京211100 National Institute of Oceanography and Applied Geophysics(OGS) TriesteItaly

我国致密油气储层勘探前景广阔,开采价值高,但其储层岩石具有低孔、低渗、强非均质性等特征,建立储层波响应与岩石物性参数之间的联系仍面临挑战,针对致密储层波响应规律的研究有待深入开展。孔隙流体性质及围压会影响岩石的剪切模量及... 详细信息

我国致密油气储层勘探前景广阔,开采价值高,但其储层岩石具有低孔、低渗、强非均质性等特征,建立储层波响应与岩石物性参数之间的联系仍面临挑战,针对致密储层波响应规律的研究有待深入开展。孔隙流体性质及围压会影响岩石的剪切模量及横波衰减,本文对部分饱和的8块致密岩石在不同围压条件下开展了超声波实验观测,采用谱比法估算岩石的横波衰减。结果显示,横波衰减随围压上升而下降,且饱水岩石的横波衰减大于饱油,饱气状态衰减最弱。气、水部分饱和岩石的测量结果中,岩石样本的横波衰减在中间含水饱和度达到峰值,此外,横波衰减随孔隙度、渗透率上升均有增大的趋势。基于实验测量的岩石物性参数,结合Voigt-Reuss-hill(VRH)平均、微分等效介质模型和喷射流模型构建了致密岩石衰减模型,分析了不同围压条件下含流体岩石的衰减特征,结果显示,该模型可合理描述横波衰减特征。在完全饱和与部分饱和条件下,模型预测的横波衰减显示出明显的压力及流体敏感性。以样本TS1-19为例,在完全饱和、变围压条件下,模型预测的横波衰减峰值在11.6~69.5范围内,衰减峰值随着围压增大而降低,且峰值频率有向高频端移动的趋势。在部分饱和、围压30mPa条件下,模型预测的横波衰减峰值在15.5~39.8范围内,衰减峰值随着含水饱和度增大而增大,且峰值频率向低频端移动。对于所有样本,以30mPa围压为例,所预测的横波衰减在5.6~38.6范围内,其中在饱和条件下,模型预测横波衰减随着孔隙度增大而增大,随着围压增大而减小;在气水部分饱和条件下,随着含水饱和度的增大,基于模型及Voigt和Reuss边界法预测的横波衰减整体呈增大的趋势,而实验观测到的横波衰减在中间饱和度达到极大值。

关键词：致密岩石横波衰减岩石物理实验围压流体饱和度喷射流模型

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IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling

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Cellular & molecular Immunology 2023年第6期20卷 651-665页

作者： Holly Bachus Erin mcLaughlin Crystal Lewis Amber m.Papillion Etty N.Benveniste Dave Durell hill Alexander F.Rosenberg AndréBallesteros-Tato Beatriz León Department of medicine Division of Clinical Immunology and RheumatologyUniversity of Alabama at BirminghamBirminghamALUSA Department of microbiology University of Alabama at BirminghamBirminghamALUSA Department of Cell Developmental and Integrative BiologyUniversity of Alabama at BirminghamBirminghamALUSA informatics Institute University of Alabama at BirminghamBirminghamALUSA Alexion Pharmaceuticals Inc.New HavenCTUSA

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house dust mite (HDm)-induced Th2 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. mechanistically, IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.

关键词： Th2 cell polarization IL-6 IL-2 SOCS3 JAK1 inhibitor

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Parvalbumin neuroplasticity compensates for somatostatin impairment, maintaining cognitive function in Alzheimer’s disease

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Translational Neurodegeneration 2022年第1期11卷 566-587页

作者： Christopher Daniel morrone Aaron Yenhsin Lai Jossana Bishay mary Elizabeth hill JoAnne mcLaurin Biological Sciences Sunnybrook Research InstituteTorontoON M4N 3M5Canada Department of Laboratory medicine and Pathobiology Temerty Faculty of MedicineUniversity of TorontoTorontoON M5S 1A8Canada

Background: Patient-to-patient variability in the degree to which β-amyloid, tau and neurodegeneration impact cognitive decline in Alzheimer’s disease (AD) complicates disease modeling and treatment. However, the underlying mechanisms leading to cognitive resilience are not resolved. We hypothesize that the variability in cognitive function and loss relates to neuronal resilience of the hippocampal GABAergic network. methods: We compared TgF344-AD and non-transgenic littermate rats at 9, 12, and 15 months of age. Neurons, β-amyloid plaques and tau inclusions were quantified in hippocampus and entorhinal cortex. Somatostatin (SST) and parvalbumin (PVB) interneurons were traced to examine hippocampal neuroplasticity and cognition was tested in the Barnes maze. Results: The 9-month-old TgF344-AD rats exhibited loss of neurons in the entorhinal cortex and hippocampus. Hippocampal neuronal compensation was observed in 12-month TgF344-AD rats, with upregulation of GABAergic interneuronal marker. By 15 months, the TgF344-AD rats had robust loss of excitatory and inhibitory neurons. β-Amyloid and tau pathology accumulated continuously across age. SST interneurons exhibited tau inclusions and atrophy from 9 months, whereas PVB interneurons were resilient until 15 months. The hippocampal PVB circuit underwent neuroplastic reorganization with increased dendritic length and complexity in 9- and 12-month-old TgF344- AD rats, before atrophy at 15 months. Strikingly, 12-month-old TgF344-AD rats were resilient in executive function and cognitive flexibility. Cognitive resilience in TgF344-AD rats occurred as maintenance of function between 9 and 12 months of age despite progressive spatial memory deficits, and was sustained by PVB neuroplasticity. Conclusions: Our results demonstrate the inherent neuronal processes leading to cognitive maintenance, and describe a novel finding of endogenous cognitive resilience in an AD model.

关键词： Alzheimer’s disease TgF344-AD rat GABAergic interneuron Parvalbumin Somatostatin Barnes maze Hippocampus Neuronal compensation Cognitive resilience

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