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Statins markedly potentiate aminopeptidase inhibitor activity against(drug-resistant)human acute myeloid leukemia cells

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Cancer Drug Resistance 2023年第3期6卷 430-446页

作者： Gerrit Jansen Marjon Al Yehuda G.Assaraf Sarah Kammerer johan van meerloo Gert J.Ossenkoppele Jacqueline Cloos Godefridus J.Peters Department of Rheumatology and Clinical Immunology Amsterdam Rheumatology and immunology CenterAmsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands The Fred Wyszkowsky Cancer Research Laboratory Faculty of BiologyThe Technion-Israel Institute of TechnologyHaifa 3200003Israel Department of Medical Oncology Amsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands Institute of Biotechnology Molecular Cell BiologyBrandenburg University of Technology Cottbus-SenftenbergSenftenberg 01968Germany Department of Hematology Amsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands Department of Biochemistry Medical University of GdanskGdansk 80-210Poland

Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) ***: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR ***: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents;and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation;this was experimentally confirmed by impaired Rheb prenylation by ***: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.

关键词： Aminopeptidase statins mevalonate pathway carboxyl esterase Rheb mTOR

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Mapping and understanding degradation of alpine wetlands in the northern Maloti-Drakensberg, southern Africa

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Journal of Mountain Science 2024年第9期21卷 2956-2966页

作者： johan van TOL Department of Soil Crop and Climate SciencesUniversity of the Free StateBloemfontein 9300South Africa

The alpine terrestrials of the Maloti-Drakensberg in southern Africa play crucial roles in ecosystem functions and livelihoods,yet they face escalating degradation from various factors including overgrazing and climate *** study employs advanced Digital Soil Mapping(DSM)techniques coupled with remote sensing to map and assess wetland coverage and degradation in the northern *** model achieved high accuracies of 96%and 92%for training and validation data,respectively,with Kappa statistics of 0.91 and 0.83,marking a pioneering automated attempt at wetland mapping in this *** attributes such as terrain wetness index(TWI)and valley depth(VD)exhibit significant positive correlations with wetland coverage and erosion gully density,Channel Network Depth and slope were negative *** density analysis revealed terrain attributes as dominant factors driving degradation,highlighting the need to consider catchment-specific susceptibility to *** challenge traditional assumptions which mainly attribute wetland degradation to external forces such as livestock overgrazing,ice rate activity and climate *** sensitivity map produced could serve as a basis for Integrated Catchment Management(ICM)projects,facilitating tailored conservation *** research should expand on this work to include other highland areas,explore additional covariates,and categorize wetlands based on hydroperiod and sensitivity to *** comprehensive study underscores the potential of DSM and remote sensing in accurately assessing and managing wetland ecosystems,crucial for sustainable resource management in alpine regions.

关键词： Digital Soil Mapping Gully density Integrated catchment management Remote sensing Wetland degradation

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Why Languages Prefer Prohibitives

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外国语 2006年第1期29卷 2-25页

作者： johan van der Auwera Center for Grammar Cognition and Typology University of Antwerp Belgium

This paper deals with prohibitive markers, i.e., negative markers that are more or less dedicated to the expression of a prohibition. It documents the variety in the formal make-up of these markers and it confirms the earlier claims that they are frequent everywhere, with at least one exception, viz., Western Europe. Four origins are discussed: prohibitive markers may derive from predicative constructions, they may appear as a side product of Jespersen’s cycle, they may derive from a univerbation of imperative and negative markers, and they may be borrowed. As explanation is offered as to why languages prefer to have prohibitive markers. It is argued that attempts to explain this preference in terms of morphosyntax are misguided. Instead a frequency-based semantic explanation is offered. The most frequent use of negatives are declarative, thereby inviting a static ‘it is not the case that’ paraphrase. It is important, however, to mark clearly that prohibitives are instances of a dynamic ‘let it be the case that’ appeal. The paper ends on a discussion of languages that do not employ prohibitive markers.

关键词：英语语法词义使用范围

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Constant Angle Surfaces in the Heisenberg Group

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Acta Mathematica Sinica,English Series 2011年第4期27卷 747-756页

作者： johan FASTENAKELS Marian Ioan MUNTEANU Joeri van DER VEKEN Department of Mathematics Katholieke Universiteit Leuven Celestijnenlaan 200B-Box 2400 BE-3001 Leuven Belgium 'Al. I. Cuza' University of Iasi Bd. Carol I n. 11 700506-Iasi Romania

In this article we extend the notion of constant angle surfaces in S2 × R and H2 ×R to general Bianchi-Cartan-Vranceanu spaces. We show that these surfaces have constant Gaussian curvature and we give a complete loc... 详细信息

关键词： Heisenberg group Bianchi-Cartan Vranceanu space constant angle surface

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Economic overview of a two-agent process for underground coal gasification with Fischer-Tropsch- based poly-generation

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Clean Energy 2019年第1期3卷 34-46页

作者： johan F.Brand johan C.van Dyk Frans B.Waanders African Carbon Energy PO Box 450Standerton 2430South Africa Centre of Excellence in Carbon-based Fuels North-West UniversityPotchefstroom 2520South Africa African Carbon Energy PO Box 254SasolburgSouth Africa

Underground Coal Gasification(UCG)is a mining-gasification process that produces synthesis gas from in situ coal by injecting air(or oxygen and steam)and extracting the produced gas via *** resulting synthesis gas(‘syngas’)produced by UCG can be used directly as a fuel-gas or deep-cleaned to produce many other products like chemicals,liquid fuels,hydrogen and synthetic natural *** has significant environmental,safety and practical advantages over conventional coal mining and utilization,foremost being cost and emissions *** South Africa,facilities of an industrial-scale Fischer-Tropsch(FT)have been operating for decades on coal-to-liquid and gas-to-liquid ***-blown UCG produces syngas,which contains a mixture of carbon monoxide(CO)and hydrogen,and these molecules can be conditioned to serve as feed for synthetic-crude-oil(‘syncrude’)conversion technologies based on the FT *** Carbon Energy(Pty)Ltd.(Africary)completed a study integrating its UCG technology with mini gas-to-liquids *** from Africary’s Theunissen Underground Coal Gasification(TUCG)project will be used for power production and synthesis of liquid fuels in a unique poly-generation *** TUCG process will consist of two parallel gasifiers,operated on different agents,making the component parts of UCG and coal-to-(any product)(CtX)tightly linked and interdependent,but reducing both cost and ***-CtX offers a lower capital investment to conventional underground mining and surface gasification due to the removal of the surface gasifier and coal-mine *** gas clean-up systems will remove undesirable components from each gasifier and blend the cleaned syngas for H2:CO ratio control and provide implementation of carbon capture and *** study has minimized the complexity and optimized the process flow to provide own-use electricity and about 4000 barrels/day equivalent fuels at a capital cost estimate(2017)of

关键词： underground coal gasification Fischer-Tropsch coal to liquids gas to liquids CCS UCG FT LNG CtX economic study South Africa

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Exploring well-being disparities between urban and rural areas:A case study in the Stavropol Territory,Russia

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Regional Sustainability 2024年第1期5卷 80-92页

作者： Anastasia CHAPLITSKAYA Wim HEIJMAN johan van OPHEM Agricultural Economics and Rural Policy Group Wageningen University and ResearchWageningen6700 ABNetherlands Department of Foreign Languages Stavropol State Agrarian UniversityStavropol355017Russia Department of Economics Faculty of Economics and ManagementCzech University of Life SciencesPrague16500Czech Urban Economics Group Wageningen University and ResearchWageningen6700 ABNetherlands

Rural areas are crucial for a country’s sustainable *** strategies are needed to develop rural areas to improve the well-being of rural population and generate new job *** is especially important in countries where agricultural production accounts for a significant share of the gross product,such as *** this study,we identified the key indicators of satisfaction and differences between rural and urban citizens based on their social,economic,and environmental backgrounds,and determined whether there are well-being disparities between rural and urban areas in the Stavropol Territory,*** collected primary data through a survey based on the European Social Survey framework to investigate the potential differences between rural and urban *** computing the regional well-being index using principal component analysis,we found that there was no statistically significant difference in well-being between rural and urban *** of key indicators showed that rural residents felt psychologically more comfortable and safer,assessed their family relationships better,and adhered more to traditions and ***,urban residents showed better economic and social conditions(e.g.,infrastructures,medical care,education,and Internet access).The results of this study imply that we can better understand the local needs,advantages,and unique qualities,thereby gaining insight into the effectiveness of government ***-makers and local authorities can consider targeted interventions based on the findings of this study and strive to enhance the well-being of both urban and rural residents.

关键词： Well-being Sustainable development Rural areas Urban areas Principal component analysis(PCA) Russia

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The impact of prehospital blood sampling on the emergency department process of patients with chest pain:a pragmatic non-randomized controlled trial

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World Journal of Emergency Medicine 2023年第4期14卷 257-264页

作者： johan L.van Nieuwkerk M.Christien van der Linden Rolf J.Verheul Merel van Loon-van Gaalen Marije Janmaat Naomi van der Linden Emergency Department Haaglanden Medical Centre&Emergency Medical Services Haaglandenthe Hague 2501 CBthe Netherlands Research and Development Haaglanden Medical Centrethe Hague 2501 CKthe Netherlands Laboratory Services Haaglanden Medical Centrethe Hague 2501 CKthe Netherlands Emergency Department Haaglanden Medical Centrethe Hague 2501 CKthe Netherlands Faculty of Health University of Applied Sciences LeidenLeiden 2300 AJthe Netherlands Faculty of Technology Policy and ManagementDelft University of TechnologyDelft 2628 BXthe Netherlands

BACKGROUND:In patients with chest pain who arrive at the emergency department(ED)by ambulance,venous access is frequently established prehospital,and could be utilized to sample *** blood sampling may save time in the diagnostic *** this study,the association of prehospital blood draw with blood sample arrival times,troponin turnaround times,and ED length of stay(LOS),number of blood sample mix-ups and blood sample quality were ***:The study was conducted from October 1,2019 to February 29,*** patients who were transported to the ED with acute chest pain with low suspicion for acute coronary syndrome(ACS),outcomes were compared between cases,in whom prehospital blood draw was performed,and controls,in whom blood was drawn at the *** analyses were used to assess the association of prehospital blood draw with the time ***:Prehospital blood draw was performed in 100 *** 406 patients,blood draw was performed at the *** blood draw was independently associated with shorter blood sample arrival times,shorter troponin turnaround times and decreased LOS(P0.05).CONCLUSION:For patients with acute chest pain with low suspicion for ACS,prehospital blood sampling is associated with shorter time intervals,while there were no significant differences between the two groups in the validity of the blood samples.

关键词： Blood specimen collection Crowding Emergency medical services Troponin

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Maximizing recovery time between knock-out races improves sprint cross-country skiing performance

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Journal of Sport and Health Science 2022年第1期11卷 21-29页

作者： Kerry McGawley Coline van Waerbeke Karl-johan Westberg Erik P.Andersson Swedish Winter Sports Research Centre Department of Health SciencesMid Sweden UniversityOstersund 83125Sweden

Background:In a sprint cross-country(XC)ski competition,the difference in recovery times separating the first and the second semi-final(SF)heats from the final(F)may affect *** aim of the current study was to compare the effects of longer *** recovery periods prescribed between the 3 knock-out races of a simulated sprint XC ski competition involving a prologue(P),quarter-final(QF),SF,and ***:Eleven well-trained XC ski athletes completed 2 simulated sprint XC ski competitions on a treadmill involving 4×883-m roller-ski bouts at a 4°incline using the gear 3 ski-skating *** first 3 bouts were completed at a fixed speed(PFIX,QFFIX,and SFFIX)corresponding to~96%of each individual’s previously determined maximal *** final bout was performed as a self-paced sprint time trial(FSTT).Test conditions differed by the time durations prescribed between the QFFIX,SFFIX,and FSTT,which simulated real-world XC ski competition conditions using maximum(MAX-REC)or minimum(MIN-REC)recovery ***:The FSTT was completed 5.4±5.5 s faster(p=0.009)during MAX-REC(179.2±18.1 s)compared to MIN-REC(184.6±20.0 s),and this was linked to a significantly higher power output(p=0.010)and total metabolic rate(p=0.009).The pre FSTT blood lactate(BLa)concentration was significantly lower during MAX-REC compared to MIN-REC(2.5±0.8 mmol/L vs.3.6±1.6 mmol/L,respectively;p=0.027),and the pre-to-post FSTT increase in BLa was greater(8.8±2.1 mmol/L vs.7.1±2.3 mmol/L,respectively;p=0.024).No other differences for MAX-REC ***-REC reached significance(p>0.05).Conclusion:Performance in a group of well-trained XC skiers is negatively affected when recovery times between sprint heats are minimized which,in competition conditions,would occur when selecting the last QF *** result is combined with a higher pre-race BLa concentration and a reduced rise in BLa concentration under shorter recovery *** findings may help inform decision making when

关键词： Energetics Repeated sprints Roller skiing Simulated competition Tactics

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New insights from low-temperature thermochronology into the tectonic and geomorphologic evolution of the south-eastern Brazilian highlands and passive margin

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Geoscience Frontiers 2020年第1期11卷 303-324页

作者： Gerben van Ranst Antônio Carlos Pedrosa-Soares Tiago Novo Pieter Vermeesch johan De Grave Laboratory for Mineralogy and Petrology Department of GeologyGhent UniversityKrijgslaan 281 S89000GhentBelgium CPMTC Institute for GeosciencesFederal University of Minas GeraisAvenida Antônio Carlos 6627CEP 31270-901Belo HorizonteBrazil Department of Earth Sciences University College London5 Gower PlaceWC1E 6BSLondonUnited Kingdom

The South Atlantic passive margin along the south-eastern Brazilian highlands exhibits a complex landscape,including a northern inselberg area and a southern elevated plateau,separated by the Doce River *** landscape is set on the Proterozoic to early Paleozoic rocks of the region that once was the hot core of the Aracuai orogen,in Ediacaran to Ordovician *** to the break-up of Gondwana and consequently the opening of the South Atlantic during the Early Cretaceous,those rocks of the Araquai orogen became the basement of a portion of the South Atlantic passive margin and related southeastern Brazilian *** goal is to provide a new set of constraints on the thermo-tectonic history of this portion of the south-eastern Brazilian margin and related surface processes,and to provide a hypothesis on the geodynamic context since *** this end,we combine the apatite fission track(AFT)and apatite(U-Th)/He(AHe)methods as input for inverse thermal history *** our AFT and AHe central ages are Late Cretaceous to early *** AFT ages vary between 62 Ma and90 Ma,with mean track lengths between 12.2μm and 13.6μ*** ages are found to be equivalent to AFT ages within uncertainty,albeit with the former exhibiting a lesser degree of *** relate this Late Cretaceous-Paleocene basement cooling to uplift with accelerated denudation at this *** variation of the denudation time can be linked to differential reactivation of the Precambrian structural network and differential erosion due to a complex interplay with the drainage *** argue that posterior large-scale sedimentation in the offshore basins may be a result of flexural isostasy combined with an expansion of the drainage *** put forward the combined compression of the Mid-Atlantic ridge and the Peruvian phase of the Andean orogeny,potentially augmented through the thermal weakening of the lower crust by the Trindade thermal anomaly,as a probable cause for th

关键词： Tectonic reactivation Differential denudation Passive margin South-eastern Brazil Apatite fission tracks Apatite(U-Th)/He

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A MINI-GUIDE TO LOGIC IN ACTION

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逻辑研究专辑 2003年第0期 21-30+111页

作者： johan van Benthem University of Amsterdam & Stanford

The Dynamic Turn in logic makes actions of communication and general information update into explicit objects of investigation. This paper is a brief tour of this research program in a new version, bringing together ideas from logic, philosophy, computer science, and game theory. In particular, we discuss epistemic, dynamic, and temporal logics, belief revision, and game logics.

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