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Pharmacological interventions targeting nuclear factor-kappa B signaling in multiple sclerosis

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Neural Regeneration Research 2021年第10期16卷 2023-2025页

作者： Kim m.A.De Kleijn gerard j.m.martens Department of molecular Animal Physiology Donders Institute for BrainCognition and BehaviourCentre for NeuroscienceFaculty of ScienceRadboud University6525AJ NijmegenThe Netherlands NeuroDrug Research Ltd 6525ED NijmegenThe Netherlands(De Kleijn KMAMartens GJM)Department of Molecular Animal PhysiologyDonders Institute for BrainCognition and BehaviourCentre for NeuroscienceFaculty of ScienceRadboud University6525AJ NijmegenThe Netherlands

multiple sclerosis(mS)is an inflammatory neurodegenerative disease of the central nervous system(CNS).Pathological characteristics of the disease include activation of CNS-intrinsic immune cells,such as microglia and astrocytes,and loss of neuronal connections,myelin and blood-brain barrier(BBB)integrity as well as peripheral immune cell infiltration into the *** has long been considered a predominantly immunological disease,which has led to the development of essentially only immune-directed *** this traditional“outside-in”mS hypothesis,a dysregulation of the peripheral immune system causes immune cell infiltration into the CNS,leading to autoreactivity against myelin sheath components and secondary BBB ***,recent findings indicate that overactivation of microglia and astrocytes represents an important first step in mS pathology,as appears to be the case for other neurodegenerative diseases such as Alzheimer’s disease(AD)and Parkinson’s disease(PD).

关键词： sclerosis outside essentially

Geochemistry of middle Holocene Sediments from South Yellow Sea: implications to Provenance and Climate Change

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journal of Earth Science 2016年第5期27卷 751-762页

作者： Xiaoxia Lii gerard j. m. Versteegh jinming Song Xuegang Li Huamao Yuan Ning Li Faculty of marine Sciences China University of Geosciences State Key Laboratory of Biogeology and Environmental Geology China University of Geosciences Heisenberg Group on marine Kerogen Center for Marine Environmental Sciences (MARUM) Bremen University institute of Oceanology Chinese Academy of Sciences

From a large number of case studies on terrestrial deposits we know that Late Holocene climate fluctuations have an important impact on the terrestrial environments. However, it is hitherto not clear how the marine sediments can be used to shed light on the environment and climate change of the catchment. To provide such insight, we used the major element, trace element and rare earth element（REE） compositions in the southern Yellow Sea（SYS） sediments to reconstruct the changes in weathering and erosion of their source regions. The sediments originate predominantly from the upper crust of East China and are transported into the basin especially by the Yellow River（Huanghe） and to a lesser extent by the Yangtze River（Changjiang）. The chemical index of alteration（CiA; 53.7–59.7） suggests low chemical weathering of the source rocks since the middle Holocene. This is consistent with the relatively cool and arid climate in North China after the Holocene megathermal. Comparison of element ratios, including Al/Ca, K/Ca, Al/Na, K/Na, Rb/Sr, Li/Ba and the CiA shows that we can use the latter as a robust proxy for climate change. The CiA-based mean annual precipitation and mean annual temperature show a series of climate fluctuations in the catchment. A relatively warm and humid Period i（5.3–2.9 cal. ka BP）, a relatively cool and dry Period ii（2.9–0.9 cal. ka BP） and an increasingly cool and dry Period iii（0.9–0.3 cal. ka BP）. These periods can be linked to climate intervals recognized elsewhere.

关键词： geochemical composition elemental ratio climate change provenance South YellowSea sediment.

Evolution of the East China Sea sedimentary environment in the past 14 kyr: insights from tetraethers-based proxies

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Science China Earth Sciences 2016年第5期59卷 927-938页

作者： GE Huangmin ZHANG ChuanLun VERSTEEGH gerard j.m. CHEN LingLing FAN DaiDu DONG Liang LiU jingjing State Key Laboratory of marine Geology Tongji University Hadal Science and Technology Research Center (Shanghai Engineering Research Center of Hadal Science and Technology) Shanghai Ocean University Heisenberg Group on marine Kerogen Center for Marine Environmental Sciences (MARUM) Bremen University

We reconstruct the environmental evolution of the East China Sea in the past 14 kyr based on glycerol dialkyl glycerol tetraethers(GDGTs) in a sediment core from the subaqueous Yangtze River Delta. Two primary phases are recognized. Phase i(13.8–8 cal kyr BP) reflects a predominantly continental influence, showing distinctly higher concentrations of branched GDGTs(averaged 143 ng/g dry sediment weight, dsw) than isoprenoid GDGTs(averaged 36 ng/g dsw), high BiT index(branched vs. isoprenoid tetraethers) values(>0.78) and a fluctuating GDGT-0/crenarchaeol ratio(R_(0/5), varied from 0.52 to 3.81). Within this interval, temporal increases of terrestrial and marine influence are attributed to Younger Dryas(YD)(ca. 12.9–12.2 cal kyr BP) cold event and melt-water pulse(mWP)-1B(11.5–11.1 cal kyr BP), respectively. The prominent transition from 8 to 7.9 cal kyr BP shows a sharp decrease in BiT index value(increase in crenarchaeol, which marks the beginning of phase ii. Afterwards, the proxies remain relatively constant, which indicates that phase ii(7.9 cal kyr BP-present) is a shelf sedimentary environment with high stand of sea level. Overall, the BiT index in our record serves as a good marker for terrestrial influence at the site, and likely reflects the flooding history of the region. The TEX_(86)(Tetra Ether index of tetraethers consisting of 86 carbons) proxy is not applicable in phase i because of an excess terrestrial influence; but it seems to be valid for revealing the annual SST in phase ii(21.6±0.9°C, n=49). in contrast, the mBT'/CBT(methylation of Branched Tetraethers and Cyclization of Branched Tetraethers) proxy appears to faithfully record the annual mean air temperature(mAT)(14.3±0.63°C, n=68) and presents an integrated signal over the middle and lower Yangtze River drainage basin.

关键词： GDGTs Proxies Sedimentary environment evolution Holocene East China Sea

Reactive Extraction of Alcohols from Apolar Hydrocarbons with Aqueous Solutions

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Tsinghua Science and Technology 2006年第2期11卷 222-227页

作者： Boris Kuzmanovi Norbert j. m. Kuipers André B. de Haan gerard Kwant Akzo Nobel Chemicals Research Arnhem The Netherlands University of Twente Enschede The Netherlands DSm Research Geleen The Netherlands

The aqueous solutions are evaluated as sustainable reactive extraction solvents for the recovery of monohydroxyl alcohols （benzyl alcohol, 1-hexanol, cyclohexanol） present in few-percent concentrations in apolar hydrocarbons （toluene, n-hexane, and cyclohexane） by considering two approaches. An aqueous solution containing a reactive extractant, like borate salts, borate complexes, a monosalt of dicarboxylic acid, hydroxypropyl-cyclodextrins, and silver nitrate, shows limited potential to be used. Another approach, in which the alcohol is chemically modified prior to the extraction into an easy-extractable form, in this case a monoester/carboxylic acid, shows much more potential. An environmentally benign aqueous solution of sodium hydrogen carbonate can provide a distribution ratio of benzyl alcohol up to 200, leaving the solubility of the organic solvent in the aqueous solution unchanged relative to pure water and therefore increasing the selectivity with two orders of magnitude. The modification of aromatic, cyclo-aliphatic, and linear aliphatic alcohols can be performed efficiently in the apolar organic solvent without need for a catalyst. The recovery of the modified alcohol can be performed by back-extraction in combination with a spontaneous hydrolysis.

关键词： reactive extraction alcohol polar hydrocarbons

Self-assembled bright luminescent hierarchical materials from a tripodal benzoate antenna and heptadentate Eu(iii) and Tb(iii) cyclen complexes

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Frontiers of Chemical Science and Engineering 2019年第1期13卷 171-184页

作者： Aramballi j.Savyasachi David F.Caffrey Kevin Byrne gerard Tobin Bruno D'Agostino Wolfgang Schmitt Thorfinnur Gunnlaugsson School of Chemistry and Trinity Biomedical Sciences institute (TBSi) University of Dublin Trinity College Dublin Dublin 2 Ireland School of Chemistry and Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN) University of Dublin Trinity College Dublin Dublin 2 Ireland

The europium heptadentate coordinatively unsaturated (Eu(iii)) and the terbium (Tb(iii)) 1,4,7,10-tetraazacyclododecane (cyclen) complexes 1 and 2 were used in conjunction with ligand 3 (1,3,5-benzene-trisethynylbenzoate) to form the supramolecular self-assembly structures 4 and 5;this being investigated in both the solid and the solution state. The resulting self-assemblies gave rise to metal centered emission (both in the solid and solution) upon excitation of 3, confirming its role as a sensitizing antenna. Drop-cased examples of ligand 3, and the solid forms of 4 and 5, formed from both organic and mixture of organic-aqueous solutions, were analyzed using Scanning Electron microscopy, which showed significant changes in morphology;the ligand giving rise to one dimensional structures, while both 4 and 5 formed amorphous materials that were highly dense solid networks containing nanoporous features. The surface area (216 and 119 m2·g^-1 for 4 and 5 respectively) and the ability of these porous materials to capture and store gases such as N2 investigated at 77 K. The self-assembly formation was also investigated in diluted solution by monitoring the various photophysical properties of 3–5. This demonstrated that the most stable structures were that consisting of a single antennae 3 and three complexes of 1 or 2 (e.g., 4 and 5) in solution. By monitoring the excited state lifetimes of the Eu(iii) and Tb(iii) ions in H2O and D2O respectively, we showed that their hydration states (the q-value) changed from -2 to 0, upon formation of the assemblies, indicating that the three benzoates of 3 coordinated directly to the each of the three lanthanide centers. Finally we demonstrate that this hierarchically porous materials can be used for the sensing of organic solvents as the emission is highly depended on the solvent environment;the lanthanide emission being quenched in the presence of acetonitrile and THF, but greatly enhanced in the presence of methanol.

关键词： self-assembly supramolecular chemistry lanthanides Eu(iii) and Tb(iii) complexes luminescence metallostars

in vitro 3D phenotypic drug screen identifies celastrol as an effective in vivo inhibitor of polycystic kidney disease

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journal of molecular Cell Biology 2020年第8期12卷 644-653页

作者： Tijmen H.Booij Wouter N.Leonhard Hester Bange Kuan Yan michiel Fokkelman Anna j.Plugge Kimberley A.m.Veraar johannes G.Dauwerse gerard j.P.van Westen Bob van de Water Leo S.Price Dorien j.m.Peters Division of Toxicology Leiden Academic Centre for Drug Research(LACDR)Leiden UniversityLeidenThe Netherlands Present address:NEXUS Personalized Health Technologies ETH ZurichSwitzerland Department of Human Genetics Leiden University Medical Center(LUMC)LeidenThe Netherlands OcellO B.V. LeidenThe Netherlands Division of medicinal Chemistry Leiden Academic Centre for Drug Research(LACDR)LeidenThe Netherlands

Polycystic kidney disease(PKD)is a prevalent genetic disorder,characterized by the formation of kidney cysts that progressively lead to kidney *** currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative *** signalling rewiring in PKD that drives cyst formation is highly complex and not fully *** a consequence,the effects of drugs are sometimes difficult to *** previously established a high-throughput microscopy phenotypic screening method for quantitative assessment of renal cyst ***,we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules,including approved *** identified 81 active molecules that inhibit cyst ***-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological ***,a triterpenoid from Tripterygium wilfordii,was identified as a potent inhibitor of cyst growth in *** an in vivo iKspCre-Pkd1^lox,lox mouse model for PKD,celastrol inhibited the growth of renal cysts and maintained kidney function.

关键词： PKD celastrol pyrvinium pamoate high-content screening 3D

RESOURCE ALLOCATiON FOR A mOBiLE APPLiCATiON ORiENTED ARCHiTECTURE

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RESOURCE ALLOCATION FOR A MOBILE APPLICATION ORIENTED ARCHIT...

Alternative Exposure Parameters and Post Process Noise Reduction Expect Considerable Dose Reduction in Single mammography Views—initial Experience on mastectomy Specimens

2005全球移动通信大会

作者： gerard j.m. Smit Faculty of EEmCS University of Twente the Netherlands

＜正＞A montium is a coarse-grained reconfigurable architecture designed by the CADTES group of the University of Twente for mobile applications. This paper presents a resource allocation method to allocate variables to storage places and to schedule data movements for the montium. The resource allocation method exploits locality of reference of the montium architecture as well as its parallelism.

关键词：

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Advances in Breast Cancer Research 2013年第3期2卷 91-96页

作者： Adriana m. j. Bluekens Ruben Evan Engen Nico Karssemeijer Klaas H. Schuur mireille j. m. Broeders gerard j. den Heeten gerard j. den Heeten Department of Radiology Radboud University Nijmegen Medical Centre Nijmegen The Netherlands National Expert and Training Centre for Breast Cancer Screening Nijmegen The Netherlands St. Elisabeth Hospital Department of Radiology Tilburg The Netherlands

Objective: To experimentally indicate a lower limit of dose in mammographic imaging yielding adequate image quality for complementary diagnostic views, by evaluation of image series with different exposure parameters and additional image processing on mastectomy specimens with diverse pathology. methods: image series were obtained on seven specimens with different target-filter combinations at different exposure values. Three experienced radiologists assessed the lowest acceptable dose level per specimen using a relative grading technique. With the standard image as reference, fibroglandular tissue and pathological structures, including microcalcifications, were evaluated. Subsequently, a series of pixel binning processes was tested and subjectively assessed on the selected images. Results: The lowest dose level at which image quality was acceptable, and achieved with a W/Ag target-filter combination at 32 kV and 4 mAs. These images can be acquired with 10.4% to 22.4% of the average glandular dose in standard images. Post process pixel binning added to the interpretability of such low dose images. Conclusion: This specimen study suggests that dose level of mammography images might be reduced substantially by general application of a W/Ag spectrum, particularly when combined with post process noise reduction. Future studies should focus on the feasibility of this technique in clinical mammography.

关键词： Digital mammography Dose Reduction

Prevalence of-and risk factors for work disability in Dutch patients with inflammatory bowel disease

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World journal of Gastroenterology 2017年第46期23卷 8182-8192页

作者： Lieke m Spekhorst Bas Oldenburg Ad A van Bodegraven Dirk j de jong Floris imhann Andrea E van der meulen-de jong marieke j Pierik janneke C van der Woude gerard Dijkstra Geert D'Haens mark Lowenberg Rinse K Weersma Eleonora Am Festen 无 Department of Gastroenterology and Hepatology University of Groningen and University Medical Centre Groningen Department of Genetics University of Groningen and University Medical Centre Groningen Department of Gastroenterology and Hepatology University Medical Center Utrecht Department of Gastroenterology and Hepatology VU University Medical Center Department of Gastroenterology and Hepatology University Medical Center St. Radboud Department of Gastroenterology and Hepatology Leiden University Medical Center Department of Gastroenterology and Hepatology University Medical Center Maastricht Department of Gastroenterology and Hepatology Erasmus Medical Center Department of Gastroenterology and Hepatology Amsterdam Medical Center Parelsnoer institute and the Dutch initiative on Crohn and Colitis

Aim To determine the prevalence of work disability in inflammatory bowel disease(iBD), and to assess risk factors associated with work *** For this retrospective cohort study, we retrieved clinical data from the Dutch iBD Biobank on july 2014, containing electronic patient records of 3388 iBD patients treated in the eight University medical Centers in the Netherlands. Prevalence of work disability was assessed in 2794 iBD patients and compared with the general Dutch population. multivariate analyses were performed for work disability(sick leave, partial and full disability) and long-term full work disability(> 80% work disability for > 2 years).RESULTS Prevalence of work disability was higher in Crohn's disease(CD)(29%) and ulcerative colitis(UC)(19%) patients compared to the general Dutch population(7%). in all iBD patients, female sex, a lower education level, and extra-intestinal manifestations, were associated with work disability. in CD patients, an age > 40 years at diagnosis, disease duration > 15 years,smoking, surgical interventions, and anti-TNFα use were associated with work disability. in UC patients, an age > 55 years, and immunomodulator use were associated with work disability. in CD patients, a lower education level(OR = 1.62, 95%Ci: 1.02-2.58), and in UC patients, disease complications(OR = 3.39, 95%Ci: 1.09-10.58) were associated with long-term full work *** The prevalence of work disability in iBD patients is higher than in the general Dutch population. Early assessment of risk factors for work disability is necessary, as work disability is substantial among iBD patients.

关键词： inflammatory bowel disease Crohn’s disease Ulcerative colitis Work disability Health care costs