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In the version of this article initially published, in the Acknowledgements, the grant number for the Start Grant TWILIGHT awarded to M.A.L. by the European Research Council was omitted. The correct wording is “Supported by...the European Research Council (...Start Grant TWILIGHT (637801) to M.A.L.).” The error has not been corrected in the original article. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Tenascin-X, is an extracellular matrix glycoprotein expressed in skin, muscle, tendons, and blood vessels with an anti-adhesive function. Biallelic Tenascin-X mutations cause classical-like Ehlers-Danlos syndrome. We report a 46-year-old woman with slowly progressive weakness of the lower limbs and myalgia from age 28 years. In the past she had Raynaud's phenomenon, multiple sprains and joint dislocations, conjunctival haemorrhages and a colonic perforation during colonoscopy. Neurologic examination showed moderate asymmetric proximal and axial muscular weakness, distal amyotrophy of 4 limbs, moderate skin hyperextensibility, and hypermobility of distal joints of fingers. Whole body Magnetic Resonance Imaging showed symmetric fatty infiltration of thigh and leg muscles, with predominant atrophy of thighs. Next Generation Sequencing revealed two pathogenic TNXB variants, g.32024681C>G, c.7826-1G>C, and g.32016181dup, c.9998dupA, p.(Asn3333Lysfs* 35). Western Blot and immunofluorescence studies confirmed a marked Tenascin-X reduction in both patient's serum and muscle. Here we further detail the clinical and genetic spectrum of a patient with classical-like Ehlers-Danlos syndrome and prominent muscle involvement. (C) 2020 Elsevier B.V. All rights reserved.

Contains fulltext : 182646.pdf (Publisher’s version ) (Open Access) Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3-dimensional skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of bacterial taxa at low micromolar concentrations. No genotype-dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del-mediated psoriasis risk.

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Background: Defensins are antimicrobial peptides that exert immunomodulatory and chemotactic functions. Based on these properties and their high expression levels in the skin, they are likely to affect skin inflammation, infection, and wound healing. This may lead to therapeutic applications in (burn) wound healing. Objective: We aimed to investigate the effects of human β-defensins (hBDs) on keratinocytes and fibroblasts, 2 major skin cell types involved in skin regeneration. Methods: Monolayer keratinocyte and fibroblast cultures were exposed to recombinant hBDs, and we overexpressed hBD2 and hBD3 in keratinocytes of reconstructed epidermal equivalents by lentiviral transduction. The effects were measured by immunohistochemistry, quantitative real-time PCR, and migration assays. Kinome analyses were performed on cultured keratinocytes to investigate the signal transduction events elicited by hBD stimulation. Results: We found that hBD3 induced the expression of cytokines and chemokines in keratinocytes, which was not observed in fibroblasts. hBD2, however, stimulated cell migration only in fibroblasts, which was not found for hBD3. Both defensins are likely to exert receptor-mediated effects in keratinocytes, as witnessed by changes in protein kinase activation following stimulation by hBD2 and hBD3. Kinome analysis suggested that protein kinase C activation was a common event for both defensins. We observed, however, considerable differences in keratinocyte responses between stimulation by exogenous recombinant defensins and endogenous defensins expressed following lentiviral transduction. Conclusion: Defensins exert modest biological effects on skin cells that are potentially beneficial in wound healing, but many questions regarding the biological mechanisms of action and relevance for the in vivo situation are still remaining.

The low-frequency contribution to the systematic and random sampling errors in single-tower eddy-covariance flux measurements is investigated using large-eddy simulation (LES). We use a continuous LES integration that covers a full year of realistic weather conditions over Cabauw, the Netherlands, and emulate eddy-covariance measurements. We focus on the daytime flux imbalance, when the turbulent flux is sufficiently resolved. Averaged over the year, daytime single-tower eddy-covariance flux measurements lead to a significant systematic underestimation of the turbulent flux. This underestimation depends on the averaging period and measurement height. For a 3600-s averaging period at 16-m height, the systematic underestimation reduces to a few percent, but for 900-s averaged tall-tower measurements at 100-m height, the fluxes are systematically underestimated by over 20 %. The year-long dataset facilitates an investigation into the environmental conditions that influence the eddy-covariance flux imbalance. The imbalance problem is found to vary widely from day to day, strongly dependent on the flow regime. In general, the imbalance problem reduces with increased mean wind speed, but days having the largest imbalance (over twice the average) are characterized by roll vortices that occur for average wind speeds, typically having a boundary-layer height (zi) to Obukhov length (L) ratio of 10zi/L<100.

Contains fulltext : 147170.pdf (Publisher’s version ) (Open Access) The present invention concerns novel pantothenone compounds having pantetheinase inhibitory activity as well as antiplasmodial activity. These compounds can suitably be used in therapeutic and or prophylactic treatment of malaria. Furthermore, the present invention provides combinations of pantothenone compounds and pantothenamides. Combining a pantothenone with a pantothenamide increases the antimalarial potency by an order of magnitude. It is hypothesized that inhibition of pantetheinase activity could protect pantothenamides against degradation by serum-derived pantetheinases, thereby revealing the hitherto unknown antimalaria activity of pantothenamides. The present invention thus, for the first time, makes available compounds and combinations of compounds for use in therapeutic and or prophylactic treatment of malaria infection in a human or animal subject in need thereof, relying on interference with host or pathogen-derived pantetheinase dependent pathways. 08 december 2011

De vorige eeuw was getuige van de opkomst van numerieke weer- en klimaatmodellen. Weersvoorspelling, voorheen een empirische procedure gebaseerd op de persoonlijke ervaring van de meteoroloog, ontwikkelde zich tot een wetenschappelijke methode om de toekomstige toestand van de atmosfeer te voorspellen op basis van de huidige toestand en tendens. Tegelijkertijd werden klimaatmodellen ontwikkeld om inzicht te krijgen in het gedrag van ons klimaat over tijdspannes van meer dan honderden jaren. Als gevolg van de enorme rekenkracht die vereist is om deze weer- of klimaatmodellen te kunnen draaien, ontstond een nauwe verwikkeling tussen atmosferische en computerwetenschap. Door de combinatie van toenemende computerkracht, beschikbaarheid van globale observaties als invoer en de onophoudelijk doorontwikkeling van weer- en klimaatmodellen, kan de wereldwijde atmosferische stroming nu worden berekend met een ongeloo?ijke nauwkeurigheid. De resterende achilleshiel van weer- en klimaatmodellen blijft echter de representatie van fenomenen op de schaal van turbulentie, zoals turbulent transport, wolken en neerslag. Deze fenomenen kunnen (nog) niet opgelost worden door hedendaagse weer- en klimaatmodellen (daar hebben deze modellen te weinig detail voor), waardoor ze vertegenwoordigd moeten worden door parametrische schema’s. Om de kwaliteit van dit soort schema’s te testen zijn specialistische modellen ontwikkeld, zogenaamde Large-Eddy Simulations (LES), die een beperkt oppervlak betrekken waarop wolken wel realistisch kunnen worden opgelost. In dit proefschrift worden LES modellen ingezet met het doel weer en klimaatvoorspellingen te verbeteren. In hoofdstuk twee worden LES resultaten gebruikt om een analytisch ’geraamte’ op te zetten met betrekking tot de evenwichtsoplossingen van cumulus-bewolking (stapelwolken) voor verschillende grootschalige weersituaties. Zo’n opzet kan ons begrip verbeteren van de manier waarop wolken reageren als de grootschalige situatie veranderd. Gezien weer- en klimaatmodellen projecties kunnen maken van de grootschalige situatie, kunnen we zo beter voorspellen hoe wolken zich zullen gedragen. De ’tradionele’ manier om kennis te combineren van LES en van weer- en klimaatstudies, zoals hierboven beschreven, leunt op de mogelijkheid om de grootschalige situatie te onderscheiden van de kleinschalige situatie. Dit is tegenwoordig echter helemaal niet meer vanzelfsprekend. Computerkracht neemt dermate snel toe dat we binnen twintig jaar in staat zullen zijn om de ontwikkeling van de globale atmosfeer voor de komende week te berekenen op een turbulentie-oplossende manier: dus op een detailniveau dat het mogelijk maakt turbulentie en individuele (stapel)wolken te beschrijven. Traditionele weer- en klimaatmodellen zijn echter niet ontworpen voor dit detailniveau, en kunnen dit niet aan zonder grote ingrepen. LES modellen zijn wel ontworpen voor dit detailniveau, maar niet voor grote oppervlaktes. Het ziet er dus naar uit dat toekomstige weer- en klimaatmodellen kenmerken van beide specializaties zullen krijgen. De rode draad van dit proefschrift is de studie in hoeverre we LES kunnen gebruiken om het ’werkelijke’ weer of klimaat te modelleren. Door de grote hoeveelheid benodigde rekenkracht worden LES modellen typisch alleen toegepast voor geidealiseerde casussen. In hoofdstuk drie wordt echter de mogelijkheid onderzocht om een nieuwe computertechniek toe te passen bij LES modellering: het gebruik van gra?sche co-processor chips (graphics processing unit, GPU). Het blijkt dat als we ons LES model aanpassen op het gebruik van deze chips, het model zodanig versneld kan worden dat nieuwe toepassingen, bijvoorbeeld in weersvoorspelling, mogelijk worden. Het GPU-LES model wordt daarom uitgerust met procedures om op een realistische manier de grond-atmosfeer interactie en de grootschalige invloeden te behandelen. In hoofdstuk vier testen we het model door middel van simulaties van het dagelijkse weer rondom Cabauw voor het gehele jaar 2012. Deze simulaties laten zien dat het LES model waarde kan toevoegen door zijn gedetailleerde representatie van turbulentie en wolkenprocessen. Daarnaast wordt in hoofdstuk vijf deze simulatie gebruikt om inzicht te geven in de kwaliteit van metingen van turbulent transport van warmte en vocht. Deze metingen zijn van groot belang om een goede weerspiegeling van de atmosferische grenslaag te kunnen maken in weer- en klimaatmodellen. Tenslotte wordt in hoofdstuk zes de grootste GPU-supercomputer van Europa ingezet om een ’proof of concept’ te bewerkstelligen van turbulentie-oplossende weersvoorspelling over Nederland met behulp van LES. Dit is een eerste kleine stap richting turbulentie-oplossende (dus met een detailniveau van individuele stapelwolken) weersvoorspelling vanuit een LES invalshoek. Het onderzoek in dit proefschrift kan zo een weg banen voor een nadere fusie van wolkensimulaties en globale weer- en klimaatmodellen.

Item does not contain fulltext PlsX is an acyl-acyl carrier protein (ACP):phosphate transacylase that interconverts the two acyl donors in Gram-positive bacterial phospholipid synthesis. The deletion of plsX in Staphylococcus aureus results in a requirement for both exogenous fatty acids and de novo type II fatty acid biosynthesis. Deletion of plsX (SP0037) in Streptococcus pneumoniae did not result in an auxotrophic phenotype. The DeltaplsX S. pneumoniae strain was refractory to myristic acid-dependent growth arrest, and unlike the wild-type strain, was susceptible to fatty acid synthesis inhibitors in the presence of exogenous oleate. The DeltaplsX strain contained longer chain saturated fatty acids imparting a distinctly altered phospholipid molecular species profile. An elevated pool of 18- and 20-carbon saturated fatty acids was detected in the DeltaplsX strain. A S. pneumoniae thioesterase (TesS, SP1408) hydrolyzed acyl-ACP in vitro, and the DeltatesS DeltaplsX double knockout strain was a fatty acid auxotroph. Thus, the TesS thioesterase hydrolyzed the accumulating acyl-ACP in the DeltaplsX strain to liberate fatty acids that were activated by fatty acid kinase to bypass a requirement for extracellular fatty acid. This work identifies tesS as the gene responsible for the difference in exogenous fatty acid growth requirement of the DeltaplsX strains of S. aureus and S. pneumoniae.

Contains fulltext : 147172.pdf (Publisher’s version ) (Open Access) 08 december 2011

Contains fulltext : 293834.pdf (Publisher’s version ) (Open Access) Radboud University, 05 juli 2023 Promotores : Bogaard, E.H.J. van den, Schalkwijk, J. Co-promotores : Zeeuwen, P.L.J.M., Jansen, P.A.M. 300 p.

Contains fulltext : 240243.pdf (Publisher’s version ) (Open Access) Radboud University, 08 december 2021 Promotores : Sauerwein, R.W., Schalkwijk, J. Co-promotor : Kooij, T.W.A. 231 p.

Contains fulltext : 201212_.pdf (Publisher’s version ) (Open Access) Radboud University, 28 maart 2019 Promotor : Schalkwijk, J. Co-promotores : Hijum, S.A.F.T. van, Boekhorst, J., Zeeuwen, P.L.J.M.

Contains fulltext : 212653.pdf (Publisher’s version ) (Open Access) Radboud University, 13 december 2019 Promotor : Schalkwijk, J. Co-promotores : Bogaard, E.H.J. van den, Zeeuwen, P.L.J.M.

This thesis describes the development of human skin equivalents that show characteristics of skin aging. The type of skin equivalent used was a fibroblast derived matrix equivalent, in which the dermal compartment is generated by fibroblasts and thus is fully of human origin. Two strategies are described to include characteristics of skin aging in skin equivalents. Firstly, skin equivalents generated with senescent fibroblasts show some signs of skin aging, like increased MMP production and increased epidermal stress. However, some characteristics, like reduced epidermal turnover, are noticably lacking. The second strategy involved using papillary and reticular fibroblasts. During aging the papillary dermis shrinks in size, which leads to a relative increase of reticular fibroblasts over papillary fibroblasts. Equivalents generated with reticular fibroblasts showed reduced epidermal turnover and disturbed epidermal differentiation compared to equivalents generated with papillary fibroblasts. In addition, we showed that papillary fibroblasts can differentiate into reticular fibroblasts in vitro. This leads to the hypothesis that during skin aging papillary fibroblasts differentiate into reticular fibroblasts, leading to changes in both dermal and epidermal homeostasis. Further research with equivalents described in this thesis can further elucidate the role of papillary and reticular fibroblasts during skin aging.

Contains fulltext : 175295.pdf (Publisher’s version ) (Open Access) Radboud University, 15 september 2017 Promotor : Schalkwijk, J. Co-promotores : Zeeuwen, P.L.J.M., Bogaard, E.H.J. van den

Contains fulltext : 139134.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 06 maart 2015 Promotores : Schalkwijk, J., Meer, J.W.M. van der Co-promotores : Simon, A., Zeeuwen, P.L.J.M.