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Search Results: 1 - 10 of 327907 matches for " Lubbertus C. F. Mulder "
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Effect of DNA Repair Protein Rad18 on Viral Infection
Aliza G Lloyd,Satoshi Tateishi,Paul D Bieniasz,Mark A Muesing,Masaru Yamaizumi,Lubbertus C. F Mulder
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020040
Abstract: Host factors belonging to the DNA repair machineries are assumed to aid retroviruses in the obligatory step of integration. Here we describe the effect of DNA repair molecule Rad18, a component of the post-replication repair pathway, on viral infection. Contrary to our expectations, cells lacking Rad18 were consistently more permissive to viral transduction as compared to Rad18+/+ controls. Remarkably, such susceptibility was integration independent, since retroviruses devoid of integration activity also showed enhancement of the initial steps of infection. Moreover, the elevated sensitivity of the Rad18?/? cells was also observed with adenovirus. These data indicate that Rad18 suppresses viral infection in a non-specific fashion, probably by targeting incoming DNA. Furthermore, considering data published recently, it appears that the interactions between DNA repair components with incoming viruses, often result in inhibition of the infection rather than cooperation toward its establishment.
Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence
Omer Gokcumen equal contributor,Qihui Zhu equal contributor,Lubbertus C. F. Mulder equal contributor,Rebecca C. Iskow,Christian Austermann,Christopher D. Scharer,Towfique Raj,Jeremy M. Boss,Shamil Sunyaev,Alkes Price,Barbara Stranger,Viviana Simon ? ,Charles Lee ?
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003404
Abstract: Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ~36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10?15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations.
Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling
Juliet Morrison equal contributor,Maudry Laurent-Rolle equal contributor,Ana M. Maestre,Ricardo Rajsbaum,Giuseppe Pisanelli,Viviana Simon,Lubbertus C. F. Mulder,Ana Fernandez-Sesma,Adolfo García-Sastre
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003265
Abstract: An estimated 50 million dengue virus (DENV) infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I) signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation.
SAMHD1-Deficient CD14+ Cells from Individuals with Aicardi-Goutières Syndrome Are Highly Susceptible to HIV-1 Infection
André Berger,Andreas F. R. Sommer equal contributor,Jenny Zwarg equal contributor,Matthias Hamdorf,Karin Welzel,Nicole Esly,Sylvia Panitz,Andreas Reuter,Irene Ramos,Asavari Jatiani,Lubbertus C. F. Mulder,Ana Fernandez-Sesma,Frank Rutsch,Viviana Simon,Renate K?nig ,Egbert Flory
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002425
Abstract: Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor.
DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING
Sebastian Aguirre,Ana M. Maestre,Sarah Pagni,Jenish R. Patel,Timothy Savage,Delia Gutman,Kevin Maringer,Dabeiba Bernal-Rubio,Reed S. Shabman,Viviana Simon,Juan R. Rodriguez-Madoz,Lubbertus C. F. Mulder,Glen N. Barber,Ana Fernandez-Sesma
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002934
Abstract: Dengue virus (DENV) is a pathogen with a high impact on human health. It replicates in a wide range of cells involved in the immune response. To efficiently infect humans, DENV must evade or inhibit fundamental elements of the innate immune system, namely the type I interferon response. DENV circumvents the host immune response by expressing proteins that antagonize the cellular innate immunity. We have recently documented the inhibition of type I IFN production by the proteolytic activity of DENV NS2B3 protease complex in human monocyte derived dendritic cells (MDDCs). In the present report we identify the human adaptor molecule STING as a target of the NS2B3 protease complex. We characterize the mechanism of inhibition of type I IFN production in primary human MDDCs by this viral factor. Using different human and mouse primary cells lacking STING, we show enhanced DENV replication. Conversely, mutated versions of STING that cannot be cleaved by the DENV NS2B3 protease induced higher levels of type I IFN after infection with DENV. Additionally, we show that DENV NS2B3 is not able to degrade the mouse version of STING, a phenomenon that severely restricts the replication of DENV in mouse cells, suggesting that STING plays a key role in the inhibition of DENV infection and spread in mice.
Positive Regulation of TRAF6-Dependent Innate Immune Responses by Protein Phosphatase PP1-γ
Amanda M. Opaluch, Monika Schneider, Chih-yuan Chiang, Quy T. Nguyen, Ana M. Maestre, Lubbertus C. F. Mulder, Ismael Secundino, Paul D. De Jesus, Renate K?nig, Viviana Simon, Victor Nizet, Graham MacLeod, Susannah Varmuza, Ana Fernandez-Sesma, Sumit K. Chanda
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089284
Abstract: Innate immune sensors such as Toll-like receptors (TLRs) differentially utilize adaptor proteins and additional molecular mediators to ensure robust and precise immune responses to pathogen challenge. Through a gain-of-function genetic screen, we identified the gamma catalytic subunit of protein phosphatase 1 (PP1-γ) as a positive regulator of MyD88-dependent proinflammatory innate immune activation. PP1-γ physically interacts with the E3 ubiquitin ligase TRAF6, and enhances the activity of TRAF6 towards itself and substrates such as IKKγ, whereas enzymatically inactive PP1-γ represses these events. Importantly, these activities were found to be critical for cellular innate responses to pathogen challenge and microbial clearance in both mouse macrophages and human monocyte lines. These data indicate that PP1-γ phosphatase activity regulates overall TRAF6 E3 ubiquitin ligase function and promotes NF-κB-mediated innate signaling responses.
Tegnologiese innovasie en Suid-Afrika
F. Shylock Mulder
Scientia Militaria : South African Journal of Military Studies , 2012, DOI: 10.5787/16-4-469
Abstract: The article below deals with technological developments in the Republic of South Africa necessitated by the arms boycotts engineered against the Republic by the United Nations Organisation. The writer of the article stresses the need for co ordination and sinchronlzation of research and development in the field of technology in South Africa especially with regard to priorities and effort. "A new form of Military Technological Strategy - each side is merely trying to outdo in performance the equipment of the other side - its object is to make them functionally obsolete -" Andre Beaufré
Tunable Frohlich Polarons in Organic Single-Crystal Transistors
I. N. Hulea,S. Fratini,H. Xie,C. L. Mulder,N. N. Iossad,G. Rastelli,S. Ciuchi,A. F. Morpurgo
Physics , 2006, DOI: 10.1038/nmat1774
Abstract: In organic field effect transistors (FETs), charges move near the surface of an organic semiconductor, at the interface with a dielectric. In the past, the nature of the microscopic motion of charge carriers -that determines the device performance- has been related to the quality of the organic semiconductor. Recently, it has been appreciated that also the nearby dielectric has an unexpectedly strong influence. The mechanisms responsible for this influence are not understood. To investigate these mechanisms we have studied transport through organic single crystal FETs with different gate insulators. We find that the temperature dependence of the mobility evolves from metallic-like to insulating-like with increasing the dielectric constant of the insulator. The phenomenon is accounted for by a two-dimensional Frohlich polaron model that quantitatively describes our observations and shows that increasing the dielectric polarizability results in a crossover from the weak to the strong polaronic coupling regime.
The kingdom, Israel and the church. Paul's thoughts on the relevance of God’s promises to Israel (Romans 9-11)
M.C. Mulder
In die Skriflig , 2001, DOI: 10.4102/ids.v35i2.560
Abstract: In Paul’s eschatology the kingdom of God is concentrated in Jesus Christ. In and through Him the kingdom has come and will come. Does this, however, imply that the old covenantal tradition has come to an end? If being in Christ is decisive for belonging to the eschatological kingdom of God, what then is the enduring relevance of the promises of God to his covenantal people, Israel? Romans 9-11 deals with these questions. Many scholars explain Romans 9-11 as an attempt to combine these two conflicting religious concepts, namely, on the one hand, the old covenantal tradition and on the other, the new eschatological soteriology, in which belonging to Christ is decisive. According to this viewpoint, different soteriologies clash in these chapters. Romans 11 represents the old covenantal tradition. Romans 9 cannot be compromised with this as a predestinational soteriology. In Romans 10 faith in Christ is decisive – faith which implies personal responsibility. Is it true that Romans 9-11 clearly demonstrates, as many scholars assert, that in Paul’s conception there cannot be a unanimous answer to these questions about belonging to the kingdom of God? In this article it is attempted to indicate that there is in fact more unity in Romans 9-11 than is frequently assumed. This unity can be demonstrated by especially paying attention to the background of the citations that Paul quotes from the Old Testament.
Ambipolar Cu- and Fe-Phthalocyanine single-crystal field-effect transistors
R. W. I. de Boer,A. F. Stassen,M. F. Craciun,C. L. Mulder,A. Molinari,S. Rogge,A. F. Morpurgo
Physics , 2005, DOI: 10.1063/1.1984093
Abstract: We report the observation of ambipolar transport in field-effect transistors fabricated on single crystals of Copper- and Iron-Phthalocyanine, using gold as a high work-function metal for the fabrication of source and drain electrodes. In these devices, the room-temperature mobility of holes reaches 0.3 cm$^2$/Vs in both materials. The highest mobility for electrons is observed for Iron-Phthalocyanines and is approximately one order of magnitude lower. Our measurements indicate that these values are limited by extrinsic contact effects due to the transistor fabrication and suggest that considerably higher values for the electron and hole mobility can be achieved in these materials.
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