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  • 1
    Keywords: Germany ; CT ; HISTORY ; GENE ; GENES ; DNA ; animals ; ACID ; ESCHERICHIA-COLI ; REGION ; SIALIC-ACID ; CELL-ADHESION MOLECULE ; N-ACETYLNEURAMINIC ACID ; 2-KETO-3-DEOXY-D-GLYCERO-D-GALACTO-NONONIC ACID ; 8-PHOSPHATE SYNTHASE ; NEISSERIA-MENINGITIDIS ; POLYSACCHARIDE BIOSYNTHESIS ; SYNTHETASE
    Abstract: alpha-Ketoacids are present in glycosylated structures in almost all organisms and must be activated by a cytidylyltransferase (CT) before their incorporation into glycoconjugates. Examples of alpha-ketoacids include KDO (keto-deoxyoctulosonic acid), which is present in bacterial lipopolysaccharide and in plant pectins, and sialic acids (Sia), such as N-acetylneuraminate (NeuAc), which are present in animals and in pathogenic microorganisms. The phylogeny of Sia and CTs is unclear but is linked to the history of the alpha-ketoacid synthases. Furthermore, horizontal gene transfer (HGT) events might have played a major role. Here we analyse the origin and the expansion process of these genes with respect to the taxonomic coherence of the phylogenetic trees, the molecular characteristics of the CT-coding DNA and the presence or absence of a long C-terminal coding region in some NeuAc-CTs. We propose a prokaryotic origin for CTs and et-ketoacid synthases, and a HGT event of these genes towards ancestors of animals and plants. Finally, some pathogenic bacteria reacquired some of these genes, which would have been modified and devoted to Sia synthesis
    Type of Publication: Journal article published
    PubMed ID: 15001188
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; Germany ; TYROSINE KINASE ; EXPOSURE ; PROTEIN ; ACTIVATION ; INFECTION ; INDUCTION ; KERATINOCYTES ; DYNAMICS ; MOLECULE ; PLASMA ; MEMBRANE ; STRESS ; human papillomavirus ; TYPE-16 ; EPITHELIAL-CELL LINE ; GOLGI-APPARATUS ; MHC CLASS-I ; PLASMA-MEMBRANE ; RECEPTORS ; HUMAN FORESKIN KERATINOCYTES ; keratinocyte ; phosphatidylcholine ; plasma membrane ; CERVICAL-CANCER WORLDWIDE ; CHOLESTEROL EFFLUX ; CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE ; CYCLODEXTRIN ; SPHINGOMYELIN
    Abstract: The E5 protein of the human papillomavirus type 16 is a small protein found associated to membranes, mainly in the Golgi apparatus, and expressed in the early stages of viral infection. Its expression modifies the cell response towards growth factors and stress exposures, and also blocks the surface expression of MHC molecules. A global explanation for these multiple effects is hitherto not available. Here we present data showing that the expression of HPV16-E5 increases the amount of free cholesterol readily extractable from the plasma membrane, without altering the total cholesterol content. In addition, HPV16-E5 modifies the composition of the cell membranes, increasing the synthesis rate of phosphatidylcholine and phosphatidylserine, while diminishing that of phosphatidylglycerol. We propose that these changes in the lipid composition of the membrane are the central effect of HPV16-E5 on the cell. The multiple and apparently disconnected effects of HPV16-E5 on tyrosine-kinase receptors, induction of the apoptosis and impairment of MHC trafficking could follow the initial alteration on the membrane composition
    Type of Publication: Journal article published
    PubMed ID: 15503216
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  • 3
    Keywords: CANCER ; Germany ; CLASSIFICATION ; EPIDEMIOLOGY ; HISTORY ; GENE ; GENES ; GENOME ; EPITHELIA ; DNA ; INFECTION ; BIOLOGY ; E7 ; SEQUENCES ; virus ; LESIONS ; CERVICAL-CANCER ; REGION ; TYPE-16 ; EVOLUTION ; E6 ; BENIGN ; L1 ; INFECTIONS ; APPEARANCE ; FRAMEWORK ; LIFE-CYCLE ; E7 PROTEINS ; EPITHELIUM ; L2 ; MULTIPLE ALIGNMENTS ; OPEN READING FRAMES
    Abstract: Papillomaviruses (PVs) infect stratified squamous epithelia in vertebrates. Some PVs are associated with different types of cancer and with certain benign lesions. It has been assumed that PVs coevolved with their hosts. However, recently it has been shown that different regions of the genome have different evolutionary histories. The PV genome has a modular nature and appeared after the addition of pre-existent blocks. This order of appearance in the PV genome is evident today in the different evolutionary rates of the different genes, with new genes - E5, E6 and E7 - diverging faster than old genes - E1, E2, L2 and L1. Here, we propose an evolutionary framework aiming to integrate genome evolution, PV biology and epidemiology of PV infections
    Type of Publication: Journal article published
    PubMed ID: 16181783
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DEATH ; CLONING ; GENE-EXPRESSION ; PROTEIN ; SAMPLE ; SAMPLES ; DIFFERENTIATION ; LIGAND ; MECHANISM ; CONTRAST ; mechanisms ; IN-SITU ; NEOPLASIA ; CELL-DEATH ; DECREASE ; RECEPTORS ; SMALL-INTESTINE ; TRAIL ; protein expression ; LACKING ; molecular ; RECOMBINANT ; MOLECULAR-MECHANISM ; VARIANT ; INCREASE ; CELL-SURFACE EXPRESSION ; PH ; regulation ; development ; MOLECULAR-MECHANISMS ; methods ; cell death ; CELIAC-DISEASE ; death receptor ; USA ; LIGAND TRAIL ; HOMEOSTASIS ; INCREASES ; apoptotic ; MUCOSAL ; ACYL-COA-SYNTHETASE-5 ; HUMAN SMALL-INTESTINE ; IMPAIRED EXPRESSION
    Abstract: Background & Aims: The constant renewal of enterocytes along the crypt-villus axis (CVA) of human small intestine is due to cell-inherent changes resulting in the apoptotic cell death of senescent enterocytes. The aim of the present study was to examine underlying molecular mechanisms of the cell death at the villus tip. Methods: Characterization of human acyl-coenzyme A (CoA) synthetase 5 (ACSL5) was performed by cloning, recombinant protein expression, biochemical approaches, and several functional and in situ analyses. Results: Our data show that different amounts of acyl-CoA synthetase 5-full length (ACSL5-fl) and a so far unknown splice variant lacking exon 20 (ACSL5-Delta 20) are found in human enterocytes. In contrast with the splice variant ACSL5-Delta 20, recombinant and purified ACSL5-fl protein is active at a highly alkaline pH. Over expression of ACSL5-fl protein is associated with a decrease of the anti-apoptotic FLIP protein in a ceramide-dependent manner and an increased cell-surface expression of the death receptor TRAIL-RI. Expression analyses revealed that the ACSL5-fl/ACSL5-Delta 20 ratio increases along the CVA, thereby sensitizing ACSL5-fl-dominated cells at the villus tip to the death ligand TRAIL, which is corroborated by functional studies with human small intestinal mucosal samples and an immortalized human small intestinal cell fine. Conclusions: Our results suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the CVA in human small intestine. Deregulation of the ACSL5-fl/ACSL5-Delta 20 homeostasis in the maturation and shedding of cells along the CVA might also be of relevance for the development of intestinal neoplasia
    Type of Publication: Journal article published
    PubMed ID: 17681178
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  • 5
    Keywords: Germany ; human ; DISEASE ; DISEASES ; HISTORY ; POPULATION ; DISTINCT ; PROTEIN ; TIME ; INFECTION ; SKIN ; papillomavirus ; ALPHA ; antibodies ; antibody ; PATTERNS ; AGE ; WOMEN ; MEN ; CAPSID PROTEIN ; human papillomavirus ; VIRUS-LIKE PARTICLES ; HIGH-RISK ; HPV ; BETA ; HUMAN-PAPILLOMAVIRUS ; Jun ; SQUAMOUS-CELL CARCINOMA ; POLYMERASE-CHAIN-REACTION ; L1 ; CHILDREN ; NATURAL-HISTORY ; PREVALENCE ; NONMELANOMA SKIN CANCERS ; glutathione-S-transferase ; SERUM ; ADULT ; ADULTS ; SAN-FRANCISCO ; review ; RE ; PATTERN ; papillomaviruses ; GAMMA ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; HPV 16 ; USA ; YOUNG-ADULTS ; INFECTIOUS-DISEASES ; microbiology ; serology ; multiplex serology ; SEROPREVALENCE ; GENERAL-POPULATION ; HPV types ; MAJOR CAPSID PROTEIN ; HPV-16 ; CUTANEOUS HUMAN PAPILLOMAVIRUSES ; FOOD-CONSUMPTION HABITS ; NORMAL CERVICAL SMEARS
    Abstract: The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age-and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life
    Type of Publication: Journal article published
    PubMed ID: 18566657
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  • 6
    Keywords: CELLS ; CELL ; COMBINATION ; Germany ; GENE ; GENES ; GENOME ; PROTEINS ; COMPLEX ; COMPLEXES ; SKIN ; papillomavirus ; ACID ; EVOLUTION ; L1 ; PHYLOGENETIC ANALYSIS ; AMINO-ACID ; hair ; LONG ; adaptation ; GENOMES ; SEQUENCE DATA ; EEPV
    Abstract: Knowledge about biological diversity is the prerequisite to reliably reconstruct the evolution of pathogens such as papillomaviruses (PV). However, complete genomes of non-human PV have only been cloned and sequenced from 8 out of 18 orders within the Placentalia, although the host-specific variety of PV is considered much larger. We isolated and sequenced the complete genome of the first insectivoran PV type from hair follicle cells of the European hedgehog (Erinaceus europaeus), designated EHPV. We conducted phylogenetic analyses (maximum-likelihood criterion and Bayesian inference) with the genomic information of a systematically representative set of 67 PV types including EHPV As inferred from amino acid sequence data of the separate genes E1, E2 and L1 as well as of the gene combination E6-E7-E1-E2-L1, EHPV clustered within the beta-gamma-pi-zeta-PV supertaxon and constituted the closest relative of genus Betapapillomavirus infecting primates. Beside the typical organization of the PV genome, EHPV exhibited a 1172 lop, non-coding region between the E2 and the L2 open reading frames. This trait has been previously described for the only distantly related Lambdapapillomavirus, but a common evolutionary origin of both non-coding regions is unlikely. Our results underscore the modular organization of the PV genome and the complex natural history of PV
    Type of Publication: Journal article published
    PubMed ID: 19218207
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  • 7
    Keywords: PEPTIDE ; CELLS ; IN-VITRO ; CELL ; Germany ; INHIBITION ; KINASE ; PATHWAYS ; VITRO ; transcription ; TRANSDUCTION ; ACTIVATION ; PROTEIN-KINASE ; signal transduction ; treatment ; SIGNAL ; TARGET ; MAP KINASE ; STRESS ; SIGNAL-TRANSDUCTION ; PKA ; CYCLIC-AMP ; sorbitol ; CROSS-TALK ; NEUTROPHILS ; GTPASES ; CDC42 ; RAP1 ; SIGNAL TRANSDUCER ; sorbitol,MLTK,AMPK,AICAr,cAMP,Rho GTPases
    Abstract: In this report, we analyse the effects of osmotic shock on signal transduction in CHO cells. We demonstrate that at least three different kinase cascades are switched on upon osmotic shock, namely PKA, AMPK, and MLTK. Whereas PKA from cells treated with forskolin activated stress kinase p38, PKA from cells treated with sorbitol did not activate p38, although the enzyme is activated in both cases as analysed in vitro using a specific peptide target. Further, osmolar shock activated AMPK but treatment of the cells with the AMPK activator 5-amino-4-imidazolecarboxamide (AICAr) did not result in p38 activation, strongly suggesting that AMPK is not involved in stress kinase activation. Transfection of CHO cells with dominant negative recombinants of MLTKalpha resulted in inhibition of sorbitol-mediated p38 activation, indicating that the mixed-lineage kinase is involved in the activation of p38 by sorbitol. Finally, in CHO cells overexpressing wildtype MLTKalpha, no activation of AMPK of PKA could be demonstrated, indicating that the activated kinase cascades are not involved in a cross-talk process. (C) 2003 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 14697338
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  • 8
    Keywords: Germany ; human ; HYBRIDIZATION ; DNA ; papillomavirus ; IDENTIFICATION ; AMPLIFICATION ; ASSAY ; WOMEN ; REPRODUCIBILITY ; CERVICAL-CANCER ; PCR ; human papillomavirus ; HIGH-RISK ; HUMAN-PAPILLOMAVIRUS ; sensitivity ; RE ; ASSAYS ; HIGH-THROUGHPUT ; TECHNOLOGY ; DNA HYBRIDIZATION ; PAP
    Abstract: Typing of human papillomaviruses (HPV) by DNA hybridization procedures, such as reverse line blot (RLB) assay, is sensitive and well validated. However, the application of these assays to high-throughput analyses is limited. Here, we describe the development of multiplex human papillomavirus genotyping (MPG), a quantitative and sensitive high-throughput procedure for the identification of multiple high- and low-risk genital HPV genotypes in a single reaction. MPG is based on the amplification of HPV DNA by a general primer PCR (GP5+/6+) and the subsequent detection of the products with type-specific oligonucleotide probes coupled to fluorescence-labeled polystyrene beads (Luminex suspension array technology). Up to 100 different HPV types can be detected simultaneously with MPG, and the method is fast and labor saving. We detected all 22 HPV types examined with high specificity and reproducibility (the median interplate coefficient of variation was below 10%). Detection limits for the different HPV types varied between 100 and 800 pg of PCR products. We compared the performance of MPG to an established RLB assay on GP5+/6+-PCR products derived from 94 clinical samples. The evaluation showed an excellent agreement (kappa = 0.922) but also indicated a higher sensitivity of MPG. In conclusion, MPG appears to be highly suitable for large-scale epidemiological studies and vaccination trials as well as for routine diagnostic purposes
    Type of Publication: Journal article published
    PubMed ID: 16455905
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  • 9
    Keywords: CANCER ; AGENTS ; Germany ; human ; GENOME ; PROTEIN ; PROTEINS ; MOLECULES ; MICE ; RESPONSES ; DNA ; INFECTION ; CARCINOGENESIS ; papillomavirus ; MOLECULE ; IMMUNE-RESPONSES ; antibody ; FORM ; NEUTRALIZING ANTIBODIES ; PARTICLES ; DELETION ; ESCHERICHIA-COLI ; cervical cancer ; CERVICAL-CANCER ; human papillomavirus ; L1 PROTEIN ; VACCINES ; VIRUS-LIKE PARTICLES ; PURIFICATION ; MONOCLONAL-ANTIBODIES ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; EPITOPE ; immune response ; IMMUNE-RESPONSE ; L1 ; IMMUNOGENICITY ; BOND ; CYTOTOXIC T-LYMPHOCYTES ; AGENT ; IMMUNIZATION ; assembly ; USA ; BACTERIA ; REPLACEMENT ; capsomeres ; CONTROLLED-TRIAL ; CONTAMINATION ; FORMULATION ; virology ; MAJOR CAPSID PROTEIN ; DISULFIDE BOND ; PAPILLOMAVIRUS TYPES ; Virus-like particle
    Abstract: L1 capsomeres purified from Escherichia coli represent an economic alternative to the recently launched virus-like particle (VLP)-based prophylactic vaccines against infection with human papillomavirus types 16 and 18 (HPV-16 and HPV-18), which are causative agents of cervical cancer. It was recently reported that capsomeres are much less immunogenic than VLPs. Numerous modifications of the L1 protein leading to the formation of capsomeres but preventing capsid assembly have been described, such as the replacement of the cysteine residues that form capsid-stabilizing disulfide bonds or the deletion of helix 4. So far, the influence of these modifications on immunogenicity has not been thoroughly investigated. Here, we describe the purification of eight different HPV-16 L1 proteins as capsomeres from Escherichia coli. We compared them for yield, structure, and immunogenicity in mice. All L1 proteins formed almost identical pentameric structures yet differed strongly in their immunogenicity, especially regarding the humoral immune responses. Immunization of TLR4(-/-) mice and DNA immunization by the same constructs confirmed that immunogenicity was independent of different degrees of contamination with copurifying immune-stimulatory molecules from E. coli. We hypothesize that immunogenicity correlates with the intrinsic ability of the capsomeres to assemble into larger particles, as only assembly-competent L1 proteins induced high antibody responses. One of the proteins (L1 Delta N10) proved to be the most immunogenic, inducing antibody titers equivalent to those generated in response to VLPs. However, preassembly prior to injection did not increase immunogenicity. Our data suggest that certain L1 constructs can be used to produce highly immunogenic capsomeres in bacteria as economic alternatives to VLP-based formulations
    Type of Publication: Journal article published
    PubMed ID: 19457985
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  • 10
    Keywords: radiation ; SEQUENCE ; virus ; INFECTIOUS-DISEASES ; PHYLOGENETIC TREES ; COTTONTAIL RABBIT PAPILLOMAVIRUS ; DIVERSIFICATION ; HOST-PARASITE ASSOCIATIONS ; GENOMIC CHARACTERIZATION ; TYPE-1 DNA
    Abstract: The associations between pathogens and their hosts are complex and can result from a variety of evolutionary processes including codivergence, lateral transfer, or duplication. Papillomaviruses (PVs) are double-stranded DNA viruses ubiquitously present in mammals and are a suitable target for rigorous statistical tests of potential virus-host codivergence. We analyze the evolutionary dynamics of PV diversification by comparing robust phylogenies of PVs and their respective hosts using different statistical approaches to assess topological and branch-length congruence. Mammalian PVs segregated into four diverse major clades that overlapped to varying degrees in terms of their mammalian host lineages. The hypothesis that PVs and hosts evolved independently was globally rejected (P = 0.0001), although only 90 of 207 virus-host associations (43%) were significant in individual tests. Virus-host codivergence accounted roughly for one-third of the evolutionary events required to reconcile PV-host evolutionary histories. When virus-host associations were analyzed locally within each of the four viral clades, numerous independent topological congruencies were identified that were incompatible with respect to the global trees. These results support an evolutionary scenario in which early PV radiation was followed by independent codivergence between viruses within each of the major clades and their hosts. Moreover, heterogeneous groups of closely related PVs infecting non-related hosts suggest several interspecies transmission events. Our results argue thus for the importance of alternative events in PV evolution, in contrast to the prevailing opinion that these viruses show a high degree of host specificity and codivergence
    Type of Publication: Journal article published
    PubMed ID: 21285031
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