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T-Zellen spielen bei der Immunüberwachung der peripheren Organe wie der Haut eine zentrale Rolle. Sie wandern als naive T-Zellen kontinuierlich in großer Zahl in den Paracortex der peripheren Lymphknoten ein. Die Lymphknoten dienen der Konzentration von antigenem Material, das in der Periphere von professionellen Antigen-präsentierenden Zellen aufgenommen und in die Lymphknoten transportiert wird. Dort treten die Antigen-präsentierenden Zellen in engen, physischen Kontakt mit naiven, Antigen-spezifischen T-Zellen und aktivieren diese. Neben der Aktivierung in diesem definierten anatomischen Kontext kommt es auch zur Aufregulation eines Codes spezifischer Adhäsionsmoleküle, die die Invasion in dasjenige Organ zur Folge hat, aus dem das Antigen drainiert wurde. Dieses organspezifische Rezirkulationsverhalten wird „Homing“ genannt und hat eine optimierte Antigenabwehr zur Folge, da unterschiedliche Antigene typischer Weise mit unterschiedlicher Frequenz in verschiedenen Organen anzutreffen sind. .... Ziel des ersten Teils der Arbeit war es somit, Auslöser der genannten entzündlichen Dermatosen molekular zu charakterisieren. Ausgehend von der klinischen Beobachtung, daß bakterielle Infektionen bzw. Besiedelung mit Gram-positiven Erregern diesen Erkrankungen vorangehen, wollten wir die Bedeutung von bakteriellen Superantigenen näher untersuchen, da diese Substanzen aufgrund ihrer starken, T-Zell stimulierenden Eigenschaften als Kandidatenmoleküle für die Induktion von T-Zell mediierten Dermatosen in Frage kamen. Dazu etablierten wir für die Psoriasis vulgaris ein xenogenes Transplantationsmodell. Bei diesem wurde humane Haut von gesunden Kontrollen oder periläsionale Haut von Patienten mit Psoriasis vulgaris auf immundefiziente SCID-Mäuse transplantiert. Die repetitive Injektion eines bakteriellen Superantigens induzierte ausschließlich bei Psoriatikern, nicht jedoch bei gesunden Kontrollen, einen psoriatischen Phänotyp. Diese Ergebnisse lassen zwei Schlüsse zu: (I) Ein bakterielles Superantigen ist unter bestimmten Voraussetzungen ausreichend, um eine Psoriasis zu induzieren. (II) Ein bestimmtes, evt. genetisch determiniertes Mikromilieu der Haut ist Voraussetzung für die Induktion der Psoriasis durch das Superantigen. ... Im zweiten Teil der Arbeit gingen wir der Frage nach, inwiefern Veränderungen des Hautimmunsystems nachweisbar sind, die auf bakterielle Superantigene zurückzuführen sind. In unseren Untersuchungen setzten wir dabei zwei Schwerpunkte: (I) Das T-Zell Rezeptor (TCR) Vbeta Repertoire, da Superantigene alpha/beta+ T-Zellen in TCR Vbeta spezifischer Weise aktivieren und (II) Adhäsionsmoleküle unter besonderer Berücksichtigung des Haut-spezifischen Adhäsionsmoleküls CLA, da T-Zell Adhäsionsmoleküle aktivierungsabhängig reguliert werden und eine veränderte T-Zell Migration in pathophysiologische Vorgänge involviert ist. Die Untersuchungen des TCR Vbeta Repertoires der Haut erfolgten an der Psoriasis vulgaris als Modell einer T-Zell vermittelten Immundermatose, die – wie oben gezeigt – u.a. durch bakterielle Superantigene induziert werden kann. Im Gegensatz zu Untersuchungen zur „akuten“ Form der Psoriasis, der Psoriasis guttata, bei der Superantigen-mediierte Veränderungen des TCR Vbeta Repertoires der Haut im Vergleich zum Blut nachgewiesen werden konnten, fanden wir und auch andere Arbeitsgruppen bei der chronisch-stationären Form der Psoriasis keine Veränderungen des TCR Vbeta Repertoires der Haut, das für einen Superantigen-mediierten Effekt spricht. Aus diesen und anderen Befunden entwickelten wir ein pathophysiologisches Konzept der Psoriasis, bei dem Superantigene zwar in die Induktion, nicht jedoch in die Aufrechterhaltung des Erkrankungsprozesses involviert sind. ...
Australia has a diversity of vectors and vector-borne human diseases. Mosquito-borne arboviruses are of greatest concern, but there are issues with other vector and pathogen systems. Mosquitoes were responsible for more than 35,000 cases of Ross River virus during 1991-1997. Barmah Forest virus is increasing nationwide, and unidentified bunyaviruses suspected of causing illness have been isolated. Cases of Murray Valley encephalitis have occurred in 14 of the past 20 years in northern Australia. Dengue is a continuing problem for northern Queensland, with various serotypes being active. Japanese encephalitis has appeared in the Torres Strait Islands and threatens mainland Australia. Although malaria is eradicated, almost 1,000 cases are imported annually and occasional cases of local transmission occur. With ticks, paralysis in children occurs annually in eastern Australia. Tick typhus (Queensland Tick Typhus--Rickettsia australis) occurs down the east coast, and (Flinders Island Spotted Fever--Rickettsia honei) in Bass Strait and probably Tasmania. Lyme disease is reported but its presence is controversial. Fleas were responsible for a recent outbreak of murine typhus (Rickettsia typhi) in Western Australia. Mites cause scrub typhus (Orientia tsutsugamushi), and there was a recent fatality in the Northern Territory. Overall, resources for investigation and control of vector-borne disease have generally been meager. However, various avenues of basic and applied research have been pursued, and have included investigations into mosquito ecology, vector competence, disease epidemiology, and vector control. Disease surveillance programs vary between states, and mosquito control programs are organized and effective in only a few regions. There are concerns for import of vectors such as Aedes albopictus and export of pathogens such as Ross River virus; the former has occurred but the species has not become established, and the latter has occurred and has resulted in a major outbreak in the South Pacific. The predicted scenarios of increased temperature and rainfall with global warming are also causing concern for increases in vector-borne diseases, particularly the endemic arboviruses. Interest by health authorities is gravitating more towards epidemiological reporting and less towards public health action. In many respects, humans have much to do to get "on top" of vectors and their pathogens "down under" in Australia.
Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor ~18–25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions.
C2-symmetric bisamidines : chiral Brønsted bases catalysing the Diels-Alder reaction of anthrones
(2008)
C2-symmetric bisamidines 8 have been tested as chiral Brønsted bases in the Diels- Alder reaction of anthrones and N-substituted maleimides. High yields of cycloadducts and significant asymmetric inductions up to 76% ee are accessible. The proposed mechanism involves proton transfer between anthrone and bisamidine, association of the resulting ions and finally a cycloaddition step stereoselectively controlled by the chiral ion pair.
Oscillatory activity in human electro- or magnetoencephalogram has been related to cortical stimulus representations and their modulation by cognitive processes. Whereas previous work has focused on gamma-band activity (GBA) during attention or maintenance of representations, there is little evidence for GBA reflecting individual stimulus representations. The present study aimed at identifying stimulus-specific GBA components during auditory spatial short-term memory. A total of 28 adults were assigned to 1 of 2 groups who were presented with only right- or left-lateralized sounds, respectively. In each group, 2 sample stimuli were used which differed in their lateralization angles (15° or 45°) with respect to the midsagittal plane. Statistical probability mapping served to identify spectral amplitude differences between 15° versus 45° stimuli. Distinct GBA components were found for each sample stimulus in different sensors over parieto-occipital cortex contralateral to the side of stimulation peaking during the middle 200–300 ms of the delay phase. The differentiation between "preferred" and "nonpreferred" stimuli during the final 100 ms of the delay phase correlated with task performance. These findings suggest that the observed GBA components reflect the activity of distinct networks tuned to spatial sound features which contribute to the maintenance of task-relevant information in short-term memory.
Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.
The degradation of the poly(A) tail is crucial for posttranscriptional gene regulation and for quality control of mRNA. Poly(A)-specific ribonuclease (PARN) is one of the major mammalian 3’ specific exo-ribonucleases involved in the degradation of the mRNA poly(A) tail, and it is also involved in the regulation of translation in early embryonic development. The interaction between PARN and the m7GpppG cap of mRNA plays a key role in stimulating the rate of deadenylation. Here we report the solution structures of the cap-binding domain of mouse PARN with and without the m7GpppG cap analog. The structure of the cap-binding domain adopts the RNA recognition motif (RRM) with a characteristic a-helical extension at its C-terminus, which covers the b-sheet surface (hereafter referred to as PARN RRM). In the complex structure of PARN RRM with the cap analog, the base of the N7-methyl guanosine (m7G) of the cap analog stacks with the solvent-exposed aromatic side chain of the distinctive tryptophan residue 468, located at the C-terminal end of the second b-strand. These unique structural features in PARN RRM reveal a novel cap-binding mode, which is distinct from the nucleotide recognition mode of the canonical RRM domains.
We performed a bioinformatical analysis of protein export elements (PEXEL) in the putative proteome of the malaria parasite Plasmodium falciparum. A protein family-specific conservation of physicochemical residue profiles was found for PEXEL-flanking sequence regions. We demonstrate that the family members can be clustered based on the flanking regions only and display characteristic hydrophobicity patterns. This raises the possibility that the flanking regions may contain additional information for a family-specific role of PEXEL. We further show that signal peptide cleavage results in a positional alignment of PEXEL from both proteins with, and without, a signal peptide.