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Highly sensitive qualitative and quantitative automatednucleic acid amplification tests (NATs) that are commercially available for the detection of hepatitis B virus (HBV)infection have been developed only in the last few years.The potential indications for HBV NATs are: follow-up ofchronic hepatitis B, therapy and antiviral resistance monitoring, determination of infectivity and transmission risk,detection of occult (HBsAg-negative and HBV DNA-positive) infection and mutant virus which may escape serologic diagnosis, blood donor screening, and resolution ofunusual or discordant serologic constellations. Although NATs are now widely implemented in the routine diagnosis of clinical laboratories, there are several importantissues which need to be further investigated. Standardisation of NATs used for the monitoring of antiviral therapyand follow-up of chronic infection is still lacking, and theclinical significance of HBV DNA levels needs to be clarified. The influence of genetic variability in terms of genotype variation has been poorly investigated so far.Although there are highly sensitive automated NATs forblood donor screening available, their implementation is still subject to discussion and certain countries rejectedHBV DNA testing for blood donation for reasons of poor cost-effectiveness.
Rafts: Rafts sind spezialisierte Domänen biologischer Membranen, die sich durch ihre spezifische Lipid- und Proteinzusammensetzung auszeichnen (zur Übersicht siehe Simons und Toomre, 2000). Die am besten beschriebenen Rafts sind die Caveolae, doch es gibt noch weitere weniger gut charakterisierte Rafttypen. Rafts werden verschiedene zelluläre Funktionen zugeschrieben wie z.B. gerichteter Transport von Membranproteinen, Endozytose und Signaltransduktion. Diese Funktionen erfüllen sie vornehmlich, indem sie verschiedene Proteine und Lipide bedingt durch ihre biophysikalischen Eigenschaften selektiv aufnehmen oder ausschließen. Viele Raftproteine sind über gesättigte Acylketten, wie Myristat oder Palmitat, oder einen GPIAnker mit der Membran assoziiert. Transmembranproteine, wie z.B. der EGFRezeptor, können jedoch auch in Rafts angereichert sein. Besonders an der Plasmamembran dienen Rafts als Signaltransduktionszentren, indem sie beteiligte Rezeptoren und Signalmoleküle konzentrieren.
Reggie-Proteine: Bei der Suche nach Proteinen, die bei der Regeneration von verletzten Sehnerven von Fischen hochreguliert werden, wurden Reggie-1 und Reggie-2 entdeckt (Schulte et al., 1997). Gleichzeitig wurden diese Proteine bei der Suche nach neuen Raftproteinen gefunden und als Flotillin-1 (=Reggie-2) und Flotillin-2 (=Reggie-1) bezeichnet (Bickel et al., 1997). Reggie-1 und -2 haben ein Molekulargewicht von 47 kDa und sind auf Aminosäuren-Basis zu 44% identisch. Homologe zu Reggie-1 wurden bislang in Mensch, Maus, Ratte und Fisch, wie auch in D. melanogaster gefunden. Die evolutionäre Konservierung der Reggies ist, mit beispielsweise 80% zwischen Ratte und Goldfisch, sehr hoch und weist auf eine wichtige Funktion hin, die Sequenzkonservierung verlangt. Reggie-1 wird ubiquitär exprimiert, wogegen Reggie-2 ein weniger verbreitetes Expressionsmuster aufweist. Reggie-1 ist vornehmlich an der Plasmamembran und an Endosomen lokalisiert. Die subzelluläre Lokalisation von Reggie-2 hängt vom Zelltyp ab...
Calreticulin is a Ca2+ -binding chaperone that resides in the lumen of the endoplasmic reticulum and is involved in the regulation of intracellular Ca2+ homeostasis and in the folding of newly synthesized glycoproteins. In this study, we have used site-specific mutagenesis to map amino acid residues that are critical in calreticulin function. We have focused on two cysteine residues (Cys(88) and Cys(120)), which form a disulfide bridge in the N-terminal domain of calreticulin, on a tryptophan residue located in the carbohydrate binding site (Trp(302)), and on certain residues located at the tip of the "hairpin-like" P-domain of the protein (Glu(238), Glu(239), Asp(241), Glu(243), and Trp(244)). Calreticulin mutants were expressed in crt(-/-) fibroblasts, and bradykinin-dependent Ca2+ release was measured as a marker of calreticulin function. Bradykinin-dependent Ca2+ release from the endoplasmic reticulum was rescued by wild-type calreticulin and by the Glu(238), Glu(239), Asp(241), and Glu(243) mutants. The Cys(88) and Cys(120) mutants rescued the calreticulin-deficient phenotype only partially ( approximately 40%), and the Trp(244) and Trp(302) mutants did not rescue it at all. We identified four amino acid residues (Glu(239), Asp(241), Glu(243), and Trp(244)) at the hairpin tip of the P-domain that are critical in the formation of a complex between ERp57 and calreticulin. Although the Glu(239), Asp(241), and Glu(243) mutants did not bind ERp57 efficiently, they fully restored bradykinin-dependent Ca2+ release in crt(-/-) cells. This indicates that binding of ERp57 to calreticulin may not be critical for the chaperone function of calreticulin with respect to the bradykinin receptor.
NAD(P)H oxidase, the main source of reactive oxygen species in vascular cells, is known to be regulated by redox processes and thiols. However, the nature of thiol-dependent regulation has not been established. Protein disulfide isomerase (PDI) is a dithiol/disulfide oxidoreductase chaperone of the thioredoxin superfamily involved in protein processing and translocation. We postulated that PDI regulates NAD(P)H oxidase activity of rabbit aortic smooth muscle cells (VSMCs). Western blotting confirmed robust PDI expression and shift to membrane fraction after incubation with angiotensin II (AII, 100 nm, 6 h). In VSMC membrane fraction, PDI antagonism with bacitracin, scrambled RNase, or neutralizing antibody led to 26-83% inhibition (p < 0.05) of oxidase activity. AII incubation led to significant increase in oxidase activity, accompanied by a 6-fold increase in PDI refolding isomerase activity. AII-induced NAD(P)H oxidase activation was inhibited by 57-71% with antisense oligonucleotide against PDI (PDIasODN). Dihydroethidium fluorescence showed decreased superoxide generation due to PDIasODN. Confocal microscopy showed co-localization between PDI and the oxidase subunits p22(phox), Nox1, and Nox4. Co-immunoprecipitation assays supported spatial association between PDI and oxidase subunits p22(phox), Nox1, and Nox4 in VSMCs. Moreover, in HEK293 cells transfected with green fluorescent protein constructs for Nox1, Nox2, and Nox4, each of these subunits co-immunoprecipitated with PDI. Akt phosphorylation, a known downstream pathway of AII-driven oxidase activation, was significantly reduced by PDIasODN. These results suggest that PDI closely associates with NAD(P)H oxidase and acts as a novel redox-sensitive regulatory protein of such enzyme complex, potentially affecting subunit traffic/assembling.
Aim of the present study was the characterization of the RORa receptor (Retinoidrelated Orphan Receptor a). RORa is a member of the nuclear receptor family and is involved into the differentiation of Purkinje cells, inflammation, arteriosclerosis, and bone mineralization. Nuclear receptors are transcription factors and mediate biological responses within target cells to outer signals such as lipophilic hormones. They are involved in development, growth, differentiation, proliferation, apoptosis, and maintenance of homeostasis. Ligand binding, posttranslational modifications, and cofactor recruitment control their activity. Nearly all nuclear receptors share a common modular structure with an Nterminal A/B region, a DNA-binding domain (DBD) that is composed of two zinc finger motifs, a hinge region, and a C-terminal ligand-binding domain (LBD). The RORs comprise the subtypes RORa, RORb, and RORg, which are encoded by different genes. All isoforms of the respective subtypes only differ in their A/B domain. This study focused mainly on the exploration of the gene structure, expression, and subcellular distribution of RORa...
STAT proteins have the function of signaling from the cell membrane into the nucleus, where they regulate gene transcription. Latent mammalian STAT proteins can form dimers in the cytoplasm even before receptor-mediated activation by specific tyrosine phosphorylation. Here we describe the 3.21-A crystal structure of an unphosphorylated STAT5a homodimer lacking the N-terminal domain as well as the C-terminal transactivation domain. The overall structure of this fragment is very similar to phosphorylated STATs. However, important differences exist in the dimerization mode. Although the interface between phosphorylated STATs is mediated by their Src-homology 2 domains, the unphosphorylated STAT5a fragment dimerizes in a completely different manner via interactions between their beta-barrel and four-helix bundle domains. The STAT4 N-terminal domain dimer can be docked onto this STAT5a core fragment dimer based on shape and charge complementarities. The separation of the dimeric arrangement, taking place upon activation and nuclear translocation of STAT5a, is demonstrated by fluorescence resonance energy transfer experiments in living cells.
Excessive accumulation of the extracellular matrix is a hallmark of many inflammatory and fibrotic diseases, including those of the kidney. This study addresses the question whether NO, in addition to inhibiting the expression of MMP-9, a prominent metalloprotease expressed by mesangial cells, additionally modulates expression of its endogenous inhibitor TIMP-1. We demonstrate that exogenous NO has no modulatory effect on the extracellular TIMP-1 content but strongly amplifies the early increase in cytokine-induced TIMP-1 mRNA and protein levels. We examined whether transforming growth factor beta (TGFbeta), a potent profibrotic cytokine, is involved in the regulation of NO-dependent TIMP-1 expression. Experiments utilizing a pan-specific neutralizing TGFbeta antibody demonstrate that the NO-induced amplification of TIMP-1 is mediated by extracellular TGFbeta. Mechanistically, NO causes a rapid increase in Smad-2 phosphorylation, which is abrogated by the addition of neutralizing TGFbeta antisera. Similarly, the NO-dependent increase in Smad-2 phosphorylation is prevented in the presence of an inhibitor of TGFbeta-RI kinase, indicating that the NO-dependent activation of Smad-2 occurs via the TGFbeta-type I receptor. Furthermore, activation of the Smad signaling cascade by NO is corroborated by the NO-dependent increase in nuclear Smad-4 level and is paralleled by increased DNA binding of Smad-2/3 containing complexes to a TIMP-1-specific Smad-binding element (SBE). Reporter gene assays revealed that NO activates a 0.6-kb TIMP-1 gene promoter fragment as well as a TGFbeta-inducible and SBE-driven control promoter. Chromatin immunoprecipitation analysis also demonstrated DNA binding activity of Smad-3 and Smad-4 proteins to the TIMP-1-specific SBE. Finally, by enzyme-linked immunosorbent assay, we demonstrated that NO causes a rapid increase in TGFbeta(1) levels in cell supernatants. Together, these experiments demonstrate that NO by induction of the Smad signaling pathway modulates TIMP-1 expression.
5-Lipoxygenase (5-LO) catalysis is positively regulated by Ca2+ ions and phospholipids that both act via the N-terminal C2-like domain of 5-LO. Previously, we have shown that 1-oleoyl-2-acetylglycerol (OAG) functions as an agonist for human polymorphonuclear leukocytes (PMNL) in stimulating 5-LO product formation. Here we have demonstrated that OAG directly stimulates 5-LO catalysis in vitro. In the absence of Ca2+ (chelated using EDTA), OAG strongly and concentration-dependently stimulated crude 5-LO in 100,000 x g supernatants as well as purified 5-LO enzyme from PMNL. Also, the monoglyceride 1-O-oleyl-rac-glycerol and 1,2-dioctanoyl-sn-glycerol were effective, whereas various phospholipids did not stimulate 5-LO. However, in the presence of Ca2+, OAG caused no stimulation of 5-LO. Also, phospholipids or cellular membranes abolished the effects of OAG. As found previously for Ca2+, OAG renders 5-LO activity resistant against inhibition by glutathione peroxidase activity, and this effect of OAG is reversed by phospholipids. Intriguingly, a 5-LO mutant lacking tryptophan residues (Trp-13, -75, and -102) important for the binding of the 5-LO C2-like domain to phospholipids was not stimulated by OAG. We conclude that OAG directly stimulates 5-LO by acting at a phospholipid binding site located within the C2-like domain.
LIN-2/7 (L27) domains are protein interaction modules that preferentially hetero-oligomerize, a property critical for their function in directing specific assembly of supramolecular signaling complexes at synapses and other polarized cell-cell junctions. We have solved the solution structure of the heterodimer composed of the L27 domains from LIN-2 and LIN-7. Comparison of this structure with other L27 domain structures has allowed us to formulate a general model for why most L27 domains form an obligate heterodimer complex. L27 domains can be divided in two types (A and B), with each heterodimer comprising an A/B pair. We have identified two keystone positions that play a central role in discrimination. The residues at these positions are energetically acceptable in the context of an A/B heterodimer, but would lead to packing defects or electrostatic repulsion in the context of A/A and B/B homodimers. As predicted by the model, mutations of keystone residues stabilize normally strongly disfavored homodimers. Thus, L27 domains are specifically optimized to avoid homodimeric interactions.
The tumor necrosis factor family member Fas ligand (FasL) induces apoptosis in Fas receptor-expressing target cells and is an important cytotoxic effector molecule used by CTL- and NK-cells. In these hematopoietic cells, newly synthesized FasL is stored in specialized secretory lysosomes and only delivered to the cell surface upon activation and target cell recognition. FasL contains an 80-amino acid-long cytoplasmic tail, which includes a proline-rich domain as a bona fide Src homology 3 domain-binding site. This proline-rich domain has been implicated in FasL sorting to secretory lysosomes, and it may also be important for reverse signaling via FasL, which has been described to influence T-cell activation. Here we report the identification of the Src homology 3 domain-containing adaptor protein PSTPIP as a FasL-interacting partner, which binds to the proline-rich domain. PSTPIP co-expression leads to an increased intracellular localization of Fas ligand, thereby regulating extracellular availability and cytotoxic activity of the molecule. In addition, we demonstrate recruitment of the tyrosine phosphatase PTP-PEST by PSTPIP into FasL·PSTPIP·PTP-PEST complexes which may contribute to FasL reverse signaling.
During the last 15 years most central and east european countries faced an era of institutional, economic and demographic transition. With the fall of the wall and the end of the Soviet Union, the former socialist countries transformed their political, economic and social institutions; today, some of them are already a member state of the European Union. The re- unificated Germany was not only affected by this process in its eastern part, the former German Democratic Republic (GDR), where the political and institutional structures were entirely exchanged; with the end of the “Rheinische Bundesrepublik”, the incarnation of a welfare and growth oriented Fordist society, also former West Germany had to adapt to this transition and still is facing a process of institutional modernisation.
Mechanical stress is known to modulate fundamental events such as cell life and death. Mechanical stretch in particular has been identified as a positive regulator of proliferation in skin keratinocytes and other cell systems. In the present study it was investigated whether antiapoptotic signaling is also stimulated by mechanical stretch. It was demonstrated that mechanical stretch rapidly induced the phosphorylation of the proto-oncogene protein kinase B (PKB)/Akt at both phosphorylation sites (serine 473/threonine 308) in different epithelial cells (HaCaT, A-431, and human embryonic kidney-293). Blocking of phosphoinositide 3-OH kinase by selective inhibitors (LY-294002 and wortmannin) abrogated the stretch-induced PKB/Akt phosphorylation. Furthermore mechanical stretch stimulated phosphorylation of epidermal growth factor receptor (EGFR) and the formation of EGFR membrane clusters. Functional blocking of EGFR phosphorylation by either selective inhibitors (AG1478 and PD168393) or dominant-negative expression suppressed stretch-induced PKB/Akt phosphorylation. Finally, the angiotensin II type 1 receptor (AT1-R) was shown to induce positive transactivation of EGFR in response to cell stretch. These findings define a novel signaling pathway of mechanical stretch, namely the activation of PKB/Akt by transactivation of EGFR via angiotensin II type 1 receptor. Evidence is provided that stretch-induced activation of PKB/Akt protects cells against induced apoptosis.
Soluble guanylyl cyclase (sGC) is the major cytosolic receptor for nitric oxide (NO) that converts GTP into the second messenger cGMP in a NO-dependent manner. Other factors controlling this key enzyme are intracellular proteins such as Hsp90 and PSD95, which bind to sGC and modulate its activity, stability, and localization. To date little is known about the effects of posttranslational modifications of sGC, although circumstantial evidence suggests that reversible phosphorylation may contribute to sGC regulation. Here we demonstrate that inhibitors of protein-tyrosine phosphatases such as pervanadate and bisperoxo(1,10-phenanthroline)oxovanadate(V) as well as reactive oxygen species such as H2O2 induce specific tyrosine phosphorylation of the β1 but not of the α1 subunit of sGC. Tyrosine phosphorylation of sGCβ1 is also inducible by pervanadate and H2O2 in intact PC12 cells, rat aortic smooth muscle cells, and in rat aortic tissues, indicating that tyrosine phosphorylation of sGC may also occur in vivo. We have mapped the major tyrosine phosphorylation site to position 192 of β1, where it forms part of a highly acidic phospho-acceptor site for Src-like kinases. In the phosphorylated state Tyr(P)-192 exposes a docking site for SH2 domains and efficiently recruits Src and Fyn to sGCβ1, thereby promoting multiple phosphorylation of the enzyme. Our results demonstrate that sGC is subject to tyrosine phosphorylation and interaction with Src-like kinases, revealing an unexpected cross-talk between the NO/cGMP and tyrosine kinase signaling pathways at the level of sGC.
Cathepsin D (CatD) is a lysosomal aspartic proteinase and plays an important role in the degradation of proteins and in apoptotic processes induced by oxidative stress, cytokines, and aging. All of these stimuli are potent inducers of endothelial cell apoptosis. Therefore, we investigated the role of CatD in endothelial cell apoptosis and determined the underlying mechanisms. Incubation with 100-500 microm H2O2 for 12 h induced apoptosis in endothelial cells. To determine a role for CatD, we co-incubated endothelial cells with the CatD inhibitor pepstatin A. Pepstatin A as well as genetic knock down of CatD abolished H2O2-induced apoptosis. In contrast, overexpression of CatD wild type but not a catalytically inactive mutant of CatD (CatDD295N) induced apoptosis under basal conditions. To gain insights into the underlying mechanisms, we investigated the effect of CatD on reactive oxygen species (ROS) formation. Indeed, knocking down CatD expression reduced H2O2-induced ROS formation and apoptosis. The major redox regulator in endothelial cells is thioredoxin-1 (Trx), which plays a crucial role in apoptosis inhibition. Thus, we hypothesized that CatD may alter Trx protein levels and thereby promote formation of ROS and apoptosis. Incubation with 100 microm H2O2 for 6 h decreased Trx protein levels, whereas Trx mRNA was not altered. H2O2-induced Trx degradation was inhibited by pepstatin A and genetic knock down of CatD but not by other protease inhibitors. Incubation of unstimulated cell lysates with recombinant CatD significantly reduced Trx protein levels in vitro, which was completely blocked by pepstatin A pre-incubation. Overexpression of CatD reduced Trx protein in cells. Moreover, H2O2 incubation led to a translocation of Trx to the lysosomes prior to the induction of apoptosis. Taken together, CatD induces apoptosis via degradation of Trx protein, which is an essential anti-apoptotic and reactive oxygen species scavenging protein in endothelial cells.
Human endothelial circulating progenitor cells (CPCs) can differentiate to cardiomyogenic cells during co-culture with neonatal rat cardiomyocytes. Wnt proteins induce myogenic specification and cardiac myogenesis. Here, we elucidated the effect of Wnts on differentiation of CPCs to cardiomyogenic cells. CPCs from peripheral blood mononuclear cells were isolated from healthy volunteers and co-cultured with neonatal rat cardiomyocytes. 6–10 days after co-culture, cardiac differentiation was determined by α-sarcomeric actinin staining of human lymphocyte antigen-positive cells (fluorescence-activated cell-sorting analysis) and mRNA expression of human myosin heavy chain and atrial natriuretic peptide. Supplementation of co-cultures with Wnt11-conditioned medium significantly enhanced the differentiation of CPCs to cardiomyocytes (1.7 ± 0.3-fold), whereas Wnt3A-conditioned medium showed no effect. Cell fusion was not affected by Wnt11-conditioned medium. Because Wnts inhibit glycogen synthase kinase-3β, we further determined whether the glycogen synthase kinase-3β inhibitor LiCl also enhanced cardiac differentiation of CPCs. However, LiCl (10 mm) did not affect CPC differentiation. In contrast, Wnt11-conditioned medium time-dependently activated protein kinase C (PKC). Moreover, the PKC inhibitors bisindolylmaleimide I and III significantly blocked differentiation of CPCs to cardiomyocytes. PKC activation by phorbol 12-myristate 13-acetate significantly increased CPC differentiation to a similar extent as compared with Wnt11-conditioned medium. Our data demonstrate that Wnt11, but not Wnt3A, augments cardiomyogenic differentiation of human CPCs. Wnt11 promotes cardiac differentiation via the non-canonical PKC-dependent signaling pathway.
Within the ADD-model, we elaborate an idea by Vacavant and Hinchliffe [J. Phys. G 27 (2001) 1839] and show quantitatively how to determine the fundamental scale of TeV-gravity and the number of compactified extra dimensions from data at LHC. We demonstrate that the ADD-model leads to strong correlations between the missing ET in gravitons at different center of mass energies. This correlation puts strong constraints on this model for extra dimensions, if probed at s=5.5 TeV and s=14 TeV at LHC.
The kaon nuclear optical potential is studied including the effect of the Θ+ pentaquark. The one-nucleon contribution is obtained using an extension of the Jülich meson-exchange potential as bare kaon–nucleon interaction. Significant differences between a fully self-consistent calculation and the usually employed low-density Tρ approach are observed. The influence of the one-nucleon absorption process, KN→Θ+, on the kaon optical potential is negligible due to the small width of the pentaquark. In contrast, the two-nucleon mechanism, KNN→Θ+N, estimated from the coupling of the pentaquark to a two-meson cloud, provides the required amount of additional kaon absorption to reconcile with data the systematically low K+-nucleus reaction cross sections found by the theoretical models.
We solve the coupled Wong Yang–Mills equations for both U(1) and SU(2) gauge groups and anisotropic particle momentum distributions numerically on a lattice. For weak fields with initial energy density much smaller than that of the particles we confirm the existence of plasma instabilities and of exponential growth of the fields which has been discussed previously. Also, the SU(2) case is qualitatively similar to U(1), and we do find significant “abelianization” of the non-Abelian fields during the period of exponential growth. However, the effect nearly disappears when the fields are strong. This is because of the very rapid isotropization of the particle momenta by deflection in a strong field on time scales comparable to that for the development of Yang–Mills instabilities. This mechanism for isotropization may lead to smaller entropy increase than collisions and multiplication of hard gluons, which is interesting for the phenomenology of high-energy heavy-ion collisions.
Large extra dimensions could lower the Planck scale to experimentally accessible values. Not only is the Planck scale the energy scale at which effects of modified gravity become important. The Planck length also acts as a minimal length in nature, providing a natural ultraviolet cutoff and a limit to the possible resolution of spacetime.
In this Letter we examine the influence of the minimal length on the Casimir energy between two plates.
Alternative NADH dehydrogenases (NADH:ubiquinone oxidoreductases) are single subunit respiratory chain enzymes found in plant and fungal mitochondria and in many bacteria. It is unclear how these peripheral membrane proteins interact with their hydrophobic substrate ubiquinone. Known inhibitors of alternative NADH dehydrogenases bind with rather low affinities. We have identified 1-hydroxy-2-dodecyl-4(1H)quinolone as a high affinity inhibitor of alternative NADH dehydrogenase from Yarrowia lipolytica. Using this compound, we have analyzed the bisubstrate and inhibition kinetics for NADH and decylubiquinone. We found that the kinetics of alternative NADH dehydrogenase follow a ping-pong mechanism. This suggests that NADH and the ubiquinone headgroup interact with the same binding pocket in an alternating fashion.
Generation of reactive oxygen species (ROS) is increasingly recognized as an important cellular process involved in numerous physiological and pathophysiological processes. Complex I (NADH:ubiquinone oxidoreductase) is considered as one of the major sources of ROS within mitochondria. Yet, the exact site and mechanism of superoxide production by this large membrane-bound multiprotein complex has remained controversial. Here we show that isolated complex I from Yarrowia lipolytica forms superoxide at a rate of 0.15% of the rate measured for catalytic turnover. Superoxide production is not inhibited by ubiquinone analogous inhibitors. Because mutant complex I lacking a detectable iron-sulfur cluster N2 exhibited the same rate of ROS production, this terminal redox center could be excluded as a source of electrons. From the effect of different ubiquinone derivatives and pH on this side reaction of complex I we concluded that oxygen accepts electrons from FMNH or FMN semiquinone either directly or via more hydrophilic ubiquinone derivatives.
The transporter associated with antigen processing (TAP)-like (TAPL, ABCB9) belongs to the ATP-binding cassette transporter family, which translocates a vast variety of solutes across membranes. The function of this half-size transporter has not yet been determined. Here, we show that TAPL forms a homodimeric complex, which translocates peptides across the membrane. Peptide transport strictly requires ATP hydrolysis. The transport follows Michaelis-Menten kinetics with low affinity and high capacity. Different nucleotides bind and energize the transport with a slight predilection for purine bases. The peptide specificity is very broad, ranging from 6-mer up to at least 59-mer peptides with a preference for 23-mers. Peptides are recognized via their backbone, including the free N and C termini as well as side chain interactions. Although related to TAP, TAPL is unique as far as its interaction partners, transport properties, and substrate specificities are concerned, thus excluding that TAPL is part of the peptide-loading complex in the classic route of antigen processing via major histocompatibility complex class I molecules.
IAD annual report 2004/05
(2005)
What is the objective or purpose of business Management? According to the dominant theory of contemporary financial management scholarship, agency theory, business managers are obligated to maximise owner or shareholder value. According to most theories of business ethics, however, some owner-value-maximising actions should not be performed, because they would be unethical. Because business management scholars and business ethics scholars have not resolved this contradiction, students of commerce receive a contradictory education. The twenty-five essays in this interdisciplinary, international volume address the question of the objective or purpose of business management from a wide range of theoretical perspectives. Since some of the writers contradict one another, it is not possible that all of them are correct. Nevertheless, the fact that many of them argue persuasively that business managers should aspire to more than maximisation of a financial variable challenges everyone with a theoretical or practical interest in commerce to reconsider acceptance of the owner-value paradigm and to develop a richer conception of the profession of business management.
This book brings together multiple voices and positions from Africa. These voices, assembled during a 2003 Soap Summit held in Nairobi, are powerful and varied and suggest ways in which issues of health could be tackled in an entertaining manner. The summit organised by Population Communications International - Africa. highlighted the critical role that the arts can play in ensuring better health, especially among the youth. It resulted from the recognition that young people in Africa are faced with a myriad of problems and complications as they struggle to deal with growth and identity formation, within a globalising social and economic setup. They are in dire need of information on their own sexuality and how to deal with it and are getting conflicting signals from the mass media, as well as their immediate environment. The youth are under intense pressure from their peers to engage in premarital sex, which is in most cases unprotected. The HIV/AIDS epidemic presents frightening challenges and all health programs should look for ways of dealing with it. Of great to concern is the vulnerability of women and girls in Africa due to rising poverty, gender violence, lack of access to youth-friendly reproductive health facilities, and lack of a conducive infrastructure especially in informal settlements and in the rural areas. The myriad problems presented by the pandemic require a multi-sectoral approach. This book brings together a number of strategies being undertaken in Africa that combine entertainment and education in a positive way. The voices from the Soap Summit are interspersed with those of the Editor to create a dialogue on entertainment-education that contributes to the discussion on the way social change might be undertaken.
Chairman of Fools
(2005)
Chairman of Fools explores the plight of Farai Chari, a supposedly successful writer, professor and self-acclaimed artist, living in an African culture in which tradition weighs heavy and middle class aspirations are crude. Farai yearns for a world in which men and women can freely associate with one another and gratify their passions without moral chastisement.
The sequel to the award-winning Writing Still, this new collection of stories paints an engaging - and sometimes challenging - picture of contemporary life and concerns in Zimbabwe. Like its predecessor, Writing Now combines well-established writers - Chinodya, Mupfudzi, Eppel, Chingono - with several new voices. Although the stories emerge from lives of economic hardship and privation, their tone is by no means uniformly. Zimbabwean writers continue to demonstrate that sharp humour and surreal fantasy can grow from the bleakest of roots.
Zimbabwe's Cultural Heritage
(2005)
' Zimbabwe's Cultural Heritage won first prize in the Zimbabwe Book Publishers Association Awards in 2006 for Non-fiction: Humanities and Social Sciences. It is a collection of pieces of the culture of the Ndebele, Shona, Tonga, Kalanga, Nambiya, Xhosa and Venda. The book gives the reader an insight into the world view of different peoples, through descriptions of their history and life events such as pregnancy, marriage and death. ''...the most enduring book ever on Zimbabwean history. This book will help people change their attitude towards each other in Zimbabwe.'' - Zimbabwe Book Publishers Association Awards citation'
Short Writings from Bulawayo won the Literature in English category at the 2005 Zimbabwe Book Publishers Association awards. It is a book of stories, poems and non-fiction pieces that are evocative of Zimbabwe's second city and its rural surroundings. The collection from 23 contributors tells of many things: of family and friendship, or fear and death, or witches and spirits, of hunger and drought, of dreams and aspirations, of leaving home and leaving Zimbabwe, of queues and loneliness, of football and bicycles and of growing old and of love. A unifying theme of many of the stories and poems is loss - of innocence, of purpose, of love, of culture, of belonging, and of life.
Elderly people still play a minor role in research on information needs and usage patterns of Internet users. Online research and advocacy groups look optimistically at the (economic and social) potential of the active and technology–skilled elderly; other approaches dealing with the social appropriation of technology see obstacles and stress the dangers of an increasing digital divide between generations. Our objective is to refer to taken for granted normative assumptions of the digital divide discourse, highlighting different requirements for the appropriation of the Internet. Using the concept of technological generations we look at formal and informal learning of young and elderly people in the German context. We use survey material and field impressions we gained in various technology related studies. The results show that the "two worlds apart" assumption (young vs. elderly people) is too simplistic. Factors like gender, education and socio–economic status still play an important role for acceptance and diffusion of a technology. The diffusion rate among the elderly is increasing, but will continue to lag behind the figures of the young users. Cultural preparations and easy access modes are essential for the elderly, who could make use of latecomer advantages. Informal learning and peer group support will be crucial for the diffusion of the Internet among the elderly. In our conclusions we look at the specific social status of the elderly cohort, which makes a comparison with other social groups very difficult.
IN A CASE STUDY IN THE GERMAN RETAIL BANKING BUSINESS IT IS SHOWN THAT ALIGNMENT BETWEEN IT AND BUSINESS UNIT IS CRUCIAL FOR THE ACTUAL USAGE OF IT SYSTEMS WHICH IN TURN IS A KEY DRIVER FOR BUSINESS PROCESS QUALITY. BANKS SHOULD THEREFORE FOSTER INTERRELATIONSHIPS BETWEEN IT AND BUSINESS AS WELL AS CROSS FUNCTIONAL WORK BIOGRAPHIES OF TEAM LEADERS
INDUSTRIALIZATION TENDENCIES WITHIN THE CREDIT BUSINESS ARE IN PARTS BROADER SOPHISTICATED THAN WITHIN FINANCIAL PROCESSES OF OTHER INDUSTRIES. CREDIT PROCESS MANAGERS OF BANKS ESTIMATE ECONOMIES OF SCALE AND SKILL ACHIEVABLE BY OUTSOURCING TO BE HIGHER THAN CHIEF FINANCIAL OFFICERS OF NON-BANKS DO. FURTHERMORE, ECONOMIES OF SCOPE, WHICH INHIBIT SELECTIVE SOURCING, ARE EVALUATED AS LESS PROBLEMATIC.
Colorectal carcinoma (CRC) is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRCderived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth.
I propose that the rising number of dualearner couples in the United States impacts the trend toward declining residential mobility and rising commute times. I describe these mobility trends in the United States, first relocation trends and then daily commuting trends. My research views the commute as the bridge in time and space between home and work that a) reflects couples' negotiation of preferences, relative job importance, barriers, and opportunities; b) has consequences for family functioning, c) reflects gender differences in the ways time and place are organized, and d) varies across the life course, by race, class, and region. I describe differences in family type and family functioning based on the commuting pattern and suggest a course of future comparative research that may improve awareness of how families and couples handle labor market demands, what structures shape the picture of couples mobility, and how nation-specific circumstances orient couples toward certain kinds of mobility and away from others.
Chlorine monoxide (ClO) plays a key role in stratospheric ozone loss processes at midlatitudes. We present two balloon-borne in situ measurements of ClO conducted in northern hemisphere midlatitudes during the period of the maximum of total inorganic chlorine loading in the atmosphere. Both ClO measurements were conducted on board the TRIPLE balloon payload, launched in November 1996 in León, Spain, and in May 1999 in Aire sur l'Adour, France. For both flights a ClO daylight and night-time vertical profile was derived over an altitude range of approximately 15-35 km. ClO mixing ratios are compared to model simulations performed with the photochemical box model version of the Chemical Lagrangian Model of the Stratosphere (CLaMS). Simulations along 24-hour backward trajectories were performed to study the diurnal variation of ClO in the midlatitude lower stratosphere. Model simulations for the flight launched in Aire sur l'Adour 1999 show an excellent agreement with the ClO measurements. For the flight launched in León 1996, an overall good agreement is found, whereas the flight is characterized by a more complex dynamical situation due to a possible mixture of vortex and non-vortex air. We note that for both flights at solar zenith angles greater than 86°-87° simulated ClO mixing ratios are higher than observed ClO mixing ratios. However, the present findings indicate that no substantial uncertainties exist in midlatitude chlorine chemistry of the stratosphere.
We determine optimal monetary policy under commitment in a forwardlooking New Keynesian model when nominal interest rates are bounded below by zero. The lower bound represents an occasionally binding constraint that causes the model and optimal policy to be nonlinear. A calibration to the U.S. economy suggests that policy should reduce nominal interest rates more aggressively than suggested by a model without lower bound. Rational agents anticipate the possibility of reaching the lower bound in the future and this amplifies the effects of adverse shocks well before the bound is reached. While the empirical magnitude of U.S. mark-up shocks seems too small to entail zero nominal interest rates, shocks affecting the natural real interest rate plausibly lead to a binding lower bound. Under optimal policy, however, this occurs quite infrequently and does not imply positive average inflation rates in equilibrium. Interestingly, the presence of binding real rate shocks alters the policy response to (non-binding) mark-up shocks.
The effects of public policy programmes which aim at internalising spill-overs due to successful innovation are analysed in a sequential double-sided moral hazard double-sided adverse selection framework. The central focus lies in analysing their impact on contract design. We show that in our framework only ex post grants are a robust instrument for implementing the first-best situation, whereas the success of guarantee programmes, ex ante grants and some public-private partnerships depends strongly on the characteristics of the project: in certain cases they not only give no further incentives but even destroy contract mechanisms and so worsen the outcome.
The effects of public policy programmes which aim at internalising spill-overs due to successful innovation are analysed in a sequential double-sided moral hazard double-sided adverse selection framework. The central focus lies in analysing their impact on contract design. We show that in our framework only ex post grants are a robust instrument for implementing the first-best situation, whereas the success of guarantee programmes, ex ante grants and some public-private partnerships depends strongly on the characteristics of the project: in certain cases they not only give no further incentives but even destroy contract mechanisms and so worsen the outcome.
The NO/cGMP pathway inhibits Rap1 activation in human platelets via cGMP-dependent protein kinase I
(2005)
The NO/cGMP signalling pathway strongly inhibits agonist-induced platelet aggregation. However, the molecular mechanisms involved are not completely defined.We have studied NO/cGMP effects on the activity of Rap1, an abundant guanine-nucleotidebinding protein in platelets. Rap1-GTP levels were reduced by NO-donors and activators of NO-sensitive soluble guanylyl cyclase. Four lines of evidence suggest that NO/cGMP effects are mediated by cGMP-dependent protein kinase (cGKI): (i) Rap1 inhibition correlated with cGKI activity as measured by the phosphorylation state ofVASP, an established substrate of cGKI, (ii) 8-pCPT-cGMP, a membrane permeable cGMP-analog and activator of cGKI, completely blocked Rap1 activation, (iii) Rp- 8pCPT-cGMPS, a cGKI inhibitor, reversed NO effects and (iv) expression of cGKI in cGKI-deficient megakaryocytes inhibited Rap1 activation. NO/cGMP/cGKI effects were independent of the type of stimulus used for Rap1 activation.Thrombin-,ADPand collagen-induced formation of Rap1-GTP in platelets as well as turbulence-induced Rap1 activation in megakaryocytes were inhibited. Furthermore, cGKI inhibited ADP-induced Rap1 activation induced by the G a i -coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling. From these studies we conclude that NO/cGMP inhibit Rap1 activation in human platelets and that this effect is mediated by cGKI. Since Rap1 controls the function of integrin a IIbß 3 , we propose that Rap1 inhibition might play a central role in the anti-aggregatory actions of NO/cGMP.
Low- dimensional and speaker-independent linear vocal tract parametrizations can be obtained using the 3-mode PARAFAC factor analysis procedure first introduced by Harshman et al. (1977) and discussed in a series of subsequent papers in the Journal of the Acoustical Society of America (Jackson (1988), Nix et al. (1996), Hoole (1999), Zheng et al. (2003)). Nevertheless, some questions of importance have been left unanswered, e.g. none of the papers using this method has provided a consistent interpretation of the terms usually referred to as "speaker weights". This study attempts an exploration of what influences their reliability as a first step towards their consistent interpretation. With this in mind, we undertook a systematic comparison of the classical PARAFAC1 algorithm with a relaxed version, of it, PARAFAC2. This comparison was carried out on two different corpora acquired by the articulograph, which varied in vowel qualities, consonantal contexts, and the paralinguistic features accent and speech rate. The difference between these statistical approaches can grossly be described as follows: In PARAFAC1, observation units pertain to the same set of variables and the observation units are comparable. In PARAFAC2, observations pertain to the same set of variables, but observation units are not comparable. Such a situation can be easily conceived in a situation such as we are describing: The operationalization we took relies on the comparability of fleshpoint data acquired from different speakers, which need not be a good assumption due to influences like sensor placement and morphological conditions.
In particular, the comparison between the two different approaches is carried out by means of so-called "leverages" on different component matrices originating in regression analysis, calculated as v = diag(A(A A)−1A ) and delivering information on how "influential" a particular loading matrix is for the model. This analysis could potentially be carried out component by component, but we confined ourselves to effects on the global factor structure. For vowels, the most influential loadings are those for the tense cognates of non-palatal vowels. For speakers, the most prominent result is the relative absence of effects of the paralinguistic variables. Results generally indicate that there is quite little influence of the model specification (i.e. PARAFAC1 or PARAFAC2) on vowel and subject components. The patterns for the articulators indicate that there are strong differences between speakers with respect to the most influential measurement as revealed by PARAFAC2: In particular, the most influential y-contribution is the tongue-back for some talkers and the tongue-dorsum for other speakers. With respect to the speaker weights, again, the leverage patterns are very similar for both PARAFAC-versions. These patterns converge with the results of the loading plots, where the articulator profiles seem to be most altered by the use of PARAFAC2. These findings, in general, are interpreted as evidence for the reliability of the PARAFAC1 speaker weights.
This work investigates laryngeal and supralaryngeal correlates of the voicing contrast in alveolar obstruent production in German. It further studies laryngealoral co-ordination observed for such productions. Three different positions of the obstruents are taken into account: the stressed, syllable initial position, the post-stressed intervocalic position, and the post-stressed word final position. For the latter the phonological rule of final devoicing applies in German. The different positions are chosen in order to study the following hypotheses:
1. The presence/absence of glottal opening is not a consistent correlate of the voicing contrast in German.
2. Supralaryngeal correlates are also involved in the contrast.
3. Supralaryngeal correlates can compensate for the lack of distinction in laryngeal adjustment.
Including the word final position is motivated by the question whether neutralization in word final position would be complete or whether some articulatory residue of the contrast can be found.
Two experiments are carried out. The first experiment investigates glottal abduction in co-ordination with tongue-palate contact patterns by means of simultaneous recordings of transillumination, fiberoptic films and Electropalatography (EPG). The second experiment focuses on supralaryngeal correlates of alveolar stops studied by means of Electromagnetic Articulography (EMA) simultaneously with EPG. Three German native speakers participated in both recordings. Results of this study provide evidence that the first hypothesis holds true for alveolar stops when different positions are taken into account. In fricative production it is also confirmed since voiceless and voiced fricatives are most of the time realised with glottal abduction. Additionally, supralaryngeal correlates are involved in the voicing contrast under two perspectives. First, laryngeal and supralaryngeal movements are well synchronised in voiceless obstruent production, particularly in the stressed position. Second, supralaryngeal correlates occur especially in the post-stressed intervocalic position. Results are discussed with respect to the phonetics-phonology interface, to the role of timing and its possible control, to the interarticulatory co-ordination, and to stress as 'localised hyperarticulation'.
This special issue of the ZAS Papers in Linguistics contains a collection of papers of the French-German Thematic Summerschool on "Cognitive and physical models of speech production, and speech perception and of their interaction".
Organized by Susanne Fuchs (ZAS Berlin), Jonathan Harrington (IPdS Kiel), Pascal Perrier (ICP Grenoble) and Bernd Pompino-Marschall (HUB and ZAS Berlin) and funded by the German-French University in Saarbrücken this summerschool was held from September 19th till 24th 2004 at the coast of the Baltic Sea at the Heimvolkshochschule Lubmin (Germany) with 45 participants from Germany, France, Great Britain, Italy and Canada. The scientific program of this summerschool that is reprinted at the end of this volume included 11 key-note presentations by invited speakers, 21 oral presentations and a poster session (8 presentations). The names and addresses of all participants are also given in the back matter of this volume.
All participants was offered the opportunity to publish an extended version of their presentation in the ZAS Papers in Linguistics. All submitted papers underwent a review and an editing procedure by external experts and the organizers of the summerschool. As it is the case in a summerschool, papers present either works in progress, or works at a more advanced stage, or tutorials. They are ordered alphabetically by their first author's name, fortunately resulting in the fact that this special issue starts out with the paper that won the award as best pre-doctoral presentation, i.e. Sophie Dupont, Jérôme Aubin and Lucie Ménard with "A study of the McGurk effect in 4 and 5-year-old French Canadian children".
A guide to bryological hotspots in Europe : [Part 2: The Rur Valley, Eifel Mountains, Germany]
(2005)
The Rur valley is situated in the extreme west of Germany in the western part of the Eifel Mountains, close to the Belgian border. The Rur valley harbours several interesting, mainly bryopyhtes. Most of the interesting species are aquatic species. Very obvious is the oceanic element, which is represented by species such as Platyhypnidium lusitanicum, Hyocomium arnoricum, and Isothecium holtii.
This paper shows that a capital budgeting process in which the division manager is required to engage in personally costly influence activities prior to a project approval has beneficial incentive effects: It provides the manager with incentives to acquire costly information about project prospects and helps to elicit the revelation of the acquired information. As a consequence, imposing influence costs on the manager can lead to improved capital allocations. The optimal level of influence costs, chosen by the firm, trades off ex ante incentives for information acquisition against efficient use of the acquired information ex post.
The ecological and faunistic research of Odonata in Ukraine has been based on three main pillars. The first are investigations of species composition, habitat preferences, trophic connections, parasites and predators, behaviour patterns, and morphological and physiological peculiarities of dragonflies by expert-odonatologists. The second pillar is the collection and identification of adults for the survey of animals from different regions, especially rare and endangered species for the Red Lists and Red Data Book. Thirdly, there is the study of Odonata larvae as components of freshwater ecosystems, particularly as food of fish.
Some present Ukrainian regions belonged to Poland, Hungary, Slovakia and Romania before 1939-1945. Odonatological investigations were held up during the Second World War and the 12 years of post-war rebuilding.
The first data on Ukrainian Odonata were published in the second part of the 19th century (Belke, 1859, 1866). Since then, several Ukrainian, Russian, Polish, Hungarian and Romanian scientists have made great contributions to the investigation of the odonate fauna and ecology. One of the most famous odonatologists, J. Dziêdzielewicz, worked in the western Ukraine from the end of the 19th to the early 20th century. At the same time G. Artobolevs’ky investigated the northern and central parts of Ukraine and the Crimea peninsula. A. Brauner and A. Bartenev carried out research in the southern Ukraine and Crimea.
R. Pavlyuk continued research in the western region of Ukraine. He carried out faunistic, ecological and parasitological investigations. A. Oliger studied faunistic and ecological aspects of dragonflies in the easternmost part of the Ukraine (Donets’k region). Recently, S. Gorb published many papers devoted to the functional morphology of dragonflies. He also provided a study of the species composition and ecological peculiarities of Odonata in northern Ukraine and a catalogue of the Ukrainian species. Today, several odonatologists are actively involved in odonatological research in Ukraine. N. Mathuskina works on the functional morphology of the ovipositor and dragonfly behaviour, L. Khrokalo on faunistics and ecology in the northeastern Ukraine and on aspects of nature conservation, O. Dyatlova on the faunistics in the southwest of the country and some aspects of morphology and behaviour. A. Martynov studies the faunistics in the eastern part of Ukraine.
The odonate fauna of Papua New Guinea (PNG) is species rich but poorly studied. Geographic ranges, ecology, and thus conservation status of many species are unknown. In this study I provide an inventory of two sites within the largest formally protected forest area in PNG, the Crater Mountain Wildlife Management Area. I sampled odonates for a total of 112 days in a pristine forest site and for 36 days in a traditional garden village, and worked with local communities to increase the awareness of dragonflies in the area. I found a total of 78 species (60 Zygoptera, 18 Anisoptera) from 13 families, including at least six currently undescribed species.
The pristine rainforest hosted more species (61) than the village (37), and a longer sampling period was required to reach an approximately equal level of the total species richness. I calculated species accumulation curves for both areas and found that 100 sampling days were required in the pristine forest, whereas 35 sampling days appeared sufficient in the modified forest. More than two-thirds of all species recorded in the pristine forest were observed in less than half of all the sampling sessions, indicating that species might be both rare and occur only during certain times of the year. The number of species recorded per sampling session indicated some seasonality in the odonate fauna of the pristine forest, which should be considered in future studies. The study suggests that modification of tropical rainforests will lead to a loss of species richness. Conservation of odonates in PNG is therefore dependent on the preservation of primary rainforests, which requires the education of native people living in these areas. Dragonflies were well known among local people inhabiting the study area, but did not play a major role in their culture. More work on dragonflies is needed to describe the diversity of the PNG odonate fauna.
A new version of a digital global map of irrigation areas was developed by combining irrigation statistics for 10825 sub-national statistical units and geo-spatial information on the location and extent of irrigation schemes. The map shows the percentage of each 5 arc minute by 5 arc minute cell that was equipped for irrigation around the year 2000. It is thus an important data set for global studies related to water and land use. This paper describes the data set and the mapping methodology and gives, for the first time, an estimate of the map quality at the scale of countries, world regions and the globe. Two indicators of map quality were developed for this purpose, and the map was compared to irrigated areas as derived from two remote sensing based global land cover inventories. We plan to further improve that data set; therefore comments, information and data that might contribute to that effort are highly welcome.
Since the fall of the Wall, a new era of East German literature has emerged. This genre of literature exists even though East Germany’s borders dissolved over a decade and half ago and is challenging the way we think about the former German Democratic Republic. East German author Thomas Brussig is pivotal in this new genre of literature. His novels Helden wie wir (1995), Am kürzeren Ende der Sonnenallee (1999) and Leander Haußmann’s cinematic adaptation, Sonnenallee (1999), confront the negative associations and stereotypes connected with East Germany to deconstruct how formal history has portrayed its past and its citizens. Brussig’s texts take a completely different approach to remembering the GDR, which simultaneously challenges history’s dominant perspective as well as the Ostalgie phenomenon. Through his texts’ recollection, Brussig subverts the East German state in hindsight and begins the construction of a new mythology with which to associate former East Germany.
We determine that the continuous-state branching processes for which the genealogy, suitably time-changed, can be described by an autonomous Markov process are precisely those arising from $\alpha$-stable branching mechanisms. The random ancestral partition is then a time-changed $\Lambda$-coalescent, where $\Lambda$ is the Beta-distribution with parameters $2-\alpha$ and $\alpha$, and the time change is given by $Z^{1-\alpha}$, where $Z$ is the total population size. For $\alpha = 2$ (Feller's branching diffusion) and $\Lambda = \delta_0$ (Kingman's coalescent), this is in the spirit of (a non-spatial version of) Perkins' Disintegration Theorem. For $\alpha =1$ and $\Lambda$ the uniform distribution on $[0,1]$, this is the duality discovered by Bertoin & Le Gall (2000) between the norming of Neveu's continuous state branching process and the Bolthausen-Sznitman coalescent.
We present two approaches: one, exploiting the `modified lookdown construction', draws heavily on Donnelly & Kurtz (1999); the other is based on direct calculations with generators.
Antibody library technology represents a powerful tool for the discovery and design of antibodies with high affinity and specificity for their targets. To extend the technique to the expression and selection of antibody libraries in an eukaryotic environment, we provide here a proof of concept that retroviruses can be engineered for the display and selection of variable single-chain fragment (scFv) libraries. A retroviral library displaying the repertoire obtained after a single round of selection of a human synthetic scFv phage display library on laminin was generated. For selection, antigen-bound virus was efficiently recovered by an overlay with cells permissive for infection. This approach allowed more than 10(3)-fold enrichment of antigen binders in a single selection cycle. After three selection cycles, several scFvs were recovered showing similar laminin-binding activities but improved expression levels in mammalian cells as compared with a laminin-specific scFv selected by the conventional phage display approach. Thus, translational problems that occur when phage-selected antibodies have to be transferred onto mammalian expression systems to exert their therapeutic potential can be avoided by the use of retroviral display libraries.
It has been shown that visual cues play a crucial role in the perception of vowels and consonants. Conflicting consonantal stimuli presented in the visual and auditory modalities can even result in the emergence of a third perceptual unit (McGurk effect). From a developmental point of view, several studies report that newborns can associate the image of a face uttering a given vowel to the auditory signal corresponding to this vowel; visual cues are thus used by the newborns. Despite the large number of studies carried out with adult speakers and newborns, very little work has been conducted with preschool-aged children. This contribution is aimed at describing the use of auditory and visual cues by 4 and 5-year-old French Canadian speakers, compared to adult speakers, in the identification of voiced consonants. Audiovisual recordings of a French Canadian speaker uttering the sequences [aba], [ada], [aga], [ava], [ibi], [idi], [igi], [ivi] have been carried out. The acoustic and visual signals have been extracted and analysed so that conflicting and non-conflicting stimuli, between the two modalities, were obtained. The resulting stimuli were presented as a perceptual test to eight 4 and 5-year-old French Canadian speakers and ten adults in three conditions: visual-only, auditory-only, and audiovisual. Results show that, even though the visual cues have a significant effect on the identification of the stimuli for adults and children, children are less sensitive to visual cues in the audiovisual condition. Such results shed light on the role of multimodal perception in the emergence and the refinement of the phonological system in children.
In this paper the issue of the nature of the representations of the speech production task in the speaker's brain is addressed in a production-perception interaction framework. Since speech is produced to be perceived, it is hypothesized that its production is associated for the speaker with the generation of specific physical characteristics that are for the listeners the objects of speech perception. Hence, in the first part of the paper, four reference theories of speech perception are presented, in order to guide and to constrain the search for possible correlates of the speech production task in the physical space: the Acoustic Invariance Theory, the Adaptive Variability Theory, the Motor Theory and the Direct-Realist Theory. Possible interpretations of these theories in terms of representations of the speech production task are proposed and analyzed. In a second part, a few selected experimental studies are presented, which shed some light on this issue. In the conclusion, on the basis of the joint analysis of theoretical and experimental aspects presented in the paper, it is proposed that representations of the speech production task are multimodal, and that a hierarchy exists among the different modalities, the acoustic modality having the highest level of priority. It is also suggested that these representations are not associated with invariant characteristics, but with regions of the acoustic, orosensory and motor control spaces.
A fundamental question in the study of speech is about the invariance of the ultimate percepts, or features. The present paper gives an overview of the noninvariance problem and offers some hints towards a solution. Examination of various data on place and voicing perception suggests the following points. Features correspond to natural boundaries between sounds, which are included in the infant's predispositions for speech perception. Adult percepts arise from couplings and contextual interactions between features. Both couplings and interactions contribute to invariance. But this is at the expense of profound qualitative changes in perceptual boundaries implying that features are neither independently nor invariantly perceived. The question then is to understand the principles which guide feature couplings and interactions during perceptual development. The answer might reside in the fact that: (1) adult boundaries converge to a single point of the perceptual space, suggesting a context-free central reference; (2) this point corresponds to the neutral vocoïd, suggesting the reference is related to production; (3) at this point perceptual boundaries correspond to the natural ones, suggesting the reference is anchored in predispositions for feature perception. In sum, perceptual invariance seems to be grounded on a radial representation of the vocal tract around a singular point at which boundaries are context-fee, natural and coincide with the neutral vocoïd.
This paper presents the results of Open Quotient measurements in EGG signals of young (18 to 30 year old) and elderly (59 to 82 year old) male and female speakers. The paper further presents quantitative results on the relation between the OQ and the perception of a speaker's age. Higgins & Saxman (1991) found a decreased OQEGG with increasing age for females, whereas the OQEGG in sustained vowel material increased for males as the speakers age increased. In Linville (2002), however, the spectral amplitudes in the region of F0 (obtained by LTAS-measurements of read speech material) increased with increasing age independent of gender; this could be interpreted indirectly as an increasing OQ. We measured the OQEGG not only for sustained vowels, but also in vowels taken from isolated words. In order to analyse the relation between breathiness in terms of an increased OQ and the mean perceived age per stimulus a perception test was carried out in which listeners were asked to estimate speaker's age based on sustained /a/-vowel stimuli varying in vocal effort (soft - normal - loud) during production. The results indicated the following: (i) The decreased OQ for elderly females originally found by Higgins & Saxman is not apparent in our data for sustained /a/-vowels. For our female speakers no significant difference between the OQ of young and old speakers was found; for elderly males, however, we also found an increasing OQ with increasing age.(ii) In addition, a statistically significant increased OQEGG occurs for the group of the elderly males for the vowels from the word material. (iii) Our results show a strong positive relation between perceived age and OQ in male voices. Regarding (i) and (ii), at least the male speaker's voice becomes more breathy as age increases. Considering (iii), increased breathiness may contribute to the listener’s perception of increased age.
Studying kinematic behavior in speech production is an indispensable and fruitful methodology in order to describe for instance phonemic contrasts, allophonic variations, prosodic effects in articulatory movements. More intriguingly, it is also interpreted with respect to its underlying control mechanisms. Several interpretations have been borrowed from motor control studies of arm, eye, and limb movements. They do either explain kinematics with respect to a fine tuned control by the Central Nervous System (CNS) or they take into account a combination of influences arising from motor control strategies at the CNS level and from the complex physical properties of the peripheral speech apparatus. We assume that the latter is more realistic and ecological. The aims of this article are: first, to show, via a literature review related to the so called '1/3 power law' in human arm motor control, that this debate is of first importance in human motor control research in general. Second, to study a number of speech specific examples offering a fruitful framework to address this issue. However, it is also suggested that speech motor control differs from general motor control principles in the sense that it uses specific physical properties such as vocal tract limitations, aerodynamics and biomechanics in order to produce the relevant sounds. Third, experimental and modelling results are described supporting the idea that the three properties are crucial in shaping speech kinematics for selected speech phenomena. Hence, caution should be taken when interpreting kinematic results based on experimental data alone.
Syllable cut is said to be a phonologically distinctive feature in some languages where the difference in vowel quantity is accompanied by a difference in vowel quality like in German. There have been several attempts to find the corresponding phonetic correlates for syllable cut, from which the energy measurements of vowels by Spiekermann (2000) proved appropriate for explaining the difference between long, i.e. smoothly, and short, i.e. abruptly cut, vowels: in smoothly cut vowels, a larger number of peaks was counted in the energy contour which were located further back than in abruptly cut segments, and the overall energy was more constant throughout the entire nucleus. On this basis, we intended to compare German as a syllable cut language and Hungarian where the feature was not expected to be relevant. However, the phonetic correlates of syllable cut found in this study do not entirely confirm Spiekermann's results. It seems that the energy features of vowels are more strongly connected to their duration than to their quality.
This study reports on the results of an airflow experiment that measured the duration of airflow and the amount of air from release of a stop to the beginning of a following vowel in stop vowel-sequences of German. The sequences involved coronal, labial and velar voiced and voiceless stops followed by the vocoids /j, i:, ı, ɛ, ʊ, a/. The experiment tested the influence of the three factors voicing of stop, place of stop articulation, and the following vocoid context on the duration and amount of air as possible explanation for assibilation processes. The results show that the voiceless stops are related to a longer duration and more air in the release phase than voiced ones. For the influence of the vocoids, a significant difference could be established between /j/ and all other vocoids for the duration of the release phase. This difference could not be found for the amount of air over this duration. The place of articulation had only restricted influence. Velars resulted in significantly longer duration of the release phase compared to non-velars. A significant difference in amount of air between the places of articulation could not be found.
The present article is a follow-up study of the investigation of labiodentals in German and Dutch by Hamann & Sennema (2005), where we looked at the perception of the Dutch labiodental three-way contrast by German listeners without any knowledge of Dutch and German learners of Dutch. The results of this previous study suggested that the German voiced labiodental fricative /v/ is perceptually closer to the Dutch approximant /ʋ/ than to the corresponding Dutch voiced labiodental fricative /v/. These perceptual indications are attested by the acoustic findings in the present study. German /v/ has a similar harmonicity median and a similar centre of gravity to Dutch /ʋ/, but differs from Dutch /v/ in these parameters. With respect to the acoustic parameter of duration, German /v/ lies closer to the Dutch /v/ than to the Dutch /ʋ/.
(Non)retroflexivity of slavic affricates and its motivation : Evidence from polish and czech <č>
(2005)
The goal of this paper is two-fold. First, it revises the common assumption that the affricate <č> denotes /t͡ʃ/ for all Slavic languages. On the basis of experimental results it is shown that Slavic <č> stands for two sounds: /t͡ʃ/ as e.g. in Czech and /ʈʂ/ as in Polish.
The second goal of the paper is to show that this difference is not accidental but it is motivated by perceptual relations among sibilants. In Polish, /t͡ʃ/ changed to /ʈʂ/ thus lowering its sibilant tonality and creating a better perceptual distance to /tɕ/, whereas in Czech /t͡ʃ/ did not turn to /ʈʂ/, as the former displayed sufficient perceptual distance to the only affricate present in the inventory, namely, the alveolar /t͡s/. Finally, an analysis of Czech and Polish affricate inventories is offered.
While the perilinguistic child is endowed with predispositions for the categorical perception of phonetic features, their adaptation to the native language results from a long evolution from the end of the first year of age up to the adolescence. This evolution entails both a better discrimination between phonological categories, a concomitant reduction of the discrimination between within-category variants, and a higher precision of perceptual boundaries between categories. The first objective of the present study was to assess the relative importance of these modifications by comparing the perceptual performances of a group of 11 children, aged from 8 to 11 years, with those of their mothers. Our second objective was to explore the functional implications of categorical perception by comparing the performances of a group of 8 deaf children, equipped with a cochlear implant, with normal-hearing chronological age controls. The results showed that the categorical boundary was slightly more precise and that categorical perception was consistently larger in adults vs. normal-hearing children. Those among the deaf children who were able to discriminate minimal distinctions between syllables displayed categorical perception performances equivalent to those of normal-hearing controls. In conclusion, the late effect of age on the categorical perception of speech seems to be anchored in a fairly mature phonological system, as evidenced the fairly high precision of categorical boundaries in pre-adolescents. These late developments have functional implications for speech perception in difficult conditions as suggested by the relationship between categorical perception and speech intelligibility in cochlear implant children.
This paper describes the processing of MRI and CT images needed for developing a 3D linear articulatory model of velum. The 3D surface that defines each organ constitutive of the vocal and nasal tracts is extracted from MRI and CT images recorded on a subject uttering a corpus of artificially sustained French vowels and consonants. First, the 2D contours of the organs have been manually extracted from the corresponding images, expanded into 3D contours, and aligned in a common 3D coordinate system. Then, for each organ, a generic mesh has been chosen and fitted by elastic deformation to each of the 46 3D shapes of the corpus. This has finally resulted in a set of organ surfaces sampled with the same number of 3D vertices for each articulation, which is appropriate for Principal Component Analysis or linear decomposition. The analysis of these data has uncovered two main uncorrelated articulatory degrees of freedom for the velum's movement. The associated parameters are used to control the model. We have in particular investigated the question of a possible correlation between jaw / tongue and velum's movement and have not find more correlation than the one found in the corpus.
This paper contributes to the understanding of vocal folds oscillation during phonation. In order to test theoretical models of phonation, a new experimental set-up using a deformable vocal folds replica is presented. The replica is shown to be able to produce self sustained oscillations under controlled experimental conditions. Therefore different parameters, such as those related to elasticity, to acoustical coupling or to the subglottal pressure can be quantitatively studied. In this work we focused on the oscillation fundamental frequency and the upstream pressure in order to start (on-set threshold) either end (off-set threshold) oscillations in presence of a downstream acoustical resonator. As an example, it is shown how this data can be used in order to test the theoretical predictions of a simple one-mass model.
A visual articulatory model and its application to therapy
of speech disorders : a pilot study
(2005)
A visual articulatory model based on static MRI-data of isolated sounds and its application in therapy of speech disorders is described. The model is capable of generating video sequences of articulatory movements or still images of articulatory target positions within the midsagittal plane. On the basis of this model (1) a visual stimulation technique for the therapy of patients suffering from speech disorders and (2) a rating test for visual recognition of speech movements was developed. Results indicate that patients produce recognition rates above level of chance already without any training and that patients are capable of increasing their recognition rate over the time course of therapy significantly.
In order to investigate the articulatory processes of the hasty and mumbled speech of clutterers, the kinematic variability was analysed by means of electromagnetic midsagittal articulography (EMMA). In contrast to stutterers, clutterers improve their intelligibility by concentrating on their speech task. Variability is an important criterion in comparable studies of stuttering and is discussed in terms of the stability of the speech motor system. The aim of the current study was to analyse the spatial and temporal variability in the speech of three clutterers and three control speakers. All speakers were native speakers of German. The speech material consisted of repetitive CV-syllables and foreign words, because clutterers have the most severe problems with long words which have a complex syllable structure. The results showed a higher quotient of variation for clutterers in the foreign word production. For the syllable repetition task, no significant differences between clutterers and controls were found. The extremely large and variable displacements were interpreted as a strategy that helps clutterers to improve the intelligibility of their speech.
This paper summarizes our research efforts in functional modelling of the relationship between the acoustic properties of vowels and perceived vowel quality. Our model is trained on 164 short steady-state stimuli. We measured F1, F2, and additionally F0 since the effect of F0 on perceptual vowel height is evident. 40 phonetically skilled subjects judged vowel quality using the Cardinal Vowel diagram. The main focus is on refining the model and describing its transformation properties between the F1/F2 formant chart and the Cardinal Vowel diagram. An evaluation of the model based on 48 additional vowels showed the generalizability of the model and confirmed that it predicts perceived vowel quality with sufficient accuracy.
We measure face deformations during speech production using a motion capture system, which provides 3D coordinate data of about 60 markers glued on the speaker's face. An arbitrary orthogonal factor analysis followed by a principal component analysis (together called a guided PCA) of the data has showed that the first 6 factors explain about 90% of the variance, for each of our 3 speakers. The 6 derived factors, therefore, allow us to efficiently analyze or to reconstruct with a reasonable accuracy the observed face deformations. Since these factors can be interpreted in articulatory terms, they can reveal underlying articulatory organizations. The comparison of lip gestures in terms of data derived factors suggests that these speakers differently maneuver the lips to achieve contrast between /s/ and /R/. Such inter-speaker variability can occur because the acoustic contrast of these fricatives is shaped not only by the lip tube but also by cavities inside the mouth such as the sublingual cavity. In other words, these tube and cavity can acoustically compensate each other to produce their required acoustic properties.
The contribution of von Kempelen's "Mechanism of Speech" to the 'phonetic sciences' will be analyzed with respect to his theoretical reasoning on speech and speech production on the one hand and on the other in connection with his practical insights during his struggle in constructing a speaking machine. Whereas in his theoretical considerations von Kempelen's view is focussed on the natural functioning of the speech organs – cf. his membraneous glottis model – in constructing his speaking machine he clearly orientates himself towards the auditory result – cf. the bag pipe model for the sound generator used for the speaking machine instead. Concerning vowel production his theoretical description remains questionable, but his practical insight that vowels and speech sounds in general are only perceived correctly in connection with their surrounding sounds – i.e. the discovery of coarticulation – is clearly a milestone in the development of the phonetic sciences: He therefore dispenses with the Kratzenstein tubes, although they might have been based on more thorough acoustic modelling.
Finally, von Kempelen's model of speech production will be discussed in relation to the discussion of the acoustic nature of vowels afterwards [Willis and Wheatstone as well as von Helmholtz and Hermann in the 19th century and Stumpf, Chiba & Kajiyama as well as Fant and Ungeheuer in the 20th century].
In order to understand the functional morphology of the human voice producing system, we are in need of data on the vocal tract anatomy of other mammalian species. The larynges and vocal tracts of four species of Artiodactyla were investigated in combination with acoustic analyses of their respective calls. Different evolutionary specializations of laryngeal characters may lead to similar effects on sound production. In the investigated species, such specializations are: the elongation and mass increase of the vocal folds, the volume increase of the laryngeal vestibulum by an enlarged thyroid cartilage and the formation of laryngeal ventricles. Both the elongation of the vocal folds and the increase of the oscillating masses lower the fundamental frequency. The influence of an increased volume of the laryngeal vestibulum on sound production remains unclear. The anatomical and acoustic results are presented together with considerations about the habitats and the mating systems of the respective species.
Four speakers repeated 8 times 15 sentences containing 'pVp' syllables (V being /a/, /i/ and /u/). The 'pVp' syllables were located in final, penultimate and antepenultimate position relatively to the Intonational Phrase (IP) boundary. They were embedded in lexical words of 1-3 syllables and were either word-initial or word-final. Results show that the closer the vowel in word-final position is to the IP boundary, the longer the duration and the higher the fundamental frequency of the vowel; it is also characterised by larger lip opening gestures. The potential reduction or coarticulation of vowels in wordinitial position compared to their counterparts in word-final position is discussed.
Articulatory token-to-token variability not only depends on linguistic aspects like the phoneme inventory of a given language but also on speaker specific morphological and motor constraints. As has been noted previously (Perkell (1997), Mooshammer et al. (2004)), speakers with coronally high "domeshaped" palates exhibit more articulatory variability than speakers with coronally low "flat" palates. One explanation for that is based on perception oriented control by the speaker. The influence of articulatory variation on the cross sectional area and consequently on the acoustics should be greater for flat palates than for domeshaped ones. This should force speakers with flat palates to place their tongue very precisely whereas speakers with domeshaped palates might tolerate a greater variability. A second explanation could be a greater amount of lateral linguo-palatal contact for flat palates holding the tongue in position. In this study both hypotheses were tested.
In order to investigate the influence of the palate shape on the variability of the acoustic output a modelling study was carried out. Parallely, an EPG experiment was conducted in order to investigate the relationship between palate shape, articulatory variability and linguo-palatal contact.
Results from the modelling study suggest that the acoustic variability resulting from a certain amount of articulatory variability is higher for flat palates than for domeshaped ones. Results from the EPG experiment with 20 speakers show that (1.) speakers with a flat palate exhibit a very low articulatory variability whereas speakers with a domeshaped palate vary, (2.) there is less articulatory variability if there is lots of linguo-palatal contact and (3.) there is no relationship between the amount of lateral linguo-palatal contact and palate shape. The results suggest that there is a relationship between token-to-token variability and palate shape, however, it is not that the two parameters correlate, but that speakers with a flat palate always have a low variability because of constraints of the variability range of the acoustic output whereas speakers with a domeshaped palate may choose the degree of variability. Since linguo-palatal contact and variability correlate it is assumed that linguo-palatal contact is a means for reducing the articulatory variability.
The author presents MASSY, the MODULAR AUDIOVISUAL SPEECH SYNTHESIZER. The system combines two approaches of visual speech synthesis. Two control models are implemented: a (data based) di-viseme model and a (rule based) dominance model where both produce control commands in a parameterized articulation space. Analogously two visualization methods are implemented: an image based (video-realistic) face model and a 3D synthetic head. Both face models can be driven by both the data based and the rule based articulation model.
The high-level visual speech synthesis generates a sequence of control commands for the visible articulation. For every virtual articulator (articulation parameter) the 3D synthetic face model defines a set of displacement vectors for the vertices of the 3D objects of the head. The vertices of the 3D synthetic head then are moved by linear combinations of these displacement vectors to visualize articulation movements. For the image based video synthesis a single reference image is deformed to fit the facial properties derived from the control commands. Facial feature points and facial displacements have to be defined for the reference image. The algorithm can also use an image database with appropriately annotated facial properties. An example database was built automatically from video recordings. Both the 3D synthetic face and the image based face generate visual speech that is capable to increase the intelligibility of audible speech.
Other well known image based audiovisual speech synthesis systems like MIKETALK and VIDEO REWRITE concatenate pre-recorded single images or video sequences, respectively. Parametric talking heads like BALDI control a parametric face with a parametric articulation model. The presented system demonstrates the compatibility of parametric and data based visual speech synthesis approaches.