Universitätspublikationen
Refine
Year of publication
- 2004 (81) (remove)
Document Type
- Article (81) (remove)
Language
- English (59)
- German (19)
- Portuguese (2)
- Multiple languages (1)
Has Fulltext
- yes (81)
Is part of the Bibliography
- no (81)
Keywords
- septic shock (2)
- Adorno (1)
- Angiogenesis (1)
- COPD (1)
- Calycotome villosa (Poiret) Link Subsp. Intermedia (1)
- Cardiac fibroblast (1)
- Chronic obstructive pulmonary disease (1)
- Critical Theory (1)
- Dual projection (1)
- Duality (1)
Institute
- Medizin (16)
- Physik (16)
- Rechtswissenschaft (9)
- E-Finance Lab e.V. (8)
- Biochemie und Chemie (6)
- Philosophie (6)
- Biowissenschaften (4)
- Informatik (4)
- Exzellenzcluster Die Herausbildung normativer Ordnungen (3)
- Gesellschaftswissenschaften (3)
The majority of bacterial membrane-bound NiFe-hydrogenases and formate dehydrogenases have homologous membrane-integral cytochrome b subunits. The prototypic NiFe-hydrogenase of Wolinella succinogenes (HydABC complex) catalyzes H2 oxidation by menaquinone during anaerobic respiration and contains a membrane-integral cytochrome b subunit (HydC) that carries the menaquinone reduction site. Using the crystal structure of the homologous FdnI subunit of Escherichia coli formate dehydrogenase-N as a model, the HydC protein was modified to examine residues thought to be involved in menaquinone binding. Variant HydABC complexes were produced in W. succinogenes, and several conserved HydC residues were identified that are essential for growth with H2 as electron donor and for quinone reduction by H2. Modification of HydC with a C-terminal Strep-tag II enabled one-step purification of the HydABC complex by Strep-Tactin affinity chromatography. The tagged HydC, separated from HydAB by isoelectric focusing, was shown to contain 1.9 mol of heme b/mol of HydC demonstrating that HydC ligates both heme b groups. The four histidine residues predicted as axial heme b ligands were individually replaced by alanine in Strep-tagged HydC. Replacement of either histidine ligand of the heme b group proximal to HydAB led to HydABC preparations that contained only one heme b group. This remaining heme b could be completely reduced by quinone supporting the view that the menaquinone reduction site is located near the distal heme b group. The results indicate that both heme b groups are involved in electron transport and that the architecture of the menaquinone reduction site near the cytoplasmic side of the membrane is similar to that proposed for E. coli FdnI.
In Archaea, bacteria, and eukarya, ATP provides metabolic energy for energy-dependent processes. It is synthesized by enzymes known as A-type or F-type ATP synthase, which are the smallest rotatory engines in nature (Yoshida, M., Muneyuki, E., and Hisabori, T. (2001) Nat. Rev. Mol. Cell. Biol. 2, 669-677; Imamura, H., Nakano, M., Noji, H., Muneyuki, E., Ohkuma, S., Yoshida, M., and Yokoyama, K. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 2312-2315). Here, we report the first projected structure of an intact A(1)A(0) ATP synthase from Methanococcus jannaschii as determined by electron microscopy and single particle analysis at a resolution of 1.8 nm. The enzyme with an overall length of 25.9 nm is organized in an A(1) headpiece (9.4 x 11.5 nm) and a membrane domain, A(0) (6.4 x 10.6 nm), which are linked by a central stalk with a length of approximately 8 nm. A part of the central stalk is surrounded by a horizontal-situated rodlike structure ("collar"), which interacts with a peripheral stalk extending from the A(0) domain up to the top of the A(1) portion, and a second structure connecting the collar structure with A(1). Superposition of the three-dimensional reconstruction and the solution structure of the A(1) complex from Methanosarcina mazei Gö1 have allowed the projections to be interpreted as the A(1) headpiece, a central and the peripheral stalk, and the integral A(0) domain. Finally, the structural organization of the A(1)A(0) complex is discussed in terms of the structural relationship to the related motors, F(1)F(0) ATP synthase and V(1)V(0) ATPases.
The signal transducer and activator of transcription (Stat) gene family comprises seven members with similarities in their domain structure and a common mode of activation. Members of this gene family mediate interferon induction of gene transcription and the response to a large number of growth factors and hormones. Extracellular ligand binding to transmembrane receptors causes the intracellular activation of associated tyrosine kinases, phosphorylation of Stat molecules, dimerization, and translocation to the nucleus. Prolactin-induced phosphorylation of Stat5 is a key event in the development and differentiation of mammary epithelial cells. In addition to the crucial phosphorylation at tyrosine 694, we have identified an O-linked N-acetylglucosamine (O-GlcNAc) as another secondary modification essential for the transcriptional induction by Stat5. This modification was only found on nuclear Stat5 after cytokine activation. Similar observations were made with Stat1, Stat3, and Stat6. Glycosylation of Stat5, however, does not seem to be a prerequisite for nuclear translocation. Mass spectrometric analysis revealed a glycosylated peptide in the N-terminal region of Stat5. Replacement of threonine 92 by an alanine residue (Stat5a-T92A) strongly reduced the prolactin induction of Stat5a glycosylation and abolished transactivation of a target gene promoter. Only the glycosylated form of Stat5 was able to bind the coactivator of transcription CBP, an essential interaction for Stat5-mediated gene transcription.
Respiratory chain complex I contains 8-9 iron-sulfur clusters. In several cases, the assignment of these clusters to subunits and binding motifs is still ambiguous. To test the proposed ligation of the tetranuclear iron-sulfur cluster N5 of respiratory chain complex I, we replaced the conserved histidine 129 in the 75-kDa subunit from Yarrowia lipolytica with alanine. In the mutant strain, reduced amounts of fully assembled but destabilized complex I could be detected. Deamino-NADH: ubiquinone oxidoreductase activity was abolished completely by the mutation. However, EPR spectroscopic analysis of mutant complex I exhibited an unchanged cluster N5 signal, excluding histidine 129 as a cluster N5 ligand.
Stable supercomplexes of bacterial respiratory chain complexes III (ubiquinol:cytochrome c oxidoreductase) and IV (cytochrome c oxidase) have been isolated as early as 1985 (Berry, E. A., and Trumpower, B. L. (1985) J. Biol. Chem. 260, 2458-2467). However, these assemblies did not comprise complex I (NADH:ubiquinone oxidoreductase). Using the mild detergent digitonin for solubilization of Paracoccus denitrificans membranes we could isolate NADH oxidase, assembled from complexes I, III, and IV in a 1:4:4 stoichiometry. This is the first chromatographic isolation of a complete “respirasome.” Inactivation of the gene for tightly bound cytochrome c552 did not prevent formation of this supercomplex, indicating that this electron carrier protein is not essential for structurally linking complexes III and IV. Complex I activity was also found in the membranes of mutant strains lacking complexes III or IV. However, no assembled complex I but only dissociated subunits were observed following the same protocols used for electrophoretic separation or chromatographic isolation of the supercomplex from the wild-type strain. This indicates that the P. denitrificans complex I is stabilized by assembly into the NADH oxidase supercomplex. In addition to substrate channeling, structural stabilization of a membrane protein complex thus appears as one of the major functions of respiratory chain supercomplexes.
Arsenic trioxide is a toxic metalloid and carcinogen that is also used as an anticancer drug, and for this reason it is important to identify the routes of arsenite uptake by cells. In this study the ability of hexose transporters to facilitate arsenic trioxide uptake in Saccharomyces cerevisiae was examined. In the absence of glucose, strains with disruption of the arsenite efflux gene ACR3 accumulated high levels of (73)As(OH)(3). The addition of glucose inhibited uptake by approximately 80%. Disruption of FPS1, the aquaglyceroporin gene, reduced glucose-independent uptake by only about 25%, and the residual uptake was nearly completely inhibited by hexoses, including glucose, galactose, mannose, and fructose but not pentoses or disaccharides. A strain lacking FPS1, ACR3, and all genes for hexose permeases except for HXT3, HXT6, HXT7, and GAL2 exhibited hexose-inhibitable (73)As(OH)(3) uptake, whereas a strain lacking all 18 hexose transport-related genes (HXT1 to HXT17 and GAL2), FPS1 and ACR3, exhibited <10% of wild type (73)As(OH)(3) transport. When HXT1, HXT3, HXT4, HXT5, HXT7, or HXT9 was individually expressed in that strain, hexose-inhibitable (73)As(OH)(3) uptake was restored. In addition, the transport of [(14)C]glucose was inhibited by As(OH)(3). These results clearly demonstrate that hexose permeases catalyze the majority of the transport of the trivalent metalloid arsenic trioxide.
Structural and functional characterization of the dimerization region of soluble guanylyl cyclase
(2004)
Soluble guanylyl cyclase (sGC) is a ubiquitous enzyme that functions as a receptor for nitric oxide. Despite the obligate heterodimeric nature of sGC, the sequence segments mediating subunit association have remained elusive. Our initial screening for relevant interaction site(s) in the most common sGC isoenzyme, α1 β1, identified two regions in each subunit, i.e. the regulatory domains and the central regions, contributing to heterodimer formation. To map the relevant segments in the β1 subunit precisely, we constructed multiple N- and C-terminal deletion variants and cotransfected them with full-length α1 in COS cells. Immunoprecipitation revealed that a sequence segment spanning positions 204–408 mediates binding of β1 to α1 The same region of β1[204–408] was found to promote β /β1 homodimerization. Fusion of [204 β1–408] to enhanced green fluorescent protein conferred binding activity to the recipient protein. Coexpression of β1[204–408] with α1 or β1 targeted the sGC subunits for proteasomal degradation, suggesting that β1[204–408] forms structurally deficient complexes with α1 and β1. Analysis of deletion constructs lacking portions of the β1 dimerization region identified two distinct segments contributing to α1 binding, i.e. an N-terminal site covering positions 204–244 and a C-terminal site at 379–408. Both sites are crucial for sGC function because deletion of either site rendered sGC dimerization-deficient and thus functionally inactive. We conclude that the dimerization region of β1 extends over 205 residues of its regulatory and central domains and that two discontinuous sites of 41 and 30 residues, respectively, facilitate binding of β1 to the α1 subunit of sGC.
Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the major cytosolic receptor for NO, catalyzing the conversion of GTP to cGMP. In a search for proteins specifically interacting with human sGC, we have identified the multidomain protein AGAP1, the prototype of an ArfGAP protein with a GTPase-like domain, Ankyrin repeats, and a pleckstrin homology domain. AGAP1 binds through its carboxyl terminal portion to both the α1 and β1 subunits of sGC. We demonstrate that AGAP1 mRNA and protein are co-expressed with sGC in human, murine, and rat cells and tissues and that the two proteins interact in vitro and in vivo. We also show that AGAP1 is prone to tyrosine phosphorylation by Src-like kinases and that tyrosine phosphorylation potently increases the interaction between AGAP1 and sGC, indicating that complex formation is modulated by reversible phosphorylation. Our findings may hint to a potential role of AGAP1 in integrating signals from Arf, NO/cGMP, and tyrosine kinase signaling pathways.
Nitric oxide (NO) represents a short lived mediator that pivotally drives keratinocyte movements during cutaneous wound healing. In this study, we have identified p68 DEAD box RNA helicase (p68) from an NO-induced differential keratinocyte cDNA library. Subsequently, we have analyzed regulation of p68 by wound-associated mediators in human and murine keratinocytes. NO, serum, growth factors, and pro-inflammatory cytokines were potent inducers of p68 expression in the cells. p68 was constitutively expressed in the epithelial compartment of murine skin. Upon injury, we found a transient down-regulation of overall p68 protein in wound tissue. However, p68 did not completely disappear during early wound repair, as we found an expression of p68 protein in isolated wound margin tissue 24 h after wounding. Moreover, immunohistochemistry and cell fractionation analysis revealed a restricted localization of p68 in keratinocyte nuclei of the developing epithelium. Accordingly, cultured keratinocytes also showed a nuclear localization of the helicase. Moreover, confocal microscopy revealed a strong localization of p68 protein within the nucleoli of the cells. Functional analyses demonstrated that p68 strongly participated in keratinocyte proliferation and gene expression. Keratinocytes that constitutively overexpressed p68 protein were characterized by a marked increase in serum-induced proliferation and vascular endothelial growth factor expression, whereas down-regulation of endogenous p68 using small interfering RNA markedly attenuated serum-induced proliferation and vascular endothelial growth factor expression. Altogether, our results suggest a tightly controlled expression and nucleolar localization of p68 in keratinocytes in vitro and during skin repair in vivo that functionally contributes to keratinocyte proliferation and gene expression.
The MAM (meprin/A5-protein/PTPmu) domain is present in numerous proteins with diverse functions. PTPμ belongs to the MAM-containing subclass of protein-tyrosine phosphatases (PTP) able to promote cell-to-cell adhesion. Here we provide experimental evidence that the MAM domain is a homophilic binding site of PTPμ. We demonstrate that the MAM domain forms oligomers in solution and binds to the PTPμ ectodomain at the cell surface. The presence of two disulfide bridges in the MAM molecule was evidenced and their integrity was found to be essential for MAM homophilic interaction. Our data also indicate that PTPμ ectodomain forms oligomers and mediates the cellular adhesion, even in the absence of MAM domain homophilic binding. Reciprocally, MAM is able to interact homophilically in the absence of ectodomain trans binding. The MAM domain therefore contains independent cis and trans interaction sites and we predict that its main role is to promote lateral dimerization of PTPμ at the cell surface. This finding contributes to the understanding of the signal transduction mechanism in MAM-containing PTPs.
Supersilylated tetrachlorodigermane (tBu3Si)Cl2GeGeCl2(SitBu3) and trigermoxetane (tBu3Si)3Ge3Cl3O
(2004)
In contrast to the tetrachlorodigermane (tBu3Si)Cl2Ge-GeCl2(SitBu3), the cis,transcyclotrigermane (tBu3SiGeCl)3 is sensitive to oxygen. Its treatment with O2 at ambient temperature leads to the trigermoxetane (tBu3Si)3Ge3Cl3O. According to an X-ray structure analysis of single crystals consisting of cocrystallized (tBu3Si)3Ge3Cl3O and (tBu3Si)Cl2Ge-GeCl2(SitBu3) the trigermaoxetane contains an almost planar Ge3O-ring while the tetrachlorodigermane (tBu3Si)Cl2Ge- GeCl2(SitBu3) possesses a Si-Ge-Ge-Si chain which is exactly all trans,
The major light-harvesting complex (LHC-II) of higher plants plays a crucial role in capturing light energy for photosynthesis and in regulating the flow of energy within the photosynthetic apparatus. Native LHC-II isolated from plant tissue consists of three isoforms, Lhcb1, Lhcb2, and Lhcb3, which form homo- and heterotrimers. All three isoforms are highly conserved among different species, suggesting distinct functional roles. We produced the three LHC-II isoforms by heterologous expression of the polypeptide in Escherichia coli and in vitro refolding with purified pigments. Although Lhcb1 and Lhcb2 are very similar in polypeptide sequence and pigment content, Lhcb3 is clearly different because it lacks an N-terminal phosphorylation site and has a higher chlorophyll a/b ratio, suggesting the absence of one chlorophyll b. Low temperature absorption and fluorescence emission spectra of the pure isoforms revealed small but significant differences in pigment organization. The oligomeric state of the pure isoforms and of their permutations was investigated by native gel electrophoresis, sucrose density gradient centrifugation, and SDS-PAGE. Lhcb1 and Lhcb2 formed trimeric complexes by themselves and with one another, but Lhcb3 was able to do so only in combination with one or both of the other isoforms. We conclude that the main role of Lhcb1 and Lhcb2 is in the adaptation of photosynthesis to different light regimes. The most likely role of Lhcb3 is as an intermediary in light energy transfer from the main Lhcb1/Lhcb2 antenna to the photosystem II core.
The transporter associated with antigen processing (TAP1/2) translocates cytosolic peptides of proteasomal degradation into the endoplasmic reticulum (ER) lumen. A peptide-loading complex of tapasin, major histocompatibility complex class I, and several auxiliary factors is assembled at the transporter to optimize antigen display to cytotoxic T-lymphocytes at the cell surface. The heterodimeric TAP complex has unique N-terminal domains in addition to a 6 + 6-transmembrane segment core common to most ABC transporters. Here we provide direct evidence that this core TAP complex is sufficient for (i) ER targeting, (ii) heterodimeric assembly within the ER membrane, (iii) peptide binding, (iv) peptide transport, and (v) specific inhibition by the herpes simplex virus protein ICP47 and the human cytomegalovirus protein US6. We show for the first time that the translocation pore of the transporter is composed of the predicted TM-(5-10) of TAP1 and TM-(4-9) of TAP2. Moreover, we demonstrate that the N-terminal domains of TAP1 and TAP2 are essential for recruitment of tapasin, consequently mediating assembly of the macromolecular peptide-loading complex.
The purification and functional reconstitution of a five-component oligopeptide ATP-binding cassette transporter with a remarkably wide substrate specificity are described. High-affinity peptide uptake was dependent on liganded substrate-binding protein OppA, which interacts with the translocator OppBCDF with higher affinity than unliganded OppA. Transport screening with combinatorial peptide libraries revealed that (i) the Opp transporter is not selective with respect to amino acid side chains of the transported peptides; (ii) any peptide that can bind to OppA is transported via Opp, including very long peptides up to 35 residues long; and (iii) the binding specificity of OppA largely determines the overall transport selectivity.
The mode of the antitumoral activity of multimutated oncolytic herpes simplex virus type 1 G207 has not been fully elucidated yet. Because the antitumoral activity of many drugs involves the inhibition of tumor blood vessel formation, we determined if G207 had an influence on angiogenesis. Monolayers of human umbilical vein endothelial cells and human dermal microvascular endothelial cells, but not human dermal fibroblasts, bronchial epithelial cells, and retinal glial cells, were highly sensitive to the replicative and cytotoxic effects of G207. Moreover, G207 infection caused the destruction of endothelial cell tubes in vitro. In the in vivo Matrigel plug assay in mice, G207 suppressed the formation of perfused vessels. Intratumoral treatment of established human rhabdomyosarcoma xenografts with G207 led to the destruction of tumor vessels and tumor regression. Ultrastructural investigations revealed the presence of viral particles in both tumor and endothelial cells of G207-treated xenografts, but not in adjacent normal tissues. These findings show that G207 may suppress tumor growth, in part, due to inhibition of angiogenesis.
We study issues of duality in 3D field theory models over a canonical noncommutative spacetime and obtain the noncommutative extension of the self-dual model induced by the Seiberg–Witten map. We apply the dual projection technique to uncover some properties of the noncommutative Maxwell–Chern–Simons theory up to first-order in the noncommutative parameter. A duality between this theory and a model similar to the ordinary self-dual model is established. The correspondence of the basic fields is obtained and the equivalence of algebras and equations of motion are directly verified. We also comment on previous results in this subject.
We perform a study of the possible existence of hybrid stars with color superconducting quark cores using a specific hadronic model in a combination with an NJL-type quark model. It is shown that the constituent mass of the non-strange quarks in vacuum is a very important parameter that controls the beginning of the hadron–quark phase transition. At relatively small values of the mass, the first quark phase that appears is the two-flavor color superconducting (2SC) phase which, at larger densities, is replaced by the color-flavor locked (CFL) phase. At large values of the mass, on the other hand, the phase transition goes from the hadronic phase directly into the CFL phase avoiding the 2SC phase. It appears, however, that the only stable hybrid stars obtained are those with the 2SC quark cores.
The production of strange pentaquark states (e.g., Theta baryons and Ξ−− states) in hadronic interactions within a Gribov–Regge approach is explored. In this approach the Θ+(1540) and the Ξ are produced by disintegration of remnants formed by the exchange of pomerons between the two protons. We predict the rapidity and transverse momentum distributions as well as the 4π multiplicity of the Θ+, Ξ−−, Ξ−, Ξ0 and Ξ+ for s=17 GeV (SPS) and 200 GeV (RHIC). For both energies more than 10−3 Θ+ and more than 10−5 Ξ per pp event should be observed by the present experiments.
The ubiquitin (Ub) ligase Cbl plays a critical role in attenuation of receptor tyrosine kinase (RTK) signaling by inducing ubiquitination of RTKs and promoting their sorting for endosomal degradation. Herein, we describe the identification of two novel Cbl-interacting proteins, p70 and Clip4 (recently assigned the names Sts-1 and Sts-2, respectively), that inhibit endocytosis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor. Sts-1 and Sts-2 contain SH3 domains that interacted with Cbl, Ub-associated domains, which bound directly to mono-Ub or to the EGFR/Ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of Sts-1/2. Ligand-induced recruitment of Sts-1/Sts-2 into activated EGFR complexes led to inhibition of receptor internalization, reduction in the number of EGFR-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. On the other hand, interference with Sts-1/Sts-2 functions diminished ligand-induced receptor degradation, cell proliferation, and oncogenic transformation in cultured fibroblasts. We suggest that Sts-1 and Sts-2 represent a novel class of Ub-binding proteins that regulate RTK endocytosis and control growth factor-induced cellular functions.
Alix/AIP1 is an adaptor protein involved in regulating the function of receptor and cytoskeleton-associated tyrosine kinases. Here, we investigated its interaction with and regulation by Src. Tyr319 of Alix bound the isolated Src homology-2 (SH2) domain and was necessary for interaction with intact Src. A proline-rich region in the C terminus of Alix bound the Src SH3 domain, but this interaction was dependent on the release of the Src SH2 domain from its Src internal ligand either by interaction with Alix Tyr319 or by mutation of Src Tyr527. Src phosphorylated Alix at a C-terminal region rich in tyrosines, an activity that was stimulated by the presence of the Alix binding partner SETA/CIN85. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. As a consequence of this, Src antagonized the negative regulation of receptor tyrosine kinase internalization and cell adhesion by Alix. We propose a model whereby Src antagonizes the effects of Alix by phosphorylation of its C terminus, leading to the disruption of interactions with target proteins.
We propose a method to experimentally study the equation of state of strongly interacting matter created at the early stage of nucleus–nucleus collisions. The method exploits the relation between relative entropy and energy fluctuations and equation of state. As a measurable quantity, the ratio of properly filtered multiplicity to energy fluctuations is proposed. Within a statistical approach to the early stage of nucleus–nucleus collisions, the fluctuation ratio manifests a non-monotonic collision energy dependence with a maximum in the domain where the onset of deconfinement occurs.
Modifications of the gyromagnetic moment of electrons and muons due to a minimal length scale combined with a modified fundamental scale Mf are explored. First-order deviations from the theoretical SM value for g−2 due to these string theory-motivated effects are derived. Constraints for the fundamental scale Mf are given.
We suggest that the fluctuations of strange hadron multiplicity could be sensitive to the equation of state and microscopic structure of strongly interacting matter created at the early stage of high energy nucleus–nucleus collisions. They may serve as an important tool in the study of the deconfinement phase transition. We predict, within the statistical model of the early stage, that the ratio of properly filtered fluctuations of strange to non-strange hadron multiplicities should have a non-monotonic energy dependence with a minimum in the mixed phase region.
We point out that during the supernova II type explosion the thermodynamical conditions of stellar matter between the protoneutron star and the shock front correspond to the nuclear liquid–gas coexistence region, which can be investigated in nuclear multifragmentation reactions. We have demonstrated, that neutron-rich hot heavy nuclei can be produced in this region. The production of these nuclei may influence dynamics of the explosion and contribute to the synthesis of heavy elements.
Phosphorylation of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1a) was studied with time-resolved Fourier transform infrared spectroscopy. ATP and ATP analogs (ITP, 2'- and 3'-dATP) were used to study the effect of the adenine ring and the ribose hydroxyl groups on ATPase phosphorylation. All modifications of ATP altered conformational changes and phosphorylation kinetics. The differences compared with ATP increased in the following order: 3'-dATP > ITP > 2'-dATP. Enzyme phosphorylation with ITP results in larger absorbance changes in the amide I region, indicating larger conformational changes of the Ca(2+)-ATPase. The respective absorbance changes obtained with 3'-dATP are significantly different from the others with different band positions and amplitudes in the amide I region, indicating different conformational changes of the protein backbone. ATPase phosphorylation with 3'-dATP is also much ( approximately 30 times) slower than with ATP. Our results indicate that modifications to functional groups of ATP (the ribose 2'- and 3'-OH and the amino group in the adenine ring) affect gamma-phosphate transfer to the phosphorylation site of the Ca(2+)-ATPase by changing the extent of conformational change and the phosphorylation rate. ADP binding to the ADP-sensitive phosphoenzyme (Ca(2)E1P) stabilizes the closed conformation of Ca(2)E1P.
We have studied the ubiquinone-reducing catalytic core of NADH:ubiquinone oxidoreductase (complex I) from Yarrowia lipolytica by a series of point mutations replacing conserved histidines and arginines in the 49-kDa subunit. Our results show that histidine 226 and arginine 141 probably do not ligate iron-sulfur cluster N2 but that exchanging these residues specifically influences the properties of this redox center. Histidines 91 and 95 were found to be essential for ubiquinone reductase activity of complex I. Mutations at the C-terminal arginine 466 affected ubiquinone affinity and inhibitor sensitivity but also destabilized complex I. These results provide further support for a high degree of structural conservation between the 49-kDa subunit of complex I and its ancestor, the large subunit of water-soluble [NiFe] hydrogenases. In several mutations of histidine 226, arginine 141, and arginine 466 the characteristic EPR signatures of iron-sulfur cluster N2 became undetectable, but specific, inhibitor-sensitive ubiquinone reductase activity was only moderately reduced. As we could not find spectroscopic indications for a modified cluster N2, we concluded that these complex I mutants were lacking most of this redox center but were still capable of catalyzing inhibitor-resistant ubiquinone reduction at near normal rates. We discuss that this at first surprising scenario may be explained by electron transfer theory; after removal of a single redox center in a chain, electron transfer rates are predicted to be still much faster than steady-state turnover of complex I. Our results question some of the central mechanistic functions that have been put forward for iron-sulfur cluster N2.
P-O bond destabilization accelerates phosphoenzyme hydrolysis of sarcoplasmic reticulum Ca2+-ATPase
(2004)
The phosphate group of the ADP-insensitive phosphoenzyme (E2-P) of sarcoplasmic reticulum Ca2+-ATPase (SERCA1a) was studied with infrared spectroscopy to understand the high hydrolysis rate of E2-P. By monitoring an autocatalyzed isotope exchange reaction, three stretching vibrations of the transiently bound phosphate group were selectively observed against a background of 50,000 protein vibrations. They were found at 1194, 1137, and 1115 cm–1. This information was evaluated using the bond valence model and empirical correlations. Compared with the model compound acetyl phosphate, structure and charge distribution of the E2-P aspartyl phosphate resemble somewhat the transition state in a dissociative phosphate transfer reaction; the aspartyl phosphate of E2-P has 0.02 Å shorter terminal P–O bonds and a 0.09 Å longer bridging P–O bond that is ∼20% weaker, the angle between the terminal P–O bonds is wider, and –0.2 formal charges are shifted from the phosphate group to the aspartyl moiety. The weaker bridging P–O bond of E2-P accounts for a 1011–1015-fold hydrolysis rate enhancement, implying that P–O bond destabilization facilitates phosphoenzyme hydrolysis. P–O bond destabilization is caused by a shift of noncovalent interactions from the phosphate oxygens to the aspartyl oxygens. We suggest that the relative positioning of Mg2+ and Lys684 between phosphate and aspartyl oxygens controls the hydrolysis rate of the ATPase phosphoenzymes and related phosphoproteins.
The transporter associated with antigen processing (TAP) is a key component of the cellular immune system. As a member of the ATP-binding cassette (ABC) superfamily, TAP hydrolyzes ATP to energize the transport of peptides from the cytosol into the lumen of the endoplasmic reticulum. TAP is composed of TAP1 and TAP2, each containing a transmembrane domain and a nucleotide-binding domain (NBD). Here we investigated the role of the ABC signature motif (C-loop) on the functional non-equivalence of the NBDs, which contain a canonical C-loop (LSGGQ) for TAP1 and a degenerate C-loop (LAAGQ) for TAP2. Mutation of the leucine or glycine (LSGGQ) in TAP1 fully abolished peptide transport. However, TAP complexes with equivalent mutations in TAP2 still showed residual peptide transport activity. To elucidate the origin of the asymmetry of the NBDs of TAP, we further examined TAP complexes with exchanged C-loops. Strikingly, the chimera with two canonical C-loops showed the highest transport rate whereas the chimera with two degenerate C-loops had the lowest transport rate, demonstrating that the ABC signature motifs control peptide transport efficiency. All single site mutants and chimeras showed similar activities in peptide or ATP binding, implying that these mutations affect the ATPase activity of TAP. In addition, these results prove that the serine of the C-loop is not essential for TAP function but rather coordinates, together with other residues of the C-loop, the ATP hydrolysis in both nucleotide-binding sites.
his Erratum replaces incorrect plots shown in Fig. 7 with the corrected ones. In the publication, the NA57 [1] ratios of Ξ− and Ξ¯¯¯¯+ to the number of wounded nucleons at ⟨NW⟩=349 by mistake were plotted at the wrong values. The ratios were calculated and plotted by mistake using ⟨NW⟩=249.
The correct normalization does not change the conclusions of the paper. The correctly normalized results are presented in Fig. 7.
Pathologic data indicate that human cytomegalovirus (HCMV) infection might be associated with the pathogenesis of several human malignancies. However, no definitive evidence of a causal link between HCMV infection and cancer dissemination has been established to date. This study describes the modulation of the invasive behavior of NCAM-expressing tumor cell lines by HCMV. Neuroblastoma (NB) cells, persistently infected with the HCMV strain AD169 (UKF-NB-4AD169 and MHH-NB-11AD169), were added to endothelial cell monolayers and adhesion and penetration kinetics were measured. The 140- and 180-kDa isoforms of the adhesion receptor NCAM were evaluated by flow cytometry, Western blot, and reverse transcriptionpolymerase chain reaction (RT-PCR). The relevance of NCAM for tumor cell binding was proven by treating NB with NCAM antisense oligonucleotides or NCAM transfection. HCMV infection profoundly increased the number of adherent and penetrated NB, compared to controls. Surface expression of NCAM was significantly lower on UKF-NB-4AD169 and MHH-NB-11AD169, compared to mock-infected cells. Western-blot and RT-PCR demonstrated reduced protein and RNA levels of the 140- and 180-kDa isoform. An inverse correlation between NCAM expression and adhesion capacity of NB has been shown by antisense and transfection experiments. We conclude that HCMV infection leads to downregulation of NCAM receptors, which is associated with enhanced tumor cell invasiveness.
THE FINANCIAL SERVICES INDUSTRY IS OPERATING IN HIGHLY VOLATILE MARKETS.
TO CONSIDER THE IMPACT OF UNCERTAIN MARKET ENVIRONMENTS ON INAND OUTSOURCING DECISIONS, WE INTRODUCE A REAL OPTIONS BASED DECISION SUPPORT MODEL. WE APPLY THE MODEL TO AN IT INFRASTRUCTURE OUTSOURCING DECISION AND DETERMINE - BASED ON COST SAVINGS RESULTING FROM OUTSOURCING AND OPTION VALUES ACCOUNTING FOR UNCERTAINTY - DIFFERENT “TRIGGER” OUTPUT VOLUMES WHICH INDICATE IF IN- OR OUTSOURCING IS PREFERABLE. FINALLY WE SHOW THAT THE MODEL CAN ALSO BE TRANSFERRED TO SOURCING DECISIONS OF TRANSACTION BASED BUSINESS PROCESSES LIKE CLEARING AND SETTLEMENT OF SECURITIES.
Da consideração de que moral e direito implicam uma referência ao ponto de vista do participante, o autor explica que o segundo compensa a fraqueza da primeira nas condições modernas. Apoiando-se na teoria do discurso de Habermas, ele argumenta por uma relação interna entre Estado de direito e democracia. Primeiro, porque direitos humanos e soberania popular se implicam mutuamente. Depois, porque a idéia de Estado de direito envolve agora o conceito de poder comunicativo: a sobreposição e interligação de formas de comunicação baseadas em argumentos. Desta segunda relação, o autor extrai uma concepção de democracia em que a fonte de legitimidade não é mais a vontade pré-determinada dos indivíduos, mas o próprio processo de deliberação.
The starting point of Demirovic's text is Adorno's idea that concepts as forms of thinking are constellations of power. Differently from many interpretations of Adorno as resigned, Demirovic shows that this assumption enables Adorno to give his own theory the character of interventions in the ideological consensus of everyday life with regard to emancipation.
Zeichen der Herrschaftsausübung, der Gerichtsbarkeit und der Marktfreiheit, öffentlich angebrachte Maße und Gewichte zur Kontrolle des Wirtschaftslebens, mittelalterliche und frühneuzeitliche Gerichtsstätten, Orte und Gegenstände des Strafvollzugs, die der Rechtshistoriker Karl Frölich in den dreißiger bis fünfziger Jahren des 20. Jahrhunderts auf große Glasplatten gebannt hat, berichten anschaulich von der Rechtsausübung vergangener Epochen, indem sie "Sachzeugen des Rechtslebens" abbilden. Die Platten dieser umfangreichen Fotosammlung werden derzeit durch die Bibliothek des Max- Planck-Instituts für europäische Rechtsgeschichte eingescannt, um die Bilder der Forschung zu erhalten und zur Verfügung zu stellen. Ein Teil der "Sammlung Frölich" befindet sich heute in der Obhut von Prof. Dr. Gerhard Dilcher, Frankfurt am Main. Ein weiterer, größerer Teil, ist nach München ins Leopold-Wenger-Institut gelangt (Prof. Dr. Hermann Nehlsen); auch diese Bilder werden nun durch Scannen mit der "Frankfurter Partie" virtuell zusammengeführt. ...
Sommer 1789: Frankreich revoltiert, Preußen evaluiert. Staatsminister Johann Christoph von Wöllner, Chef des geistlichen Departements, entsendet einen bewährten Berliner Schulmann ins deutsche Reich, mit dem Auftrag, die außerpreußischen Lehranstalten zu begutachten, "teils überhaupt die Verfassung der fremden Universitäten kennen zu lernen, teils von dem Vortrag solcher Professoren, auf die einmal bei irgend einer preußischen Universität reflektiert werden könnte, zuverlässig Nachricht und Kenntnis einzuziehen". Es ist Friedrich Gedike, der durch ministeriale Order zum Headhunter für das Königreich ernannt wird. Seine Beobachtungen legt er in einem Bericht an den König nieder, der, 1905 ediert, 61 Blätter umfasst. ...
Vom Terror : [Szene aus einer Montage-Fassung des Dramenfragments "Moloch" von Friedrich Hebbel]
(2004)
Szene aus einer Montage-Fassung des Dramenfragments "Moloch" von Friedrich Hebbel. Die Szene steht als Einschub zwischen dem Ersten und Zweiten Akt der Tragödie, als eine Art Interludium. Im Laufe des Stückes wechselt die Perspektive mehrmals zwischen den Schauplätzen Germanischer Wald und Rom, dem Zentrum des Imperiums. Geplant ist eine Aufführung der Gesamtbearbeitung an der Volksbühne Berlin, voraussichtlich Ende 2004.
The article presents a brief overview of research and publication in the history of international law in Europe today. The upsurge of interest in historical studies is traced back to a sense of present transformation, with historical studies seeking to explore both aspects of continuity and change in the international legal system. The article outlines three tasks for the discipline in the future: to begin work for international law’s Ideengeschichte, to focus on the relationship between the West and its "Other", and to undertake studies in the historical sociology of international law.
Eine in Verfassungslehre und Europarechtswissenschaft weit verbreitete Annahme lautet: "Europa muss, um eine Zukunft haben zu können, sich zu einer Geschichtsgemeinschaft entwickeln." Was man dabei übersieht: So wenig sich nationale Geschichtsgemeinschaften identifizieren lassen, so wenig wird sich eine europäische Geschichtsgemeinschaft konstituieren.
Am anderen Ende derWelt, in einem argentinischen Städtchen im Bundesstaat Buenos Aires, versetzten die epochalen Ereignisse in Europa nach dem Fall des Eisernen Vorhangs den Bürger Dinko Šakić in Entzücken. Fünfzig Jahre nachdem er aus seiner Heimat geflüchtet war, führten die tektonischen Umwälzungen nach dem Ende des Kommunismus und der europäischen Teilung sogar zur staatlichen Verselbständigung seiner einstigen Heimat Kroatien – zu einer jahrzehntelang nicht einmal im Traum denkbaren Entwicklung. Dinko Šakić setzte sich daraufhin öffentlich für seine frühere Heimat ein. Es fiel ihm gar nicht ein, dass ihn seine Vergangenheit einholen könnte. Wahrscheinlich weil er "ein gutes Gewissen" hatte, ein von ihm gern benutzter Ausdruck, oder weil er in der jungen Republik Kroatien eine Art Fortsetzung jenes Staatsgebildes sah, dem er in seiner Jugend "gedient" hatte (auch ein beliebter Ausdruck Šakićs). In der größten lateinamerikanischen Kroatengemeinde in Argentinien gab es wahrscheinlich nichts, was ihn zur Vorsicht hätte mahnen können. Er schien die Öffentlichkeit geradezu gesucht, womöglich sogar eine Anerkennung erwartet zu haben. Bei einem Empfang zu Ehren des kroatischen Präsidenten während dessen Staatsbesuchs in Argentinien wurde Šakić von Journalisten beobachtet, wie er Tudjman nicht von der Seite weichen wollte, was diesen sichtlich irritierte und zu Hause für Empörung sorgte. Šakić, der sich selbst bei mehreren Gelegenheiten als glühenden kroatischen Nationalisten schilderte, weshalb er schon als Jugendlicher Anhänger der Ustascha-Organisation geworden sei, ahnte offensichtlich nicht, dass seine Art der Heimatliebe dort Entsetzen hervorrufen würde. ...
"Ein jegliches hat seine Zeit und alles Vornehmen unter dem Himmel hat seine Stunde". Wir wissen das. Wir wussten es vermutlich schon lange bevor der "Prediger" Salomo (3.1), der ein Philosoph war, uns vor nunmehr gut 2200 Jahren darüber belehrte. Aber wir handeln nur selten nach unseren Einsichten. Trennungen fallen schwer und Gewohnheiten verkleiden sich bereitwillig als Notwendigkeit. Verschwendung ist den Reichen keine Kategorie, und wer vom Verschwender lebt, erhebt keine Vorwürfe. Schließlich das Wichtigste: Wer außer Gott hat Kraft und Befugnis "Zeit" und "Stunde" zu bestimmen? ...
Nach Hause…
(2004)
Read only memory. Eine CD ROM ist ein Festwertspeicher. Die Daten kann man lesen, aber nicht verändern, ergänzen oder löschen. Man kann die Scheibe zertrümmern oder die Platte zerstören, aber die Daten manipulieren kann man nicht. Eine CD ROM schützt sich selbst vor Variation. Die Erfindung dieser Technik hat eine neue, kleine Gewissheit in der chronisch unsicheren Welt geschaffen. Was auf der CD ROM steht, steht fest. Und da viel auf ihr stehen kann – ganze Bibliotheken der Vergangenheit –, steht viel fest. Das macht Historiker glücklich. Drohen ihnen schon die Fakten abhanden zu kommen, verfügen sie immerhin noch über Festwerte, die aus einer zuverlässigen "Quelle" (Oexle, S. 165) fließen. ...
Wohl kaum wird der amerikanische "Imperator" den gefangenen "Barbaren von Bagdad" im Triumphwagen durch die Straßen von Washington ziehen lassen, auch wenn sich die publizistische Rhetorik seit den Kriegen gegen Afghanistan und den Irak mit Vergleichen zwischen dem antiken Rom und dem neuen Amerika förmlich überschlägt. "Sind die Amerikaner die Römer unserer Zeit?", fragt sich als einer unter vielen der Publizist und Althistoriker Peter Bender. Expansionen der alten wie der neuen Imperatoren werden miteinander verglichen, Parallelen und Unterschiede in der geographischen Lage, in den Interessen und Willen der Akteure ausgemacht. So habe bei den Amerikanern der Sendungsglaube als universale Macht schon am Anfang des Imperiums und nicht erst an dessen Ende wie bei den Römern gestanden. Roms Ostkriege und der kalteOst-West-Krieg hingegen zeitigten dasselbe historische Ergebnis: "Davor waren Rom und Amerika die ersten Weltmächte ihrer Zeit, danach waren sie die einzigen." Von "Aufstiegen" ist die Rede, nicht aber von "Untergängen", wie es die zyklischen Zivilisationsgeschichten der Kulturmorphologen verkünden. Das hat seinen Grund. Hinter der Analyse kommt Normatives zum Vorschein, wenn es um den Schutz der "Zivilisation des Abendlandes" in "einer künftigen Welt" geht, "in der andere Kulturen sich gegen den 'Westen' behaupten, stärken und vordringen …" Bender lässt das imperium romanum nicht untergehen, weil er das amerikanische Imperium als Bollwerk westlicher Kultur braucht. ...
"Eines der schwierigsten geschichtlichen Probleme stellt sich mit der Frage, wie der Aufstieg Roms zu erklären ist und wie sein Untergang. Das Verständnis für diese weltgeschichtlichen Vorgänge wird erleichtert, wenn man sich vergegenwärtigt, dass sie nicht eine, sondern viele Ursachen hatten. Der Untergang des Römischen Weltreiches war kein Ereignis, sondern ein Prozess, der sich über 300 Jahre erstreckte. Es gibt Nationen, die nicht so lange existiert haben, wie Rom allein brauchte, um unterzugehen." So die bedeutungsvollen Worte aus dem Off über dem Vorspann des fast dreistündigen Hollywood-Filmes "Der Untergang des Römischen Reiches" (1963) von Anthony Mann – in den Hauptrollen Alec Guinness als Marc Aurel und Sophia Loren als dessen Tochter Lucilla. ...
Im Niemandsland
(2004)
Dass die Regierungen westlicher Staaten eine offene oder verdeckte Tendenz haben, die ihnen in einem langen historischen Prozess auferlegten rechtsstaatlichen Bindungen aus politischen Gründen wenn nicht abzustreifen, so doch zu lockern, ist ein Thema, das Juristen, Ökonomen, Politologen und Soziologen gleichermaßen beschäftigt. Giorgio Agamben, italienischer Philosoph und Ästhetiker, spitzt die Thematik mit der These zu, die "Normalität" staatlichen Lebens existiere nicht mehr, es sei das "Niemandsland" des Ausnahmezustandes, "in dem wir leben" ("lo stato di eccezione 'in cui viviamo'"). Er sei die "fundamentale politische Struktur" unserer Zeit; er habe inzwischen die "größte planetarische Entfaltung" erreicht, die Menschen auf die "nuda vita", das nackte Leben, reduziert, das dem Kalkül der Macht unterworfen sei und in eine "beispiellose biopolitische Katastrophe" auszuarten drohe. Seine "Materialisierung" hat der Ausnahmezustand in den nationalsozialistischen Konzentrationslagern wie in allen Lagern gefunden, in denen Menschen von der "normalen Ordnung" ausgeschlossen werden; Guantánamo ist für Agamben ein aktuelles Beispiel. Die "Lager" in allen ihren Erscheinungsformen sind die "verborgene Matrix der Politik". Der Ausnahmezustand ist ein arcanum imperii, dessen "Demaskierung" die einzige Möglichkeit ist, den durch ihn bewirkten "Bann" zu brechen. ...
Letzte Fragen
(2004)
Eine Debatte anzuzetteln ist immer ein Risiko. Wer von den – sorgsam, wenn auch letztlich arbiträr ausgewählten – Angeschriebenen und Angesprochenen wird auf die freundliche Einladung einen freundlichen Absagebrief schreiben oder gar nichts schreiben oder nur telephonieren? Wer aus der weiten Welt der Rechtsgeschichte-Leser wird sich beteiligen, ohne ermuntert worden zu sein? Wer wird sich auf die Sache, und das heißt hier die Frage, einlassen? Und wie? Wird es eine spannende Debatte werden oder eine langweilige Bestandsaufnahme? Phantasie oder Inventur? Fußnoten oder Thesen? ...
Vom Kerbholz zur Konzernbilanz? : Wege und Holzwege zu einem autonomen Recht der global economy
(2004)
Die lex mercatoria, die sich abzeichnende transnationale Rechtsordnung der Weltmärkte, ist in aller Munde. Abgesehen von der vagen Idee eines eigenständigen privaten Rechts der internationalen Handels- und Wirtschaftsbeziehungen, das sich jenseits von nationalem Recht und Völkerrecht entwickeln soll, sind indes selbst die Grundfragen der mercatoristischen Doktrin im Streit: So fechten internationale Wirtschaftsjuristen "einen dreißigjährigen Krieg um die Frage der Unabhängigkeit der lex mercatoria aus, ohne daß Münster und Osnabrück in Sicht wären". Auch die Rechtsgeschichte wurde von den streitenden Parteien in diesen Glaubenskrieg verwickelt, geht die neue lex mercatoria angeblich doch zurück auf "das mittelalterliche universale Kaufmannsgewohnheitsrecht des interregionalen und internationalen Handels- und Wirtschaftsverkehrs, das sich außerhalb des römischen Rechts autonom und in eigenständigen handels- und gesellschaftsrechtlichen Formen entwickelt hatte". Strittig ist, ob die neue lex mercatoria ihren Namen zu Recht trägt oder nur dessen historische Dignität ausbeutet und dadurch eine ihr nicht zukommende Universalität und Autonomie suggeriert; kaum hinterfragt wurde dagegen, ob das immer wieder bemühte historische Vorbild auch tatsächlich die ihm zugeschriebenen Eigenschaften aufweist. ...
Solidarität!
(2004)
Rechtshistorikern ist das Thema der Solidarität – und das damit verbundene Antithema eines ausufernden Individualismus – alt vertraut. Die Frage des sozialen Defizits jener Privatrechtskodifikation, die uns das 19. Jahrhundert hinterlassen hat, gehört zu den Königsthemen der Disziplin, seit Menger und Gierke mit den rechtstheoretischen Protagonisten des BGB die Klingen kreuzten. Und vor allem die Diskurse des Arbeits-, Sozial- und Verfassungsrechts, aber beileibe nicht nur sie, haben sich seit jenen Tagen in eindringlicher Weise mit den Konsequenzen beschäftigt, die sich aus der Integration kollektiver und solidaristischer Elemente in die Rechtsstruktur für das Recht selbst und für seine innergesellschaftliche Umwelt ergeben haben. ...
Regieren durch Solidarität?
(2004)
In Thomas Bernhards "Am Ziel" blickt der Dramatische Schriftsteller auf die Familienkämpfe seiner Jugend zurück: "Sie zogen mir eine Jacke an und sagten – so das ist die lebenslängliche Jacke für dich – und ich zog die Jacke wieder aus. Sie zogen Sie mir an – und ich zog sie wieder aus – immer so fort sie zogen sie mir an – ich zog sie wieder aus." "Ich ging weg ich machte mich selbständig." Dann gleichsam bilanzierend: "Ich fühlte mich mit mir selbst solidarisch – mit keinem Andern – Ich rettete mich aus den Andern heraus." Und die Kommunikationspartnerin echot unwidersprochen: "Sie retteten sich auf Kosten der Ihrigen." ...
Case numbers of endemic Ca-deficiency rickets (CDR) have been reported to be alarmingly rising among children of subsistence farms in developing countries within the last 30 years. Fluoride toxicities in the environment are known to not be related to the disease. To investigate if, instead, CDR is caused by a nutrient deficiency in the environment, subsistence farms in an endemic CDR area near Kaduna, northern Nigeria, were investigated for bedrock, slope forms, soil types, and soil characteristics. The natural environment was investigated according to the World Reference Base, soil texture was analysed by pipette and sieving, and plant-available macronutrients were determined using barium-chloride or Ca-acetate-lactate extraction. The analyses showed that granite and slope deposits were the dominant parent materials. The typical slope forms and soil types were Lixisols and Acrisols on pediments, Fluvisols in river valleys, and Plinthosols and Acrisols on plains. Compared with West African background values, all of the soils had normal soil textures but were low in macronutrients. Comparisons to critical limits, however, showed that only the P concentrations were critically low, which are typical for savanna soils. A link between nutrient deficiency in soils and CDR in the Kaduna area was therefore considered unlikely.
The adaptive response of Sorghum bicolor landraces from Egypt to drought stress and following recovery was analyzed using two-dimensional difference gel electrophoresis, 2D-DIGE. Physiological measurements and proteome alterations of accession number 11434, drought tolerant, and accession number 11431, drought sensitive, were compared to their relative control values after drought stress and following recovery. Differentially expressed proteins were analysed by Matrix assisted laser desorption ionisation time-of-flight mass spectrometry, MALDI-TOF-MS. Alterations in protein contents related to the energy balance, metabolism (sensu Mewes et al. 1997), and chaperons were the most apparent features to elucidate the differences between the drought tolerant and sensitive accessions. Further alterations in the levels of proteins related to transcription and protein synthesis are discussed.
Vor gut 150 Jahren erschien 1852 der erste Band eines ebenso anspruchsvollen wie bis heute respektierten Buches unter dem Titel "Geist des römischen Rechts auf den verschiedenen Stufen seiner Entwicklung". Geschrieben hatte dieses Buch Rudolf Jhering, damals Professor des römischen Rechts in Gießen. Es sollte sein Lebenswerk bleiben – bis hinein in die große Fortsetzung zum "Zweck des Rechts". Das Buch hat Geschichte gemacht, denn der Autor suchte nicht Geschichten, sondern die Geschichte des Rechts überhaupt. Das Bleibende, die "letzten Gründe" trieben ihn um, so wie seinen Altergenossen Karl Marx, der lebenslang nach der "letzten Instanz" in aller Geschichte suchte. Beide waren fest überzeugt, dieses "Letzte" wissenschaftlich ermitteln zu können. Rechtsgeschichte betrieb Jhering daher zugleich als Universalgeschichte, allgemeine Rechtslehre und Rechtsphilosophie. Was das bedeuten kann und was davon bleibt, geht uns nach wie vor unmittelbar an. Auch wir hängen an den Marionettenfäden historischer und philosophischer Grundhaltungen und Grundbegriffe. Auch wir kommen ohne sie nicht aus. Wissenschaft kann und soll das bewusst machen. Die Unschuld der Naivität ist ihr nicht erlaubt. Dazu muss man zeigen, was dieser Jhering bedeutete, wer er war, welches Problem er mit seinem Hauptwerk aufnahm, und welche Lösungen er dafür anbot. ...
"Solidarität" ist ein Wieselwort von gallertartiger Konsistenz. Es ist allgegenwärtig, gibt sich bedeutungsschwer und meist auch etwas vorwurfsvoll. Sein Kontext ist durchweg normativ. Es taucht dort auf, wo es um den Appell an Personen auf der gleichen Ebene geht. Typischerweise rufen Gruppen nach "Solidarität", deren innere Bindungen bröckeln oder die sich in Gefahrenlagen zusammenscharen. Als es noch Standesgenossen gab, erinnerten sie gerne an die Solidarität, wenn es darum ging, den Zusammenhalt derselben Schicht zu wahren. Die alten Zünfte, Gilden, Gaffeln, Einungen und Genossenschaften waren Solidaritätsverbände. Die Arbeiterbewegung übernahm hiervon nicht nur das Wort "Genossen", sondern auch den Appell an die Klassensolidarität. Und selbst wer heutzutage einen Krieg führen will, erinnert an alte Dankesschulden und appelliert an die Solidarität der Bundesgenossen. ...
Epigraphic documents attest that the two neighbouring, inland sites, Idalion and Tamassos, were kingdoms during the Cypro-Archaic period, and that-within an interval of nearly a century - they were both incorporated by the kingdom of Kition during the Cypro-Classical period, thereby losing their independent status. The geographical position of Idalion and Tamassos must have been both a blessing and a curse: while the two polities could thrive on the exploitation of the nearby copper mines, they also had to withstand the economic interest of other Cypriote polities in these natural resources. In addition, we may assume that, because of their inland position, Idalion and Tamassos were forced to seek economic collaboration with polities that had direct access to the sea for the export and exchange of commodities beyond the island. We may further expect that the control of ore-mining and forestry activities must have been a potential source of territorial strife between the two inland kingdoms. Therefore, the geo-economic reality likely induced Idalion and Tamassos to a dualistic relationship of being both allies and competitors. ...
The development of image-guided neurosurgery represents a substantial improvement in the microsurgical treatment of tumors, vascular malformations and other intracranial lesions. Despite the wide applicability and many fascinating aspects of image-guided navigation systems, a major drawback of this technology is they use images, mainly MRI pictures, acquired preoperatively, on which the planning of the operative procedure as well as its intraoperative performance is based. As dynamic changes of the intracranial contents regularly occur during the surgical procedure, the surgeon is faced with a continuously changing intraoperative field. Only intraoperatively acquired images will provide the neurosurgeon with the information he needs to perform real intraoperative image-guided surgery. A number of tools have been developed in recent years, like intraoperative ultrasound and dedicated moveable intraoperative CT units. Because of its excellent imaging qualities, combined with the avoidance of ionizing radiation, MRI currently is and definitely will be in the future for the superior imaging method for intraoperative image guidance. In this short overview, the development as well as some of the current and possible future applications of MRI-guided neurosurgery is outlined.
Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a revival in the last decade. Mainly, it was used in concurrent combination with radiation in organ-preserving settings. The modern method of transfemoral approach for catheterisation, superselective perfusion of the tumour-feeding vessel, and high-dose (150 mg m−2) administration of cisplatin with parallel systemic neutralisation with sodium thiosulphate (9 g m−2) made preoperative usage feasible. The present paper presents the results of a pilot study on a population of 52 patients with resectable stage 1–4 carcinomas of the oral cavity and the oropharynx, who were treated with one cycle of preoperative IA chemotherapy executed as mentioned above and radical surgery. There have been no interventional complications of IA chemotherapy, and acute side effects have been low. One tracheotomy had to be carried out due to swelling. The overall clinical local response has been 69%. There was no interference with surgery, which was carried out 3–4 weeks later. Pathological complete remission was assessed in 25%. The mean observation time was 3 years. A 3-year overall and disease-free survival was 82 and 69%, respectively, and at 5 years 77 and 59%, respectively. Survival results were compared to a treatment-dependent prognosis index for the same population. As a conclusion, it can be stated that IA high-dose chemotherapy with cisplatin and systemic neutralisation in a neoadjuvant setting should be considered a feasible, safe, and effective treatment modality for resectable oral and oropharyngeal cancer. The low toxicity of this local chemotherapy recommends usage especially in stage 1–2 patients. The potential of survival benefit as indicated by the comparison to the prognosis index should be controlled in a randomised study.
In eukaryotes, double-stranded (ds) RNA induces sequence-specific inhibition of gene expression referred to as RNA interference (RNAi). We exploited RNAi to define the role of HER2/neu in the neoplastic proliferation of human breast cancer cells. We transfected SK-BR-3, BT-474, MCF-7, and MDA-MB-468 breast cancer cells with short interfering RNA (siRNA) targeted against human HER2/neu and analyzed the specific inhibition of HER2/neu expression by Northern and Western blots. Transfection with HER2/neu-specific siRNA resulted in a sequence-specific decrease in HER2/neu mRNA and protein levels. Moreover, transfection with HER2/neu siRNA caused cell cycle arrest at G0/G1 in the breast cancer cell lines SKBR-3 and BT-474, consistent with a powerful RNA silencing effect. siRNA treatment resulted in an antiproliferative and apoptotic response in cells overexpressing HER2/neu, but had no influence in cells with almost no expression of HER2/neu proteins like MDA-MB-468 cells. These data indicate that HER2/neu function is essential for the proliferation of HER2/neuoverexpressing breast cancer cells. Our observations suggest that siRNA targeted against human HER2/neu may be valuable tools as anti proliferative agents that display activity against neoplastic cells at very low doses.
Electric stimulation of the auditory nerve via cochlear implants has made the treatment of sensory deafness possible. Advanced signal processing and stimulation paradigms have led to continuously improved results in speech understanding. Consequently, indication criteria have been extended to patients with profound and severe-to-profound hearing loss and limited speech understanding with conventional acoustic amplification.
Outside this group, a considerable number of patients presents with rather wellpreserved, low frequency hearing of 30-60 dB up to 1 kHz, but severe loss in the mid to high frequency range of more than 60-70 dB. Monosyllabic word scores in these patients do not generally exceed 35%, due to missing consonant information. But, even increasing the audibility of these high frequencies by acoustic amplification still has very limited efficiency for discriminating speech, and therefore, these patients obtain only minor benefit from conventional hearing aids. On the other hand, standard cochlear implantation would carry a high risk of causing complete hearing loss. This situation has led to considering a combination of both modes of stimulation for these patients who are on the borderline between hearing aids and cochlear implant.
In our present model, the surviving low frequency region of the cochlea could still be stimulated acoustically-combined with additional electrical stimulation of the impaired mid and high frequency region of the cochlea.
Several questions still have to be answered with regard to combined electric and acoustic stimulation (EAS). The possible interaction of electric and acoustic stimuli on the different levels off the auditory system is a major issue. Animal experiments clearly demonstrate that tuning properties of auditory neurons, in response to acute acoustic stimulation, are essentially preserved in the presence of electric stimulation even at high levels of electric stimulation, and that chronic electric stimulation of tie intact inner ear does not have a significant effect on the compound action potentials (CAP) thresholds or inner ear function.
In a previous report, we were able to show that this combined F.A.S of the auditory system is possible in humans, and that it has a synergistic effect on speech understanding. Further major issues regard the surgical feasibility and reproducibility of cochlear implantation with the preservation of residual hearing.
Encouraged by our findings, a clinical study was initiated on the application of EAS. So far, seven adults have been included in this study. In addition, one child has been implanted outside the study.
A small electrostatic storage ring is the central machine of the Frankfurt Ion Storage Experiments (FIRE) which will be built at the new Stern-Gerlach Center of Frankfurt University. As a true multiuser, multipurpose facility with ion energies up to 50 keV, it will allow new methods to analyze complex many-particle systems from atoms to very large biomolecules. With envisaged storage times of some seconds and beam emittances in the order of a few mm mrad, measurements with up to 6 orders of magnitude better resolutions as compared to single-pass experiments become possible. In comparison to earlier designs, the ring lattice was modified in many details: Problems in earlier designs were related to, e.g., the detection of light particles and highly charged ions with different charge states. Therefore, the deflectors were redesigned completely, allowing a more flexible positioning of the diagnostics. Here, after an introduction to the concept of electrostatic machines, an overview of the planned FIRE is given and the ring lattice and elements are described in detail.
Quantitative analysis of the cardiac fibroblast transcriptome implications for NO/cGMP signaling
(2004)
Cardiac fibroblasts regulate tissue repair and remodeling in the heart. To quantify transcript levels in these cells we performed a comprehensive gene expression study using serial analysis of gene expression (SAGE). Among 110,169 sequenced tags we could identify 30,507 unique transcripts. A comparison of SAGE data from cardiac fibroblasts with data derived from total mouse heart revealed a number of fibroblast-specific genes. Cardiac fibroblasts expressed a specific collection of collagens, matrix proteins and metalloproteinases, growth factors, and components of signaling pathways. The NO/cGMP signaling pathway was represented by the mRNAs for α1 and β1 subunits of guanylyl cyclase, cGMP-dependent protein kinase type I (cGK I), and, interestingly, the G-kinase-anchoring protein GKAP42. The expression of cGK I was verified by RT-PCR and Western blot. To establish a functional role for cGK I in cardiac fibroblasts we studied its effect on cell proliferation. Selective activation of cGK I with a cGMP analog inhibited the proliferation of serum-stimulated cardiac fibroblasts, which express cGK I, but not higher passage fibroblasts, which contain no detectable cGK I. Currently, our data suggest that cGK I mediates the inhibitory effects of the NO/cGMP pathway on cardiac fibroblast growth. Furthermore the SAGE library of transcripts expressed in cardiac fibroblasts provides a basis for future investigations into the pathological regulatory mechanisms underlying cardiac fibrosis.
The objective of this paper is the study of the equilibrium behavior of a population on the hierarchical group ΩN consisting of families of individuals undergoing critical branching random walk and in addition these families also develop according to a critical branching process. Strong transience of the random walk guarantees existence of an equilibrium for this two-level branching system. In the limit N→∞ (called the hierarchical mean field limit), the equilibrium aggregated populations in a nested sequence of balls B(N)ℓ of hierarchical radius ℓ converge to a backward Markov chain on R+. This limiting Markov chain can be explicitly represented in terms of a cascade of subordinators which in turn makes possible a description of the genealogy of the population.
Balloon-borne measurements of CFC-11 (on flights of the DIRAC in situ gas chromatograph and the DESCARTES grab sampler), ClO and O3 were made during the 1999/2000 winter as part of the SOLVE-THESEO 2000 campaign. Here we present the CFC-11 data from nine flights and compare them first with data from other instruments which flew during the campaign and then with the vertical distributions calculated by the SLIMCAT 3-D CTM. We calculate ozone loss inside the Arctic vortex between late January and early March using the relation between CFC-11 and O3 measured on the flights, the peak ozone loss (1200 ppbv) occurs in the 440–470 K region in early March in reasonable agreement with other published empirical estimates. There is also a good agreement between ozone losses derived from three independent balloon tracer data sets used here. The magnitude and vertical distribution of the loss derived from the measurements is in good agreement with the loss calculated from SLIMCAT over Kiruna for the same days.
Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.
Two tetrahydroisoquinoline alkaloids were extracted from the alkaloid fraction of a methanol extract of the seeds of Calycotome Villosa Subsp. intermedia. Their structures were established as (R)-1-hydroxymethyl-7-8-dimethoxy-1,2,3,4-tetrahydro- isoquinoline (1) and (S)-7-hydroxymethyl-2-3-dimethoxy-7,8,9,10-tetrahydroisoquinoline chloride (2) by spectroscopic techniques and X-ray diffraction analysis.
We have used the SLIMCAT 3-D off-line chemical transport model (CTM) to quantify the Arctic chemical ozone loss in the year 2002/2003 and compare it with similar calculations for the winters 1999/2000 and 2003/2004. Recent changes to the CTM have improved the model's ability to reproduce polar chemical and dynamical processes. The updated CTM uses σ-θ as a vertical coordinate which allows it to extend down to the surface. The CTM has a detailed stratospheric chemistry scheme and now includes a simple NAT-based denitrification scheme in the stratosphere.
In the model runs presented here the model was forced by ECMWF ERA40 and operational analyses. The model used 24 levels extending from the surface to ~55 km and a horizontal resolution of either 7.5°×7.5° or 2.8°×2.8°. Two different radiation schemes, MIDRAD and the CCM scheme, were used to diagnose the vertical motion in the stratosphere. Based on tracer observations from balloons and aircraft, the more sophisticated CCM scheme gives a better representation of the vertical transport in this model which includes the troposphere. The higher resolution model generally produces larger chemical O3 depletion, which agrees better with observations.
The CTM results show that very early chemical ozone loss occurred in December 2002 due to extremely low temperatures and early chlorine activation in the lower stratosphere. Thus, chemical loss in this winter started earlier than in the other two winters studied here. In 2002/2003 the local polar ozone loss in the lower stratosphere was ~40% before the stratospheric final warming. Larger ozone loss occurred in the cold year 1999/2000 which had a persistently cold and stable vortex during most of the winter. For this winter the current model, at a resolution of 2.8°×2.8°, can reproduce the observed loss of over 70% locally. In the warm and more disturbed winter 2003/2004 the chemical O3 loss was generally much smaller, except above 620 K where large losses occurred due to a period of very low minimum temperatures at these altitudes.
Since the description of sepsis by Schottmüller in 1914, the amount on knowledge available on sepsis and its underlying pathophysiology has substantially increased. Epidemiologic examinations of abdominal septic shock patients show the potential for high risk posed by and the extensive therapy situation in the intensive care unit (ICU) (5). Unfortunately, until now it has not been possible to significantly reduce the mortality rate of septic shock, which is as high as 50-60% worldwide, although PROWESS' results (1) are encouraging. This paper summarizes the main results of the MEDAN project and their medical impacts. Several aspects are already published, see the references. The heterogeneity of patient groups and the variations in therapy strategies is seen as one of the main problems for sepsis trials. In the MEDAN multi-center study of 71 intensive care units in Germany, a group of 382 patients made up exclusively of abdominal septic shock patients who met the consensus criteria for septic shock (3) was analysed. For use within scores or stand-alone experiments variables are often studied as isolated variables, not as a multidimensional whole, e.g. a recent study takes a look at the role thrombocytes play (15). To avoid this limitation, our study compares several established scores (SOFA, APACHE II, SAPS II, MODS) by a multi-dimensional neuronal network analysis. For outcome prediction the data of 382 patients was analysed by using most of the commonly documented vital parameters and doses of medicine (metric variables). Data was collected in German hospitals from 1998 to 2001. The 382 handwritten patient records were transferred to an electronic database giving the amount of 2.5 million data entries. The metric data contained in the database is composed of daily measurements and doses of medicine. We used range and plausibility checks to allow no faulty data in the electronic database. 187 of the 382 patients are deceased (49 %).
Data driven automatic model selection and parameter adaptation – a case study for septic shock
(2004)
In bioinformatics, biochemical pathways can be modeled by many differential equations. It is still an open problem how to fit the huge amount of parameters of the equations to the available data. Here, the approach of systematically learning the parameters is necessary. This paper propose as model selection criterion the least complex description of the observed data by the model, the minimum description length. For the small, but important example of inflammation modeling the performance of the approach is evaluated.
In bioinformatics, biochemical signal pathways can be modeled by many differential equations. It is still an open problem how to fit the huge amount of parameters of the equations to the available data. Here, the approach of systematically obtaining the most appropriate model and learning its parameters is extremely interesting. One of the most often used approaches for model selection is to choose the least complex model which “fits the needs”. For noisy measurements, the model which has the smallest mean squared error of the observed data results in a model which fits too accurately to the data – it is overfitting. Such a model will perform good on the training data, but worse on unknown data. This paper propose as model selection criterion the least complex description of the observed data by the model, the minimum description length. For the small, but important example of inflammation modeling the performance of the approach is evaluated. Keywords: biochemical pathways, differential equations, septic shock, parameter estimation, overfitting, minimum description length.
In bioinformatics, biochemical pathways can be modeled by many differential equations. It is still an open problem how to fit the huge amount of parameters of the equations to the available data. Here, the approach of systematically learning the parameters is necessary. In this paper, for the small, important example of inflammation modeling a network is constructed and different learning algorithms are proposed. It turned out that due to the nonlinear dynamics evolutionary approaches are necessary to fit the parameters for sparse, given data. Keywords: model parameter adaption, septic shock. coupled differential equations, genetic algorithm.
We report on the rapidity and centrality dependence of proton and antiproton transverse mass distributions from 197Au + 197Au collisions at sqrt[sNN ]=130 GeV as measured by the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). Our results are from the rapidity and transverse momentum range of |y| <0.5 and 0.35< pt <1.00 GeV/c . For both protons and antiprotons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y| <0.5 . Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton (antiproton) yields and transverse mass distributions the possibility of prehadronic collective expansion may have to be taken into account.
We report results on rho (770)0--> pi + pi - production at midrapidity in p+p and peripheral Au+Au collisions at sqrt[sNN]=200 GeV. This is the first direct measurement of rho (770)0--> pi + pi - in heavy-ion collisions. The measured rho 0 peak in the invariant mass distribution is shifted by ~40 MeV/c2 in minimum bias p+p interactions and ~70 MeV/c2 in peripheral Au+Au collisions. The rho 0 mass shift is dependent on transverse momentum and multiplicity. The modification of the rho 0 meson mass, width, and shape due to phase space and dynamical effects are discussed.
The main results obtained within the energy scan program at the CERN SPS are presented. The anomalies in energy dependence of hadron production indicate that the onset of deconfinement phase transition is located at about 30 A GeV. For the first time we seem to have clear evidence for the existence of a deconfined state of matter in nature. PACS numbers: 24.85.+p
The transverse mass mt distributions for deuterons and protons are measured in Pb+Pb reactions near midrapidity and in the range 0<mt–m<1.0 (1.5) GeV/c2 for minimum bias collisions at 158A GeV and for central collisions at 40 and 80 A GeV beam energies. The rapidity density dn/dy, inverse slope parameter T and mean transverse mass <mt> derived from mt distributions as well as the coalescence parameter B2 are studied as a function of the incident energy and the collision centrality. The deuteron mt spectra are significantly harder than those of protons, especially in central collisions. The coalescence factor B2 shows three systematic trends. First, it decreases strongly with increasing centrality reflecting an enlargement of the deuteron coalescence volume in central Pb+Pb collisions. Second, it increases with mt. Finally, B2 shows an increase with decreasing incident beam energy even within the SPS energy range. The results are discussed and compared to the predictions of models that include the collective expansion of the source created in Pb+Pb collisions.