Type II secretion system

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Identification of cellular mechanisms interfering with the Helicobacter pylori cag type IV secretion system

Identification of cellular mechanisms interfering with the Helicobacter pylori cag type IV secretion system

(Molecular Devices), Ionomycin (Sigma), Cycloheximide (ready made, Sigma-Aldrich), Rotiphorese NF-Acrylamid / Bis-Lösung 30% (Roth), Ammonium Persulfate (Sigma), Tetramethylethylenediamine (TEMED, Sigma), 2,2,2-Trichlorethanol (Aldrich), TMB substrate (BD-Biosciences), Immobilon Western developing solution (Millipore), Vectastain ABC HRP Kit (Vector Laboratories), Tween-20 (Roth), Phenylmethylsulfonyl fluoride (PMSF, in Isopropanol, Sigma), Leupeptin (in H2O, Sigma), Pepstatin A (in Methanol, Sigma), Ortho-Vanadate (in H2O, Sigma), DNAse I from bovine pancreas grade II (Roche), L-Serine (Roth), Glycin (MP Biomedicals), L-Asparagin-monohydrat (Sigma), Ethanol (Roth), propidium iodid (10µg/ml, MACS Miltenyl Biotech), QIAmp DNA Mini Kit (250) (Qiagen), Sodiumchlorid >99,5% (Roth), Precision Plus Protein All Blue Standard (BioRad), Bovin Serum Albumin, Fraction V (BSA, Biomol), Methanol (Roth), Sodium-Dodecylsulfate in pellets (SDS, Serva), Glycerol >99,5% (Roth), Ethylenediamine-tetraaceticacid (EDTA, Roth); Sulfuric acid (H2SO4, Merck), Tris(hydroxymethyl)-aminomethan (TRIS, MP Biomedicals), Hydrochloric acid (Roth), Sodium dihydrogen phosphate (NaH2PO4, Sigma), Nonylphenylpolyethylene glycol (NP-40, Fluka), Sodium deoxycholate (Sigma),
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Nucleic acid transit through the R1-16 type 4 secretion system / Paul Kirchberger

Nucleic acid transit through the R1-16 type 4 secretion system / Paul Kirchberger

A knockout of nic and consequently oriT sites could not be complemented with a mobilizable plasmid containing the R1 oriT site. This plasmid can be readily transferred in conjugation by facilitating the assembly of a different relaxosome on its oriT site. Several reasons for this are possible: I) The involvement of additional plasmid encoded factors necessary for the infection of R17. One set of such factors might be located at the parMRC locus, which will be discussed later on. II) Simple competition for relaxosome components between the R1 oriT sites of several copies of the mobilizable plasmids. The cell might simply not express enough proteins for successful relaxosome assembly on all plasmids, thus preventing normal T4SS function. This problem could be prevented by the addition of a mobilizable plasmid containing its own relaxosome complex. III) Furthermore, plasmid size might be somehow relevant in the infection process. One might speculate that smaller DNA substrates result in a shorter T4SS activation time, too short to facilitate phage infection. A simple way to test this hypothesis would be the complementation of an infection deficient
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One ring to rule them all : Identification and characterization of the type IV pili secretin associated protein TsaP and analysis of the type IV secretion system of Neisseria gonorrhoeae

One ring to rule them all : Identification and characterization of the type IV pili secretin associated protein TsaP and analysis of the type IV secretion system of Neisseria gonorrhoeae

manner; the deletion of the LysM domain results in reduced motility, secretin levels and surface piliation. Wehbi et al. could show that FimV promotes secretin formation, which depends on the PG- binding domain LysM [155, 156]. LysM domains are used by bacteria to keep specific proteins at the cell surface by attaching them in a non-covalently manner to the peptidoglycan. The LysM domain was discovered as a epeat of a i o a ids i the l soz e of the Ba illus phage φ [157]. Now that many genomes have been sequenced, the LysM domain has been identified in many proteins like bacterial lysins, bacteriophage proteins, bacterial peptidoglycan hydrolases, peptidases, chitinases, esterases, reductases and nucleotidase and even in some eukaryotic proteins. They have not been identified in archaeal proteins [158]. The number of this domain per protein and the position(s) within the proteins differ. A Hidden Markov model showed that the LysM sequence is conserved over the first 16 amino acids and less conserved over the last 10 residues. The first solved LysM structure was the LysM domain of the outer membrane-bound lytic murein transglycosylase MltD of E. coli . The st u tu e of MltD sho ed a βααβ se o da st u tu e ith the t o α-helices pa ki g o to the sa e side of a a tipa allel β-sheet [159]. In general LysM containing proteins can be classified into two categories, (i) PG-binding proteins and (ii) PG-hydrolyzing proteins. So far, most of the proteins encoding a LysM domain belong to the PG-hydrolyzing category. Nevertheless, PG- binding proteins have been identified, such as FimV of P. aeruginosa or AcmA of Lactococcus lactis [156, 160].
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Scale-up of a Type I secretion system in E. coli using a defined mineral medium

Scale-up of a Type I secretion system in E. coli using a defined mineral medium

density (open stars) also increases exponentially. In contrast to that, induction with 10 mM (=1.5 g/L) arabinose leads to a phase of constant OTR after induction (Figure 3a, middle diagram, open circles and closed squares), which is followed by a slight kink after around 9 hr. Afterward, the OTR increases exponentially until glycerol is depleted. This behavior is independent of the presence of IPTG. The offline data for the culture induced with 10 mM (=1.5 g/L) arabinose and IPTG (Figure 3a, bottom diagram) prove that the cultivation can be divided into four different phases that are already visible from the OTR signal itself: In the first 3 hr (Phase I) the cells grow non-induced on glycerol (Figure 3a, bottom, open squares). In this phase no expression and secretion of HlyA1 occurs (Figure 3b,c). During Phase II, the optical density (Figure 3a, bot- tom diagram, closed stars) increases only slightly and arabinose (Figure 3a, bottom diagram, open triangles) is consumed. The amount of HlyA1 in the supernatant increases over time (Figure 3b). This “induc- tion phase ” is reflected by a constant level of the OTR. The phenome- non of a more or less constant OTR after induction is well known from auto-induction media containing glucose, lactose, and glycerol. Several studies identified a phase of rather constant OTR after induction with IPTG or its analogue lactose as production phase and indication of the strength of metabolic burden. 33,44,45 An equivalent behavior is shown
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Cortisol secretion patterns in the elderly

Cortisol secretion patterns in the elderly

Psychological stress, by the activation of the HPA axis, plays a key role in the development of frailty and cognitive impairment. This thesis presented novel findings on the detrimental effects of dysregulated cortisol, in specific cortisol secretion patterns, on two important age- related conditions, namely the frailty syndrome and cognitive function as presented in manuscripts 1 and 2, respectively. Firstly, this thesis confirms and expands the view that blunted diurnal cortisol responses were observed in both men and women with increasing frailty burden. Findings from manuscript 1 successfully identify that the lack of diurnal variability, as reflected by a lower morning to evening cortisol ratio, is associated with frailty burden. Our observations support the predominant role of muscle atrophy, reflected in the grip strength and gait speed criteria, and cortisol dysregulation even in the pre-frail state.
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Gutenberg Open Science: Geometry and supersymmetry in type II string theory

Gutenberg Open Science: Geometry and supersymmetry in type II string theory

In the first part, I treat only the purely geometric properties of the concrete setup that I will use in my thesis for the internal six-dimensional space of type IIA string theory. The concrete structure of this background space and of certain subspaces thereof is crucial for my work, and this is why I will present the characteristics here at full length. After that, I summarise the physical quantities that appear in these backgrounds in type IIA string theory, i.e. bosonic and fermionic fields, generated by certain oscillation modes of closed and open strings. I will mostly restrict the discussion to the different kinds of massless bosonic fields since these have important implications for the deformations, and especially because these incorporate the aforementioned K¨ ahler and complex structure moduli. In addition, the higher-dimensional physical Dp-branes and Op-planes will be introduced, as mentioned in the introductory chapter 1, which play a major role in string model building.
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Formal verification of the equivalence of system F and the pure type system L2

Formal verification of the equivalence of system F and the pure type system L2

Note that the relative ordering of universal and generic quantifiers is highly relevant. To see why, let us consider the expression ∀L.∇x.L. The freshness guarantees which follow from the axioms governing ∇ ensure that x does not occur in L. More generally, a ∇-bound identifier is guaranteed to be fresh for everything that is bound above the respective ∇. This includes, in particular, those identifiers in Abella theorems without any explicit binder, as these are assumed to be universally bound at the top level of the theorem. In contrast to this, the term L in the body of ∇x.∀L.L, may have free occurrences of x. If we want to change the order of the quantifiers without changing the meaning of the expression, we have to employ a technique known as raising, which can be seen as dual to Skolemisation [MN12, cf. Section 4.4.1]. For the present example, this yields ∀L.∇x.L x. Since L is now syntactically prevented from having free occurrences of x, it has to take x as an explicit argument. Note that raising changes the type of L to incorporate this added dependency. One says that L is raised over the type of x. It may of course be the case that the type of x is not a subordinate of the type of L. In this case, no (vacuous) abstraction is formed and we simply obtain ∀L.∇x.L, without any changes to the type of L.
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Prevalence of prediabetes and diabetes mellitus type II in bipolar disorder

Prevalence of prediabetes and diabetes mellitus type II in bipolar disorder

had a BMI >= 25. In our BiDi sample, 78% of the participants had a BMI > 25. Taken together, we propose that overweight and obesity might be the mediating factors between BD and T2D, and that the risk for T2D in BD in comparison to the general population may not be increased in BD as such but rather the risk towards obesity. A previous Italian study and a follow-up study could also show that abdominal obesity as a major factor of the metabolic syndrome was associated with a higher rate of T2D in bipolar patients ( 54 , 55 ). The higher rate of obesity can be due to either lifestyle factors (food pattern, sedentary lifestyle), medication in fluence (especially second-generation antipsychotics such as olanzapine and quetiapine) ( 56 ) as well as shared risk genes for BD and BMI ( 57 ). However, as a limiting factor in our study, we did not include other factors that, especially in men, have shown to increase the risk of T2D like smoking and arterial hypertension ( 58 , 59 ). In our sample, there was however no signi ficant difference between the types of mood stabilizing medication in the diabetic vs. the nondiabetic group. But then, also valproate and lithium can lead to weight gain and not only atypical antipsychotics ( 19 , 60 ). Also, our sample size in the medication subgroups was too small to make de finite conclusions hereon. Interestingly, in a multivariate analysis comparing the nondiabetic and (pre-)diabetic bipolar groups, disease duration and number of depressive episodes, as well as BMI and age, remained statistically signi ficant between the groups. Furthermore, metabolic parameters were significantly correlated with the number of depressed episodes. There are previous studies that suggest that comorbid insulin resistance, diabetes mellitus type II, and an increased BMI might lead to a more severe course in bipolar patients ( 61 – 63 ). From our data, we might conclude that increased BMI is the major contributor to an increased risk for T2D in BD in comparison to the general population; however, disease duration and depressive polarity might add to the risk of developing T2D in BD patients. However, as our study was a cross-sectional and not a longitudinal study, we cannot con firm the direction of the association of impaired metabolic parameters and a more severe course. Diagnosing and monitoring of overweight and prediabetes and T2DM in BD are furthermore of importance as there is growing evidence that impaired glucose metabolism and
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Bixbyite-type phases in the system Ta-Zr-O-N

Bixbyite-type phases in the system Ta-Zr-O-N

It is remarkable that the quaternary system Ta–Zr– O–N has also been investigated in detail. The first publica- tion about this topic was presented by Schönberg in 1954 [40], and the most comprehensive work was presented by Grins et al. [41]. They reported on synthesis and charac- terization of phase-pure baddeleyite- and anosovite-type phases, which can be derived from m-ZrO 2 /β-TaON and Ta 3 N 5 , respectively. In addition, a cubic and an orthorhom- bic phase, both obtained as side phases, have also been reported. Unfortunately, a detailed description of those phases was not possible. Investigations regarding the optical properties of the phase-pure baddeleyite- and anosovite-type compounds were presented later [42, 43]. The existence of a high-pressure polymorph of TaZrO 3 N
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Cross-talk between type three secretion system and metabolism in Yersinia.

Cross-talk between type three secretion system and metabolism in Yersinia.

native gel electrophoresis to test binding of recombinant PEPC to recombinant YscM1 and YscM2, respectively. Fig. 1A displays a Coomassie-stained native gel, demonstrating that GST-YscM1 causes a mobility shift of PEPC. PEPC mobility was also shifted in the presence of YscM1 released from GST (Fig. 1B). Electrophoretic mobility of PEPC was only slightly retarded when it was incubated with YscM2 prior to gel loading. Therefore, the native gel was electroblotted to verify the YscM2/PEPC interaction (Fig. 1C). The same blot was developed with anti-PEPC and anti-YscM2 sera successively. YscM2, when loaded alone, could not be detected, because YscM2 did not enter the gel under the conditions applied (38). This is due to the basic isoelectric point of YscM2 (9.79) and a pH of 7.4 of the native gel system. However, when a mixture of PEPC and YscM2 was applied on the gel, YscM2 co- localized with PEPC and could be detected after immunoblotting. Taken together, recombinant PEPC interacts with recombinant YscM1 and YscM2, respectively.
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Angiotensin II type 2 receptor stimulation: a novel options of therapeutic interference with the renin-angiotensin system
in myocardial infarction?

Angiotensin II type 2 receptor stimulation: a novel options of therapeutic interference with the renin-angiotensin system in myocardial infarction?

Cardiovascular MRI has a high spatial resolution and moderate temporal resolution. It is a well-validated standard for the assessment of myocardial function. Cardiac- triggered cine and scar magnetic resonance imaging was performed on a conventional clinical 3.0 Tesla scanner (Philips Achieva CV 3.0T, Best, The Netherlands) equipped with a QuasarDual gradient system (80mT/m; 200mT/m/ms slew rate) using specifically designed software (release 2.5.1 with implementation of a small animal software patch developed by GyroTools Ltd., Zurich, Switzerland). All animals were examined in the supine position and placed in a solenoid radiofrequency coil used for signal detection. Cardiac synchronization was
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Niacin supplementation induces type II to type I muscle fiber transition in skeletal muscle of sheep

Niacin supplementation induces type II to type I muscle fiber transition in skeletal muscle of sheep

Type I fibers, also called slow-twitch oxidative fibers, contain a high number of mitochondria, have a high oxi- dative capacity, and preferentially use fatty acids for en- ergy production [8,9]. This oxidative metabolic phenotype of type I fibers is the consequence of a markedly higher expression of genes involved in fatty acid transport and uptake, β-oxidation, carnitine shuttle, TCA cycle and re- spiratory chain compared to glycolytic type II fibers [26,27]. In addition, type I fibers exhibit a higher expres- sion of angiogenic factors, like VEGFA, which favors the preferential use of fatty acids by type I fibers because an- giogenic factors increase capillary density and thereby blood perfusion but also the expression of fatty acid trans- port proteins [29]. In the present study we could demon- strate that several genes encoding proteins involved in oxidative metabolism (SDHA, COX5A, COX6A1, VEGFA, CPT1B, SLC25A20) were up-regulated in the muscles of the niacin group compared to the control group which is in line with the niacin-induced changes in fiber type distri- bution and expression of MHC isoforms. Although we did not provide data showing that the increased expression of oxidative genes is also accompanied by an enhanced activ- ity of the encoded enzymes and an elevated capillary dens- ity, we suggest that the niacin-induced changes in skeletal muscle mRNA levels are indicative of an improved oxida- tive capacity because it is well known that the changes in the muscle’s metabolic and contractile phenotype are in- duced at the transcriptional level through an enhanced ac- tivity of PGC-1α and PPARδ [26,27].
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Role of the type VI secretion systems during disease interactions of Erwinia amylovora with its plant host

Role of the type VI secretion systems during disease interactions of Erwinia amylovora with its plant host

The lambda red recombination system [38] was used to replace consecutive genes EAMY_3020–3021 and EAMY_3227–3228 (coding for TssB1/TssC1 and TssB2/ TssC2) in both T6SS clusters. The resulting single mu- tants were named T6-d1, T6-d3, and the double mutant T6-d1d3. Plasmids used are listed in Table 1. Plasmid pKD3 was used as template to amplify the chloram- phenicol resistance cassette with the primer pairs listed in Additional file 1: Table S1. PCR products were intro- duced by electroporation into competent E. amylovora CFBP 1430 cells carrying plasmid pKD46. The single mutants were constructed by deletion of the complete reading frames of tssB/tssC in each cluster. To create the double mutant, the plasmid pKD46 was removed from the T6-d1 by overnight incubation on LB plates at 37 °C and colonies were screened for loss of antibiotic resistance. Plasmid pCP20 was introduced to eliminate the chloramphenicol resistance cassette and mutation of tssB/tssC in T6SS-3 was performed as described above. All knock-out mutants were confirmed by PCR and sequencing.
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Seeking a Type: the Czech Party System after 1989

Seeking a Type: the Czech Party System after 1989

The later history of party systems from the 1980s onward show up some of the problematic spots in Sartori’s typology. These concern not only some characteris- tics of certain selected model types of party system, which we will discuss below (the concept of an anti-systemic party or the term “polarization”), but also some of the unspoken assumptions behind Sartori’s approach. Sartori implicitly worked with a concept under which a single political system contained a single party sys- tem. The decentralization of (not only) European polities which has taken place in the meantime, has led some political scientists to reevaluate the dimension within which current party systems must be examined. Luciano Bardi and Peter Mair (2008: 154 and subsequent) in their article recommend working with three dimen- sions within polities: vertical, horizontal, and functional. The vertical dimension does not concern the Czech party system much, for it applies to a segmented society in which the reduction of party competition to left-right competition might not be applied; but this is not the Czech case. Bardi and Mair apply the horizontal division to countries in which there has been a federalization or major decentralization, and thus present an example of multi-level governance and therefore of multi-level party competition. The Czech Republic is not a strongly decentralized polity in which regional elections are an independent electoral contest of a major kind; in- stead the party system is structured primarily on the nation-wide level.
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Type I interferon promotes alveolar epithelial type II cell survival during pulmonary inflammation / submitted by Barbara Maier

Type I interferon promotes alveolar epithelial type II cell survival during pulmonary inflammation / submitted by Barbara Maier

The homeostasis of several immune cell populations is dependent on constitutive low-level secretion of IFN-ß. IFNAR deficient mice, that are not able to process IFN-I signals, show decreased numbers of NK-cells and B-cells in the spleen and enhanced responsiveness of myeloid populations to Csf-1 [95,96]. Macrophage function is modulated by constitutive IFN-I signaling, indicated by the decreased phagocytic capacity of macrophages incapable of mounting IFN-I responses in response to LPS [97]. Also the bone resorption function of osteoclasts is impaired in the absence of IFNAR in mice [98]. Another important aspect of baseline IFN-I signaling is the modulation of expression levels of STAT proteins. In case the relative abundance between STAT proteins is shifted, hetero- or homodimer formation using specific forms of STAT is favored which in turn leads to a bias in signal transduction [99]. In steady state thymic epithelial cells show the highest detectable IFN-ß expression shown with a luciferase reporter mouse. Other IFN-ß expressing tissues are spleen, lymph nodes, liver, kidney and intestine [100].
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Biochemical characterization of the relaxase TraI, the coupling protein TraD and the hypothetical protein Yaf of the novel Type IV Secretion System from the human pathogen Neisseria gonorrhoeae

Biochemical characterization of the relaxase TraI, the coupling protein TraD and the hypothetical protein Yaf of the novel Type IV Secretion System from the human pathogen Neisseria gonorrhoeae

Page | 23 Relaxases fulfill several functions simultaneously to enable the conjugative DNA processing and transfer in T4SSs (212). Therefore, these proteins usually consist of at least two different domains, which are an N-terminal relaxase domain responsible for the DNA cleavage, a helicase domain that unwinds in an ATP dependent reaction the cleaved DNA strand from the 5’ to the 3’ direction, and sometimes an additional C-terminal domain (e.g. DUF1528) for protein-protein interactions that contains also a signal sequence to trigger the nucleo-protein complex to the secretion pore (103, 105, 212, 235). The composition of the distinct domains varies within different relaxases and strongly influences the mechanism of DNA processing. Biochemical data has revealed that the enzymatic activity of the helicase domain provides the required force that is necessary for a sufficient strand transfer (e.g. TraI F ) (212). However, not all relaxases contain a helicase domain (e.g. TraI RP4 ) and use external replicative helicases to unwind the DNA (212). The relaxase domain is the only domain which is present in all relaxases and catalyzes the cleavage of the dsDNA at the nic site in the oriT region. The nicking reaction of relaxases is a site- and strand-specific transesterification reaction (212). The free energy released from the broken phosphoester-bond is restored in the covalent attachment of the 5’ end of the DNA to the relaxase via a phosphotyrosyl-linkage. The resulting nucleo-protein complex forms a stable long-term intermediate (209, 236-238). The 3’ end of the nicked transfer DNA strand remains bound to the relaxase during the unwinding process, keeping the superhelical topology of the DNA, but does not form a covalent bond with the protein (209, 236, 238). This bond is released after terminating the unwinding of the DNA and the single stranded T-DNA is further transferred via the secretion complex. The nicking reaction is terminated by a
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Definition of a Type System for Generic and Reflective Graph Transformations

Definition of a Type System for Generic and Reflective Graph Transformations

In the automotive industry, the model-driven development has become a standard. MATLAB/Simulink/Stateflow, as domain-specific language, provides the suitable support for specifying, designing, implementing, and checking the functionality of new control functions. Embedded controller software is either manually developed by programmers using MATLAB SL/SF models as executable requirements speci- fications or generated automatically by code generators which translate MATLAB SL/SF models into rather efficient C code. In both cases the reliability, robust- ness, and efficiency of the developed code heavily depends on the quality of the specified models. The reliability and robustness of the code are essential in the context of safety-critical systems like many automotive embedded software. The efficiency is also important since the resources of the embedded system on which the generated code is running are limited. Therefore, generally accepted modeling guidelines such as the MathWorks Automotive Advisory Board (MAAB) guide- lines [Mat07] are usually adopted. We will present some MAAB guidelines in Section 3.1.2. The guidelines support the developer in preventing typical model- ing problems, for instance non-connected elements. They also define conventions such as naming convention or element setting that facilitate the team working and improve the reusability of the models.
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Das EWS II - ein europäisches System à la Bretton Woods?

Das EWS II - ein europäisches System à la Bretton Woods?

nicht gefährdet werden, bedarf es einer gemeinsamen Wechselkurspolitik von Teilnehmerländern und - vorläufigen - Nichtteilnehmerländern. Wie könnte ein sinnvolles Wechselkurssystem aussehen? W enn die Europäische Währungsunion (EWU) planmäßig zum 1.1.1999 in Kraft treten wird, werden w ahrscheinlich nicht alle E U-M itgliedstaaten von Anfang an teilnehm en. Es stellt sich dam it die Fra­ ge, w ie das Wechselkursarrangement zwischen dem Euro und den verbleibenden EU-W ährungen ausse­ hen soll. Von d er A n tw o rt auf diese Frage hängt m ög­ licherw eise auch das weitere Schicksal der EWU ab: Nur w enn aus S icht der potentiellen N ichtteilnehm er eine zufriedenstellende Lösung gefunden w ird, w er­ den sie darauf verzichten, beider entscheidenden S it­ zung des Europäischen Rates im Frühjahr 1998 die Auswahl de r Teilnehmerländer und dam it den weiteren Weg in die W ährungsunion zu blockieren. Um gekehrt w erden einige potentielle Teilnehmerländer nur dann m it der W ährungsunion vorangehen w ollen, wenn sta­ bile oder zum indest kontrollierbare W echselkurse m it den Nichtteilnehm ern gewährleistet sind. W elche Ge­ fahren werden bei einer monetären Spaltung der EU in EW U-Teilnehm er („Ins“ ) und EW U -N ichtteilnehm er („O uts“) befürchtet? Welche Ziele werden dem nach m it einem solchen Wechselkursarrangement, einem EWS II, verfolgt?
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Konzept und Ziel der »Experimentierklausel« nach § 6c SGB II im System der Grundsicherung

Konzept und Ziel der »Experimentierklausel« nach § 6c SGB II im System der Grundsicherung

Eine neue Wendung hat die Erprobung verschiedener Formen der Aufgaben- wahrnehmung im SGB II und die politi- sche Diskussion über die einschlägigen rechtlichen Rahmenbedingungen für die Zeit nach 2010 durch einen Beschluss des Bundesverfassungsgerichts vom 20. Dezember 2007 (2 BvR 2433/04; 2 BvR 2434/04) genommen. Darin erklärt das Gericht das Modell der ARGEn – spe- ziell die Bestimmungen in § 44b SGB II zur Übertragung von Aufgaben der kom- munalen Träger auf ARGEn und zur Vor-

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Development of new inhibitors for the type II transmembrane serine protease matriptase

Development of new inhibitors for the type II transmembrane serine protease matriptase

Many TTSPs show relatively strict patterns of expression and were detected in different tissues and cells of the human body. For example, enteropeptidase is expressed on the apical surface of enterocytes and goblet cells in the proximal small intestine and is the principle trypsinogen activator. [44] Hepsin is mainly found in hepatocytes, while its expression has been identified in a number of additional tissues including thymus, thyroid, lung, pancreas, pituitary gland, prostate, and kidney, as well as in cultured human endothelial cells grown in 3D type I collagen matrices. [45, 46] It is thought to play a role in the growth of some cells as well as potently activating the proform of hepatocyte growth factor (HGF) [46] and pro-uPA. [47] Corin is highly expressed in cardiomyocytes and converts pro-ANP and pro-BNP (atrial and brain natriuretic peptides, cardiac hormones that regulate blood pressure and cardiac function by promoting natriuresis, dieresis, and vasodilation) into smaller biologically active molecules. [48, 49] HAT is mainly localized in human trachea and bronchi, and its upregulation is found to be associated with inflammatory environments. It also cleaves the surface glycoprotein hemaglutinin (HA) of the human and avian influenza viruses of subtypes H1, H2, and H3 at a monobasic cleavage site, which is a prerequisite for influenza virus replication. [50, 51] HAT has been demonstrated to have the capacity to degrade fibrinogen to activate pro-uPA to activate membrane receptors such as PAR- 2. [52, 53] However matriptase is an exception as it is not restricted to any particular organ. An overview of these proteases expression patterns and their physiological functions were described and summarized in several review articles. [7, 28, 33]
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