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GPCRs and ligand-gated ion channels mediate a great variety of physiological effects within the human brain and periphery. The search for selective ligands at these target sites as pharmacological tools or new drug candidates is of great interest. With increasing knowledge of the great diversity of some receptor families, compounds formerly considered to be selective, turned out to be non-selective with regard to recently identified subtypes, splice variants or additional receptor subunits. This work provides SAR studies by means of radioligand binding experiments at serotonergic h5-HT3A and h5-HT4(b) receptors, histamine hH1 receptors and muscarinic hM1-5 receptors. ...
Resistive Plate Chambers (RPCs) are gaseous parallel plate avalanche detectors that implement electrodes made from a material with a high volume resistivity between 10 high 7 and 10 high 12 omega cm. Large area RPCs with 2mm single gaps operated in avalanche mode provide above 98% efficiency and a time resolution of around 1 ns up to a flux of several kHz/cm high 2. These Trigger RPCs will, as an example, equip the muon detector system of the ATLAS experiment at CERN on an area of 3650 m high 2 and with 355.000 independent read out channels. Timing RPCs with a gas gap of 0.2 to 0.3mm are widely used in multi gap configurations and provide 99% efficiency and time resolution down to 50 ps. While their performance is comparable to existing scintillator-based Time-Of-Flight (TOF) technology, Timing RPCs feature a significantly, up to an order of magnitude, lower price per channel. They will for example equip the 176 m high 2 TOF barrel of the ALICE experiment at CERN with 160.000 independent read out cells. RPCs were originally operated in streamer mode providing large signals which simplifies readout electronics and gap uniformity requirements. However, high rate applications and detector aging issues made the operation in avalanche mode popular. This was also facilitated by the development of new highly quenching C2F4H2-based gas mixtures with small contents of SF6. While the physics of streamers is difficult to study, the avalanche mode opened the possibility for a detailed simulation of the detector physics processes in RPCs. Even though RPCs were introduced in the early eighties and have been (will be) used in experiments, there are still disagreements about the explanation of several aspects of the RPC performance. The high efficiency of single gap RPCs would require a large ionization density of the used gases, which according to some authors contradicts measurements. Even in the case of a large ionization density the gas gain has to be extremely large, in order to arrive at the observed RPC efficiency. This raises other questions: A very strong space charge effect is required to explain the observed small avalanche charges around 1 pC. Doubts have been raised whether an avalanche can progress under such extreme conditions without developing into a streamer. To overcome these difficulties, other processes, like the emission of an electron from the cathode, were suggested. Moreover, the shape of measured charge spectra of single gap RPCs differs largely from what is expected from the statistics of the primary ionization and the avalanche multiplication. In this thesis we discuss the detector physics processes of RPCs, from the primary ionization and the avalanche statistics to the signal induction and the read out electronics. We present Monte-Carlo simulation procedures that implement the described processes. While the fundament of the described model and some results were already published elsewhere [1], the subject of this thesis is the implementation of the space charge effect. We present analytic formulas for the electrostatic potential of a point charge in the gas gap of an RPC. These formulas were developed in collaboration with the University of Graz [2] and were published in [3, 4]. The simulation model presented in [1] is completed by the dynamic calculation of the space charge field using these formulas. Since the gas parameters like drift velocity and the Townsend and attachment coefficients depend on the electric field, they are calculated dynamically as well. The functional dependence of these parameters on the field is obtained with the simulation programs MAGBOLTZ and IMONTE. For the primary ionization parameters, we use the values that are predicted by the program HEED. While the described procedure only simulates the longitudinal avalanche development towards the anode of the RPC, we also present more dimensional models that allow a careful study of the transverse repulsive and attractive forces of the space charge fields, and of the consequences for the avalanche propagation. We shall show that the efficiencies of single gap Timing RPCs is indeed explained by the high primary ionization density (about 9.5 /cm as predicted by HEED) and a large effective Townsend coefficient (around 113 /mm as predicted by IMONTE). We show that the space charge field reaches the same magnitude as the applied electric field in avalanches at large gas gain. This strong space charge effect effectively suppresses large values for the avalanche charges. The shape of the simulated charge spectra is very similar to the measurements. Also the simulated average charges are close to the experimental results. RPCs are operated in a strong space charge regime over a large range of applied voltage, contrary to wire chambers. We apply only standard detector physics simulations to RPCs. The performance of Timing and Trigger RPCs is well reproduced by our simulations. The results concerning the space charge effect were presented and discussed at the 'RPC 2001' workshop [5] and on the '2002 NSS/MIC' conference [6].
This thesis presented the measurement of antideuteron and antihelium-3 production in central AuAu collisions at V SNN = 200 GeV center-of-mass energy at RHIC. The analysis is based on STAR data, about 3 x 10 high 6 events at top 10% centrality. Within the data sample a total number of about 5000 antideuterons and 193 antihelium-3 were observed in the STARTPC at mid-rapidity. The specific energy loss measurement in the TPC provides antideuteron identification only in a small momentum window, antihelium-3 however can be identified nearly background free with almost complete momentum range coverage. Following the statistical analysis of the hadronic composition at chemical freeze-out of the fireball, the antinuclei abundances were analyzed in terms of the same statistical description. Now applied to the clusterization of the fireball, the statistical analysis yields a fireball temperature of (135+-10) MeV and chemical potential of (5+-10) MeV at kinetic freeze-out. In the same way as the hadronization, the clusterization process is phase-space dominated and clusters are born into a state of maximum entropy. The large sample of observed antihelium-3 allowed for the first time in heavy-ion physics to calculate a differential multiplicity and invariant cross section as a function of transverse momentum. As expected, the collective transverse flow in the fireball flattens the shape of the transverse momentum spectrum and leads to the high inverse slope parameter of (950+-140) MeV of the antihelium-3 spectrum. With the extracted mean transverse momentum of antihelium-3, the collective flow velocity in transverse direction could be estimated. As the average thermal velocity is small compared to the mean collective flow velocity for heavy particles, the mean transverse momentum of antihelium-3 by itself constrains the flow velocity. Here, a simple ideal-gas approximation was fitted to the distribution of the mean transverse momentum as a function of particle mass and provided direct access to the kinetic freeze-out temperature and the flow velocity. A concept, which is complementary to the combined analysis of momentum spectra and two-particle HBT correlation methods commonly used to extract these parameters, and a cross check for the statistical analysis. The upper limit for the transverse collective flow velocity from the antihelium-3 measurement alone is v flow <= (0.68+-0.06)c, whereas the ideal-gas approximation yields a temperature of (130+-40) MeV and v flow = (0.46+-0.08)c. The results indicate, that the kinetic freeze-out conditions at SPS and RHIC are very similar, except for a smaller baryon chemical potential at RHIC. The simultaneous inclusive measurement of antiprotons allowed to study the cluster production in terms of the coalescence picture. With the large momentum coverage of the antihelium-3 momentum spectrum, the coalescence parameter could be calculated as a function of transverse momentum. Due to the difference between antiproton and antihelium-3 inverse slopes, increases with increasing transverse momentum - again a direct consequence of collective transverse flow. Both B2 and B3 follow the common behavior of decreasing coalescence parameters as a function of collision energy. According to the simple thermodynamic coalescence model, this indicates an increasing freeze-out volume for higher energies and is confirmed by the interpretation of the coalescence parameters in the framework of Scheibl and Heinz. Their model includes a dynamically expanding source in a quantum mechanical description of the coalescence process and expresses the coalescence parameter as a function of the homogeneity volume V hom accessible also in two-particle HBT correlation analyzes. The values for the antideuteron and antihelium-3 results agree well with the homogeneity volume from pion-pion correlations, but do not seem to follow the same transverse mass dependence. A comparison with proton-proton correlations may clarify this point and provide an important cross check for this analysis. Compared to SPS the homogeneity volume increases nearly by a factor of two. The analysis of the antinuclei emission at RHIC allowed to study the kinetic freeze-out of the created fireball. The results show, that the temperature and mean transverse velocity in the expanding system does not change significantly, when the collision energy increases by one order of magnitude. Only the source volume, i.e. the homogeneity volume, increases. That leaves open questions for the theoreticians to the details of the system evolution from the initial hot and dense phase - the initial energy density is a factor of two to three higher at RHIC than at SPS - to the final kinetic freeze-out with similar conditions. At the same time, the results are important constraints for the theoretical descriptions. The successful implementation of the Level-3 trigger system in STAR opens the door for the measurement of very rare signals. Indeed, in the coalescence physics perspective, the first observations of anti-alpha 4 He nuclei and antihypertritons 3/Delta H will come within the reach of STAR, in addition to a high statistics sample of antihelium-3.
At the outset of this dissertation one might pose the question why retroflex consonants should still be of interest for phonetics and for phonological theory since ample work on this segmental class already exists. Bhat (1973) conducted a quite extensive study on retroflexion that treated the geographical spread of this class, some phonological processes its members can undergo, and the phonetic motivation for these processes. Furthermore, several phonological representations of retroflexes have been proposed in the framework of Feature Geometry, as in work by Sagey (1986), Pulleyblank (1989), Gnanadesikan (1993), and Clements (2001). Most recently, Steriade (1995, 2001) has discussed the perceptual cues of retroflexes and has argued that the distribution of these cues can account for the phonotactic restrictions on retroflexes and their assimilatory behaviour. Purely phonetically oriented studies such as Dixit (1990) and Simonsen, Moen & Cowen (2000) have shown the large articulatory variation that can be found for retroflexes and hint at the insufficiency of existing definitions.
Glide formation, a process whereby an underlying high front vowel is realized as a palatal glide, is shown to occur only in unstressed prevocalic position in German, and to be blocked by specific surface restrictions such as *ji and *“j. Traditional descriptions of glide formation (including derivational as well as Optimality theoretic approaches) refer to the syllable in order to capture its conditions. The present study illustrates that glide formation (plus the distribution of long and short tense /i/) in German can better be captured in a Functional Phonology account (Boersma 1998) which makes reference to stress instead of the syllable and thus overcomes problems of former approaches.
A common topic in recent literature on phonology is the question of whether phonological processes and segments are licensed by prosodic position or by perceptual cues. The former is the traditional view, as represented by e.g. Lombardi (1995) and Beckman (1998), and holds that segments occur in specific prosodic positions such as the coda. In a licensing by cue approach, as represented by Steriade (1995, 1999), on the other hand, segments are assumed to occur in those positions only where their perceptual cues are prominent, independent of the prosodic position. In positions where the cues are not salient, neutralization occurs.
I would like to begin my presentation with the quotation of the first sentence of Shafii’s Trea-tise er-Risala, the first work which has been reached us until now, concerning foundation of Islamic jurisprudence. “Praise be to God gratitude for one of His favors can only be paid through another favor of him. And this favor generates favor to be bestowed, wherefore, one should feel obliged continuously to pay gratitude to God for each favor.” It is possible to conceive that Mercy (al-Rahma), the common expression of all favors granted by the Almighty Creature of human beings, has two salient characteristics: one is vertical that is with regard to the Creator and creatures, and the other is horizontal that is concerning hu-man relations among themselves as well as with other creatures. When the concept of Mercy is evaluated in perspective of God-human being relations in the existing world, it indicates that God’s favors, without discrimination, are granted to all human beings. ...
First, why I have avoided to use in this paper the expression ‘the Composite Culture’, which even is used in our Constitution of India to describe unified one culture of our country.1 It is because such a demand is not only against one of the basic realities of our Indian way of life, it also goes against the divine will, which was and is behind this created world with different shades and colours. In this regard the following observation made by Dr. Ram Singh is also noteworthy: It is debatable issue whether there is a separate entity called “composite culture” of India, or it is merely the interaction of various cultures which, instead of resulting into an integrated culture, are still in a position to maintain their separate identities. Beside what Dr. Ram Singh says, the reality is that multi or pluralism is part of our Indian or even Asian way of life. It is quite a different thing, if some of us are not willing to accept this truth. But it is still there, in the form of multi-cultures, multi-languages, multireligions and multiethnicities. Therefore the question of ‘composite culture’ is not only debatable, but also a doubtful principle, unless we are willing to take it as an eschatology reality. I do not intend to deal with this point in detail here, because of the time factor. But we may be able to come back to this question of ‘composite culture, in our discussion if you will wish to do so. ...
Vascular occlusive diseases are one of the leading mortality causes in westernised countries. Occlusions of one of the major arteries can be overcome without devastating consequences provided a timely induction of compensating collateral arteries occurs. Perhaps the most outstanding feature of collateral vessel growth is the proliferation of smooth muscle cells (SMCs). Understanding the molecular mechanisms and identifying key molecular players of SMC proliferation would contribute significantly to the development of efficient therapies to intervene with all processes involving neointima formation, including collateral growth. mRNA and protein coding for co-transcription factor Egr1 were found to be up-regulated in growing collateral vessels 6, 12 or 24 hours following femoral artery ligation in mice. Since Egr1 is required for SMC proliferation in vitro and in vivo and likely to be implicated in the initiation of collateral artery growth, the key signalling mediators regulating Egr1 expression specifically in proliferating vascular SMCs were investigated. Northern blot and Western blot analysis revealed a strong up-regulation of Egr1 within 2 hours of stimulation with PDGF-AB and FGF-2. These two potent SMC mitogens involved in neointima formation were used to stimulate vascular SMCs not only to delineate the regulators of Egr1 expression but also to identify additional key mediators of SMC proliferation. FGF-2 but not PDGF-AB led to a drastic reduction of desmin amount in proliferating SMCs, correlating closely with the phenotypic modulation of SMCs in vivo. Both growth factors triggered a dramatic increase in DNA-synthesis rate with a concomitant loss of p27 exp Kip1. Stimulation with PDGF-AB and FGF-2 triggered a rapid and transient activation of PDGFRβ and FGFR1 respectively, thus providing the basis for activation of down-stream targets. Analysis of an array of signalling pathways demonstrated a strong activation of the Ras-Raf-MEK-ERK cascade in response to both factors as measured by the level of phosphorylation of prominent members MEK, ERK1/2 and c-Myc. SAPK/JNK and p38, which also belong to the superfamily of MAP kinases, did not become activated following stimulation with either PDGF-AB or FGF-2. The analysis of various PKC isoforms identified PKCδ and PKCθ to be the key mediators of PDGF-AB- and FGF-2-induced mitogenesis in proliferating SMCs. Whereas PDGF-AB potently stimulated PKB/Akt with concomitant GSK3β phosphorylation, FGF-2-induced inactivation of GSK3β was independent of PKB/Akt. Specific inhibition in order to evaluate the contribution of individual pathways to Egr1 expression and vascular SMC proliferation revealed that inhibition of the Raf-MEK-ERK module by UO126 completely abolished DNA-synthesis and Egr1 expression without a compensation by alternative pathways. Surprisingly, inhibition of PI3K led to a switch to the mitogenic RafMEK-ERK signalling cascade which resulted in an augmented Egr1 expression. In conclusion, in porcine vascular SMCs, activation of the Ras-Raf-MEK-ERK signalling module appears to be the main prerequisite for Egr1 expression and DNA synthesis induction in response to PDGF-AB and FGF-2 whereas related kinases SAPK/JNK and p38 play no significant role. Inhibition of the PI3K-Akt cascade represents an alternative way to activate ERK1/2 and induce Egr1 expression. Whereas MEK is the central regulator of mitogenic effects in proliferating vascular SMCs, the PI3K-Akt pathway most likely exerts survival function. Inactivation of MEK by its specific inhibitors identified hyperphosphorylation as ayet unknown mechanism of kinase inhibition.
In this paper I discuss the properties of particle verbs in light of a proposal about syntactic projection. In section 2 I suggest that projection involves functional structure in two important ways: (i) only functional phrases can be complements, and (ii) lexical heads that take complements and project must be inflected. In section 3, I show that the structure of particle verbs is not uniform with respect to (i) and (ii). On the one hand, a particle always combines with an inflected verb; in this respect, particle verbs look like verb-complement constructions. On the other hand, the particle is not a functional phrase and therefore is not a proper complement, which makes the combination of the particle and the verb look more like a morphologically complex verb. I argue that syntactic rules can in fact interpret the node dominating the particle and the verb as a projection and as a complex head. In section 4, I show that many of the characteristic properties of particle verbs in the Germanic languages follow from the fact that they are structural hybrids.