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Unlimited self-renewal is an absolute prerequisite for any malignancy, and is the ultimate arbiter of the continuous growth and metastasis of tumors. It has been suggested that the self-renewal properties of a tumor are exclusively contained within a small population, i.e., the so-called cancer stem cells. Enhanced self-renewal potential plays a pivotal role in the development of leukemia. My data have shown that APL associated translocation products PML/RARalpha and PLZF/RARalpha increased the replating efficiency of mouse lin-/Sca1+ hematopoietic stem cells (HSCs). This effect is partly mediated by induction of gamma–catenin which is an important mediator of the Wnt signaling pathway and has been shown to be up regulated by the AML associated translocation products(AATPs). Suppression of gamma–catenin by siRNA can abrogate the increased replating efficiency induced by AATPs. Transduction of gamma–catenin in lin-/Sca1+ HSCs led to increased replating efficiency and the expression of stem cell markers Sca1 and c-kit. Additionally it induced accelerated cell cycle progression of mouse bone marrow HSCs. Transduction/transplantation mouse models have shown that ectopic expression of gamma–catenin in HSCs led to acute myeloid leukemia without maturation. These data suggest important roles of Wnt signaling pathway in the leukemogenesis induced by PML/RARalpha, PLZF/RARalpha and AML1/ETO. In contrast to AATPs, CML and Ph+-ALL associated translocation products p185(BCR-ABL) and p210(BCR-ABL) did not affect the self-renewal potential of hematopoietic stem/progenitor cells. However my studies indicated that their reciprocal translocation products p40(ABL/BCR) and p96(ABL/BCR) actually increased the replating efficiency of hematopoietic stem/progenitor cells. The effect is stronger when induced by p96(ABL/BCR) than by p40(ABL/BCR). It is very intriguing that p96(ABL/BCR) can activate Wnt signaling and up regulate the expression of HoxB4. Transduction/transplantation mouse model has shown that p40(ABL/BCR) and p96(ABL/BCR) both have their own leukemogenic potential. Given the fact that leukemic stem cells maintain the growth of tumor and are the origin of relapse, the cure of leukemia is dependent on the eradication of the leukemic stem cell and abrogation of aberrantly regulated self-renewal capability. Both t-RA and As2O3 have been shown to induce complete remission in APL patients with PML/RARalpha translocation product. However, t-RA as a single agent achieves completeremission (CR) but not complete molecular remissions (CMR). Therefore, virtually all patients will experience a relapse within a few months. In contrast to t-RA, As2O3 as a single agent is able to induce CR as well as CMR followed by long-term relapse-free survival in about 50% of APL patients even if relapsed after treatment with t-RA-containing chemotherapy regimens. Nothing is known about the mechanisms leading to the complete different clinical outcomes by the two compounds although both have been shown to induce differentiation of blast cells, proliferation arrest, induction of apoptosis and degradation of PML/RARalpha. We investigated the effect of t-RA and arsenic on PML/RARalpha-expressing cell population with stem cell capacity derived from the APL cell line NB4 as well as Sca1+/lin- murine bone marrow cells. We found that t-RA did not reduce the replating efficiency in PML/RARalpha- and PLZF/RARalpha-infected Sca1+/lincells whereas it selected small compact colonies representing very early progenitor cells. T-RA was unable to reduce the capacity to form colony forming units-spleen (CFU-S) of Sca1+/lin-cells expressing PML/RARalpha, additionally t-RA did not impair the capability of engraftment of NB4 cells in NOD/SCID mouse. On the contrary to t-RA, As2O3 abolished the aberrant self-renewal potential of Sca1+/lin- cells expressing PML/RARalpha. As2O3 not only abolished the replating efficiency of PML/RARalpha positive cells but also completely abrogated the ability of PML/RARalpha-positive HSC to produce CFU-S in vivo. On the contrary to As2O3, t-RA increased the absolute cell number and the percentage of cells in the side population with respect to the whole cell population in NB4 cells. Taken together these data suggest that arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RARalpha positive leukemic stem cells. My data prove for the first time that there is a direct relationship between the capacity of compounds to effectively target the LSC and their capacity to eradicate the leukemia, and, thereby, to induce complete molecular remission and long-term relapse-free survival. Thus, in order to increase the curative potential of leukemia therapies, future studies need to include the effect of given compounds on the stem cell compartment to determine their ability to eradicate the LSC.
Questions in Northern Sotho
(2006)
This article gives an overview of the marking of polar and constituent questions in Northern Sotho, a Bantu language of South Africa. It thereby provides a contribution to the typological investigation of sentence types in the world’s languages. As will be shown, Northern Sotho follows cross-linguistic tendencies in marking interrogative sentences: It uses intonation as main indicator in polar questions and question words as main indicator in constituent questions. Nevertheless, it also shows interesting language-specific variation, e.g. with respect to the location of raised intonation in polar questions, the presence of two pragmatically distinct question particles in polar questions, or a split in the formation of constituent questions based on the grammatical function of the questioned constituent.
Die Hauptthese dieser Dissertation ist, dass Nord-Sotho keinen obligatorischen Gebrauch von grammatischen Mitteln zur Markierung von Fokus macht, weder in der Syntax noch in der Prosodie oder Morphologie. Trotzdem strukturiert diese Sprache eine Äußerung nach informationsstrukturellen Aspekten. Konstituenten, die im Diskurs gegeben sind, werden entweder getilgt, pronominalisiert oder an den rechten oder linken Satzrand versetzt. Diese (morpho-)syntaktischen Prozesse wirken so zusammen, dass die fokussierte Konstituente oft final in ihrem Teilsatz erscheint. Obwohl die finale Position keine designierte Fokusposition ist, ist das Wissen um diese Tendenz doch entscheidend für das Verständnis einer morphologischen Alternation, die in Nord-Sotho am Verb erscheint und die in der Literatur im Zusammenhang mit Fokus diskutiert wurde.
Obwohl also ein direkter grammatischer Ausdruck von formaler F(okus)-Markierung im Nord-Sotho fehlt, ist F-Markierung trotzdem entscheidend für die Grammatik dieser Sprache: Fokussierte logische Subjekte können nicht in kanonischer präverbaler Position erscheinen. Sie erscheinen stattdessen entweder postverbal oder in einem Spaltsatz, abhängig von der Valenz des Verbs. Obwohl Nord-Sotho bei Objekten im Gebrauch von Spaltsätzen eine Korrespondenz von komplexer Form mit komplexer Bedeutung zeigt, gilt diese Korrespondenz nicht für logische Subjekte.
Die vorliegende Dissertation modelliert die oben genannten Ergebnisse im theoretischen Rahmen der Optimalitätstheorie (OT). Syntaktischer in situ Fokus und die Abwesenheit von prosodischer Fokusmarkierung können mit unkontroversen Beschränkungen erfasst werden. Für die Ungrammatikaliät fokussierter logischer Subjekte in präverbaler Position schlägt die vorliegende Arbeit die Modifizierung einer in der Literatur vorhandenen Beschränkung vor, die in Nord-Sotho von entscheidener Bedeutung ist. Die Form-Bedeutungs-Korrespondenz wird, wie andere Phänomene pragmatischer Arbeitsteilung auch, innerhalb der schwach bidirektionalen Optimalitätstheorie behandelt.
In this paper I argue that the set of formal features that can head a functional projection is not given by UG but derived through L1 acquisition. I formulate a hypothesis that says that initially every functional category F is realised as a semantic feature [F]; whenever there is an overt doubling effect in the L1 input with respect to F, this semantic feature [F] is reanalysed as a formal feature [i/uF]. In the first part of the paper I provide a theoretical motivation for this hypothesis, in the second part I test this proposal for a case-study, namely the cross-linguistic distribution of Negative Concord (NC). I demonstrate that in NC languages negation has been reanalysed as a formal feature [i/uNEG], whereas in Double Negation languages this feature remains a semantic feature [NEG] (always interpreted as a negative operator), thus paving the way for an explanation of NC in terms of syntactic agreement. In the third part I discuss that the application of the hypothesis to the phenomenon of negation yields two predictions that can be tested empirically. First I demonstrate that negative markers X° can be available only in NC languages; second, independent change of the syntactic status of negative markers, can invoke a change with respect to the exhibition of NC in a particular language. Both predictions are proven to be correct. I finally argue what the consequences of the proposal presented in this paper are for both the syntactic structure of the clause and second for the way parameters are associated to lexical items.
Languages cross-linguistically differ with respect to whether they accept or ban True Negative Imperatives (TNIs). In this paper I show that this ban follows from three generally accepted assumptions: (i) the fact that the operator that encodes the illocutionary force of an imperative universally takes scope from C°; (ii) the fact that this operator may not be operated on by a negative operator and (iii) the Head Movement Constraint (an instance of Relativized Minimality). In my paper I argue that languages differ too with respect to both the syntactic status (head/phrasal) and the semantic value (negative/non-negative) of their negative markers. Given these difference across languages and the analysis of TNIs based on the three above mentioned assumptions, two typological generalisations can be predicted: (i) every language with an overt negative marker X° that is semantically negative bans TNIs; and (ii) every language that bans TNIs exhibits an overt negative marker X°. I demonstrate in my paper that both typological predictions are born out.
As editor of the next iteration of the Köchel Catalogue, I have to deal with the current (sixth) edition’s Appendix C, devoted to "Doubtful and Misattributed Works." My goal is to reduce the potentially vast dimensions of that appendix to only those works for which some connection to Mozart cannot be ruled out. In the decades since 1964, when the current edition of Köchel was published, many of the works listed in Appendix C have been convincingly attributed to other composers. Other works therein can confidently be dismissed as never having had any meaningful connection to Mozart. Yet even after removing the reattributed and trivially misattributed works from the appendix, we are left with a handful of works that may possibly have had something to do with Mozart, even if clear evidence one way or the other remains elusive. One must, of course, be cautious in removing questionable and doubtful works from the catalogue, as the present case-study will illustrate. The work under consideration, catalogued as K6 Anh. C 9.07, is an unaccompanied piece for three or four voices with the text "Venerabilis barba capucinorum." ...
The mango flower beetle, Protaetia fusca (Herbst), an Asiatic pest of several commercial crops, was first found in Florida in 1985. All subsequent Florida specimens are recorded here, as well as the first documented records from the Bahamas and Barbados. Illustrations are provided and comparisons are made to the similar native Euphoria sepulcralis (Fabricius), which is also recorded for the first time from the Bahamas. Extensive host records and a bibliography (especially tracking P. fusca spread in Hawaii) are included.
Focus on verbal operators such as aspect or tense ("predication focus", lucidly described by Hyman & Watters (1984) under the label "auxiliary focus") has been noticed to exist in African languages of Afroasiatic and Niger-Congo affiliation, but not so far in Saharan. The Saharan language Kanuri is assumed to have substantially reorganized its TAM system, particularly in the perfective aspect domain (Cyffer [2006] dates major changes between the years 1820 and 1900). The paper discusses, for the first time in Kanuri scholarship, the existence of a neat subsystem of predication focus marking by suffix in the perfective aspect which is made up of a total of six conjugational paradigms that uniformly encode predication focus by suffix {-ò}. Kanuri dialects differ in strategies and scope of focus marking encoded in verb morphology. In the light of data from the Yerwa (Nigeria) and Manga (Niger) dialects the paper discusses some "anomalies" with regard to general focus theory which we account for by describing the "Kanuri Focus Shift" as a diachronic process which is responsible for leftward displacement of scope of focus.
For this thesis photon and pi0 spectra in Gold-Gold-collisions at an energy of sqrt(s_NN) = 62 GeV were measured using the STAR-experiment at RHIC. Heavy ion collisions allow to study strongly interacting matter under extreme condiditons in the laborartory. Nuclear matter is strongly compressed and heated. Theories predict in a system of strongy interacting matter at high temperature and pressure a phase transition from hadronic matter, in which quarks are bound into hadrons, to a plasma of free quarks and gluons (QGP). To study the properties of this created medium, a number of different observables is available. One possibility to determine the temperature of such a system, is to measure the photon emission from the medium. The experimental difficulty is that there are more mechanisms producing photons than just the thermal production. Photons are produced in hard scattering processes or can be the result of the interaction of hard partons with the medium. According to theoretical calculations the photon yield from hard processes exceeds the thermal production for transverse momenta above 3 GeV/c. Photons from hard processes and thermal photons are referred to as direct photons, because they are produced inside of the medium. The largest part of the photons below pt=3GeV/c, however, comes from electromagnetic decays of hadrons in the final state of the collision. The largest fraction comes from the pi0- and the eta-mesons. Their contribution to the photon spectra can be determined by measuring the spectra of these decaying particles and calculating the resulting, corresponding photon spectra. The experimental difficulty is to measure these spectra to an accuracy of a few percent because the decay photons make up about 90% of all photons in the relevant phase space region. The STAR-experiment provides different detectors to measure photons and pi0-mesons. The primary detector for this kind of measurement are the electromagnetic calorimeters. However, the analysis described in this thesis uses the time projection chamber (TPC). Because photons don't carry electric charge and the TPC is only sensitive to charged particles, a conversion of the photon into an electron-positron-pair is required. This happens inside the electromagnetic fields of the nuclei and the electrons in the atomic shell of the detector material in the experimental setup of STAR. The resulting electron and positron tracks are measrued in the TPC. In chapter 3 the reconstruction of conversions from the measured tracks is described. Chapter 4 discusses the efficiency of the measurement, which is determined with a Monte-Carlo-Method, and the uncertainties of the correction. Chapter 5 presents the results of the analysis. The data set, on which the analysis is based, consists of Gold-Gold-Collisions an a center of mass energy of sqrt(s_NN)=62GeV. The selection criteria for individual events during data taking and during the analysis are explained. The data set is divided into four centrality selection classes. The first result are the transverse momentum and rapidity spectra of inclusive photons for all four centralities and the whole data set. Pi0-spectra versus transverse momentum for the four centralities and the whole data set are also shown. The pi0-spectra are compared to the spectra of pi0-mesons measured by the PHENIX-Collaboration at the same energy and with pi0-spectra measured by STAR at full RHIC energy. In addition a comparison to charged pi+- and pi--spectra is shown, which were also measured by the STAR collaboration. It is attempted to extract the fraction of direct photons by dividing the spectra of inclusive photons by the spectra of simulated decay photons. In these simulations pi0- and eta-spectra are modeled based on the pi+- and pi--spectra. Studying the uncertainties of this procedure shows that the size of the uncertainties is of the same magnitude as the signal of direct photons. Also the systematic uncertainties of the pi+- and pi--spectra are similar. Therefore the measurement of direct photon spectra is not possible. In chapter 6 possibilities are described to reduce the large systematic uncertainties. In addition it is discussed, what could be done with an already existing data set at full RHIC energy and how the addition of a dedicated converter during a future data taking period could reduce the systematic errors. The result of this thesis are inklusive photon and pi0 spectra. The systematic uncertainties were extensively studied. It is described, which enhancements are necessary to provide the perspective for measuring direct photons in the area of 1 to 3 GeV/c transverse momentum.