Loss of heterozygosity (LOH) of 16q is an early event occurring in 36-60% of primary sporadic breast cancers. CBFA2T3 (MTG16) is a putative breast cancer tumour suppressor gene, localized at chromosome band 16q24.3. CBFA2T3 (MTG16) belongs to the CBFA2T protein family and shares a high homology with other two members, CBFA2T1 (MTG8) and CBFA2T2 (MTGR1). CBFA2T1 and CBFA2T3 proteins form transcriptional repressor complexes with the DNA binding zinc finger proteins like BCL6, PLZF, Gfi1 and ZNF652. CBFA2T3 protein exists as isoform “a” and “b” that arise from alternate start sites. These isoform differ in their N-terminal sequences. Previous studies determined that CBFA2T3a localized to the nucleolus, while CBFA2T3b has a putative role as tumour suppressor protein. The present study confirms that the database entries of CBFA2T3a are incomplete and an extended N-terminus region is present to CBFA2T3a (NCBI NM_005187) isoform by RTPCR and DNA sequencing. Two rabbit polyclonal anti CBFA2T3 antibodies were raised against the region unique to CBFA2T3. These antibodies specifically detect the endogenous CBFA2T3 proteins and not CBFA2T1 and CBFA2T2. Cell fractionation studies show that endogenous CBFA2T3a localized to the cytoplasm, while CBFA2T3b targeted to the nucleus. The N-terminus region specific to “a” isoform determined the cytoplasmic localization. The detailed studies show that CBFA2T3a localized to centrosome and this was confirmed by co–localization with known centrosomal proteins γ- tubulin. This was further confirmed by immunoprecipitation of γ-tubulin with N-terminus regions of CBFA2T3a protein. Further investigation showed that CBFA2T3a localizes to the centrosome through out the centrosomal duplication. Presence of CBFA2T3a on procentriole was further confirmed by co-localization with known proteins having a crucial role in centrosome duplication like HsSAS6 and polyglutamilated tubulin. Experiments were conducted to determined if the different subcellular localization of “a” and “b” isoforms resulted into functional differences between two isoforms. Immunoprecipitation experiments with known DNA binding proteins like BCL6 and PLZF showed that CBFA2T3b interacts with BCL6, while no interaction was found with PLZF. Consistent with the known transcriptional co-repressor function, real time RT-PCR showed that CBFA2T3b has an additive effect on BCL6 mediated repression of its target cyclin D2, while no effect was observed with CBFA2T3a. Real time RT-PCR data also showed that BCL6 not only recruits CBFA2T3b to repress its target but also have repressive effects on CBFA2T3 transcription. CBFA2T3b transcription regulation by BCL6 was found to be mediated through one or two BCL6 putative binding sites in CBFA2T3b promoter. Immuno histochemical studies were carried out to analyse CBFA2T3b function as a breast cancer tumour suppressor. CBFA2T3 proteins are highly expressed in epithelial cell lineage of normal breast ducts, while its expression is lost in some tumours. CBFA2T3 expression was further analysed in a cohort of commercially available breast tumour sections. Data from these studies showed the loss of CBFA2T3 nuclear expression in some tumours, which was significantly correlated with tumours positive for HER2 expression, molecular subtypes and histological staging of the tumours. CBFA2T3 cytoplasmic expression was also down regulated in tumour sections. A significant association of CBFA2T3 cytoplasmic expression was observed with the TNM grading for tumour invasion and centrosomal abnormalities in BR701 TMA. Knock down studies using shRNA were conducted to investigate the role of CBFA2T3a. Following CBFA2T3 knock down in cells with minimal CBFA2T3b expression, an increase in centrosomal abnormalities was observed. These abnormalities were associated with a significant increase in metaphase anomalies. Since the “a” isoform is localized to cytoplasm and particularly centrosome, it was considered that this isoform is determining centrosome integrity. This work has provided a new insight into the localization pattern of CBFA2T3 isoforms, as CBFA2T3a and b isoforms were localized to different cellular compartments and were involved in distinct functions. CBFA2T3b function as a transcriptional co repressor, CBFA2T3b expression was lost in a group of breast tumours sections. Given that CBFA2T3a has a critical centrosomal function, the expression of this isoform would be expected to be maintained, even in the absence of the CBFA2T3b isoform in tumours. CBFA2T3a specific knock down studies may give a full insight on direct targets of CBFA2T3a, having a controlling role in normal centrosome duplication cycle. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1474414

Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1992. / Vita. Abstract. Includes bibliographical references (leaves 115-118). Also available via the Internet.

We present an effective field theory for interacting electrons in clean semimetals (both three dimensional Dirac semimetals and graphene) in terms of their soft or massless bosonic degrees of freedom. We show, by means of a Ward identity, that the intrinsic semimetal ground state breaks the Sp(4M) symmetry of the theory. In Fermi liquids this enables one to identify the massive, non-Goldstone modes of the theory and integrate them out. Due to the vanishing density of states in semimetals, unlike in Fermi liquids, both Goldstone and non-Goldstone modes are equally soft, and so all two-particle correlations need to be kept. The resulting theory is not perturbative with respect to the electron-electron interaction; rather, it is controlled by means of a systematic loop expansion and allows one to determine the exact asymptotic form of observables in the limits of small frequencies and/or wave vectors. Equivalently, it provides a mechanism of determining the long time-tail and long wavelength behavior of observables and excitations. As a representative application, we use the theory to compute the zero-bias anomaly for the density of states for both short and long-range interactions in two and three dimensions. We find that the leading nonanalyticity in semimetals with a long-ranged interaction appears at the same order in frequency as the one in Fermi liquids, since the effects of the vanishing density of states at the Fermi level are offset by the breakdown of screening. Consequently, we are able to provide a logical scheme to determine the leading non-analytical behavior of observables in semimetals using knowledge of the corresponding non-analyticities in a Fermi liquid. / 2020-01-11

Submitted by Reginaldo Soares de Freitas (reginaldo.freitas@ufv.br) on 2016-06-14T11:23:47Z No. of bitstreams: 1 texto completo.pdf: 947659 bytes, checksum: e40a84800499bceebcf0b0b2051d2265 (MD5) / Made available in DSpace on 2016-06-14T11:23:47Z (GMT). No. of bitstreams: 1 texto completo.pdf: 947659 bytes, checksum: e40a84800499bceebcf0b0b2051d2265 (MD5) Previous issue date: 2007-07-17 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Geminivírus constituem um grupo de vírus com genoma composto de DNA de fita simples que se replicam no núcleo de células do hospedeiro através de um intermediário dupla fita, podendo ser constituídos por um genoma mono ou bi-segmentado. O transporte do DNA viral do núcleo para o citoplasma de geminivírus bi-segmentados requer a proteína viral designada NSP, Nuclear Shuttle Protein (BV1). A localização de NSP e seu papel proposto no movimento célula-a-célula do DNA viral predizem que podem ocorrer interações com fatores do hospedeiro tanto no citoplasma quanto no núcleo. Inicialmente foi demonstrado que a proteína NSP de geminivírus que infecta Arabidopsis Cabbage leaf Curl Virus (CaLCuV) interage com receptores cinase (RLK) contendo repetições ricas em leucina (LRR) designadas NIK (NSP-Interacting Kinase). A interação NSP-NIK foi mapeada em NIK1 e ocorre através de uma região de 81 resíduos de aminoácidos do domínio cinase (aa 422-502) que compreende o potencial sítio ativo ser/tre cinase (subdomínio VIbHrDvKssNxLLD) e a alça de ativação (subdomínio VII-DFGAk/rx, mais subdomínio VIII GtxGyiaPEY). A proteína comportou-se como um autêntico receptor cinase, sofrendo autofosforilação in vitro. Sendo, entretanto, a atividade cinase inibida pela proteína NSP. A fim de analisar o papel biológico da interação NSP-NIK, ensaios de infecção foram realizados em plantas contendo alelos nulos para o gene NIK1. Estes resultados demonstraram que a inativação dos alelos NIK1 e NIK3 aumentou a suscetibilidade à infecção causada pelo CaLCuV. Dada a sobreposição do domínio de interação com NSP com domínios regulatórios, foram realizados estudos bioquímicos através de mutagênese sítio dirigida em NIK1. A fim de mapear os sítios envolvidos na ativação da fosforilação de NIK1, o resíduo Thr-474 na alça de ativação foi substituído para resíduos de Ala, Asp ou Glu. Além disso, os resíduos Thr-468, Thr-469 e Ser-465 foram trocados por Ala. Foi demonstrado que a proteína receptora NIK1 exibe um padrão complexo de sítios de fosforilação, que agem independentemente em reações de transfosforilação e fosforilação de substratos. O resíduo de Thr-474 possui um papel central na ativação da proteína cinase, uma vez que os mutantes T474A e T474E apresentaram baixas atividades de auto e fosforilação do substrato. Similarmente, substituição do resíduo Gly-473 por Val juntamente com substituição de Thr-474 por Ala aboliu a autofosforilação e a fosforilação do substrato, sugerindo que, esta mutação acarreta modificações estruturais da alça de ativação que promovem impedimentos estéricos. Em contraste, a substituição dos resíduos Thr-469 e Ser465 por alaninas não causou impacto acentuado na autofosforilação, mas aumentou a atividade de fosforilação do substrato. Provavelmente, fosforilação desses resíduos provocam um efeito inibitório na atividade cinase. Além disso, foram conduzidos experimentos de complementação em A. thaliana nocautes para NIK. Complementação de NIK1 restaurou o fenótipo selvagem com a diminuição da suscetibilidade ao vírus. Em contraste, a expressão de NIK1 mutante com o domínio cinase inativo não reverteu o fenótipo do nocaute nik1, mantendo a elevada taxa de infecção. Estes resultados suportam o argumento de que o domínio cinase de NIK1 medeia uma via de sinalização que culmina em uma resposta de defesa. / Geminiviruses are small, single-stranded DNA viruses that replicate through doublestranded DNA intermediates in the nuclei of their plant hosts and can be mono or bipartite. The transport of bipartite viral DNA from the nucleus to the cytoplasm requires the viral protein NSP, and the nuclear shuttle protein NSP (BV1), both required for systemic infection. The localization of NSP and its proposed role in cell-to-cell movement of the viral DNA predict that interactions with host factors may occur in both the cytoplasm and the nucleus. Initially we have demonstrated that the NSP from an Arabidopsis-infecting geminivirus, Cabbage leaf Curl Virus (CaLCuV) interacts with a leucine rich repeat (LRR) receptor like kinases (RLK) designated NIK (NSP-Interacting Kinase). The NSP-NIK interaction occurs in NIK1 through an 81 amino acid region of the kinase domain (aa 422502) that encompasses the putative active site for ser/thr kinases (sub-domain VIbHrDvKssNxLLD) and the activation loop (sub-domain VII-DFGAk/rx, plus subdomain VIII -GtxGyiaPEY).The protein behaved like authentic receptor kinase undergo autophosphorylation in vitro. However, NSP protein inhibits the kinase activity. To unravel the biological significance of the NSP-NIK interaction we have selected nik null alleles for infection assays. Inactivation of NIK1 and NIK3 alleles enhanced the susceptibility to geminivirus infection. Given the overlap of the NSP-interacting domain with regulatory domains for kinase activity, we focused on site-directed mutagenesis studies on NIK1 To map the phosphorylation sites involved in activation of NIK1, we have replaced Thr-474 in the activation loop by Ala, Asp or Glu residues, whereas Thr-468, Thr-469 and Ser 465 were replaced by Ala. We found that NIK1 exhibits a complex pattern of phosphorylation sites that function independently in auto- and in substrate phosphorylation. The Thr-474 residue seems to play a pivotal role in the activation of the kinase protein, since the mutants T474A and T474E exhibited low auto- and substrate phosphorylation activities. Furthermore, the replacement of Gly-473 by Val in addition to Thr-474 by Ala abolished autophosphorylation and phosphorylation of substrate, sugesting that this mutation promotes a structural rearrangement of the A-loop that compromises activity. In contrast, the replacement of Thr469 and Ser-465 for alanines did not impact autophosphorylation significantly, but increased substrate phosphorylation activity. Possibly the phosphorylation of these residues impairs the kinase activity. In addition, we conducted complementation experiments in the nik1 genetic background. NIK1 expression in nik1 complemented the mutant and restored the wild type phenotype, with decreased virus susceptibility. In contrast, an inactive kinase domaincontaining NIK1 mutant did not reverse the enhanced susceptibility phenotype of the knockout lines and kept a high infection rate. These results are consistent with a model in which the kinase domain of NIK mediates a signaling pathway that culminates in antiviral defense.

abstract: This work examines star formation in the debris associated with collisions of dwarf and spiral galaxies. While the spectacular displays of major mergers are famous (e.g., NGC 4038/9, ``The Antennae''), equal mass galaxy mergers are relatively rare compared to minor mergers (mass ratio <0.3) Minor mergers are less energetic than major mergers, but more common in the observable universe and, thus, likely played a pivotal role in the formation of most large galaxies. Centers of mergers host vigorous star formation from high gas density and turbulence and are surveyed over cosmological distances. However, the tidal debris resulting from these mergers have not been well studied. Such regions have large reservoirs of gaseous material that can be used as fuel for subsequent star formation but also have lower gas density. Tracers of star formation at the local and global scale have been examined for three tidal tails in two minor merger systems. These tracers include young star cluster populations, H-alpha, and [CII] emission. The rate of apparent star formation derived from these tracers is compared to the gas available to estimate the star formation efficiency (SFE). The Western tail of NGC 2782 formed isolated star clusters while massive star cluster complexes are found in the UGC 10214 (``The Tadpole'') and Eastern tail of NGC 2782. Due to the lack of both observable CO and [CII] emission, the observed star formation in the Western tail of NGC 2782 may have a low carbon abundance and represent only the first round of local star formation. While the Western tail has a normal SFE, the Eastern tail in the same galaxy has an low observed SFE. In contrast, the Tadpole tidal tail has a high observed star formation rate and a corresponding high SFE. The low SFE observed in the Eastern tail of NGC 2782 may be due to its origin as a splash region where localized gas heating is important. However, the other tails may be tidally formed regions where gravitational compression likely dominates and enhances the local star formation. / Dissertation/Thesis / Ph.D. Astrophysics 2013

In this thesis we investigate numerically SU(2) theories with Dirac—or Majorana—fermions in the adjoint representation. Majorana fermions have historically proven difficult to treat numerically; here, a change of basis is introduced that allows two Majorana fermions to be expressed in terms of one Dirac fermion. This also provides greater insight into the analysis of the properties of theories with Dirac fermions. Attention is focused on the SU(2) theory with a single Dirac flavour (or equivalently two Majorana flavours). Its lattice phase diagram, spectrum, and the anomalous dimension of the chiral condensate are investigated. We observe a long region of constant mass ratios and an anomalous dimension 0.9 ≲ γ∗ ≲ 0.95. The behaviour of the pion mass and the presence of a light scalar in particular point to behaviour that is not traditionally confining; instead the theory appears to lie in or near the conformal window. The topological susceptibility and instanton size distribution are also investigated, for the one-Dirac-flavour theory and additionally the pure-gauge and two-Dirac-flavour (Minimal Walking Technicolor) theories. The properties are found to not depend on number of flavours, indicating a quenching of the fermions in the topology, also consistent with (near-)conformal behaviour (as has previously been reported in studies of other observables for Minimal Walking Technicolor). The code used is described, and a high-performance computing benchmark developed from it is detailed. While the benchmark was originally developed to investigate the performance of different supercomputer architectures for the class of problems we are interested in. Due to the nature of the code on which it is based, it has an unusual flexibility in the demands it may place on machine’s performance characteristics, which may allow it to be applicable to problems outside of lattice physics. The benchmark is used to characterise a number of machines’ relative performance.

Philosophiae Doctor - PhD / Prevailing astronomical and astrophysical observations suggest that we live in a spatially flat cold dark matter (CDM) universe - currently going through a period of accelerated expansion possibly driven by “dark energy” in form of a cosmological constant. Within the standard cosmological paradigm, dark energy and dark matter are the dual dominant sources in the evolution of the late-time universe contributing about 70% and 25% respectively to the total energy density in the Universe, but these are only currently detected via their gravitational interaction. There could be a non-gravitational interaction within the “dark sector” without violating current observational data, thus giving rise to changes in the dark equations of state and affecting the process of galaxy formation. In this thesis, we investigate two new interesting large-scale structure formation scenarios using interacting fluids. Firstly, in departure from the standard approach in which dark matter is treated as a single independent fluid, we split the dark matter fluid into two interacting components: a strongly clustered “halo” component and a weakly clustered “free” component- accreted by the halos. By defining the fraction of the matter inside CDM “halos” to the total matter as a time evolving function of the total matter density F (ρm), we derive the governing background and perturbation equations and the energy-momentum transfer four-vectors. We then perform numerical calculations for three models for F (ρm) that are in agreement with recently published results from halo theory of N-body simulations, and compare our results to the standard ΛCDM model. Our results show that, whereas there’s a good agreement between our model and the ΛCDM model, the perturbations are much more sensitive to the interaction and can deviate strongly from the standard case for large interaction strengths. Secondly, motivated by our current poor knowledge on the underlying “dark- sector” physics and the need to understand the nature of the two most dominant components of our universe: dark energy and dark matter; we investigate a new scenario in which the two dark components interact via an energy-momentum exchange. By re-writing the evolution equations in a more suitable form, we eliminate previously reported singularities in interacting dark energy models in which dark energy is tested to be vacuum energy with w → −1. This makes it possible to numerically integrate the resulting background and perturbation equations, comparing our results to the standard model. We show that this treatment, yields a simple model that provides a good natural extension to the standard ΛCDM model. We go further to explore in detail the cosmological implications of the interaction strength and the direction of the energy-momentum transfer in vacuum interacting dark energy. This thesis provides useful insights on the possible significance of a dark sector interaction in structure formation and shows that such an interaction provides a good natural explanation for the high value of the Hubble parameters measured by BOSS and SDSS surveys. Indeed a small and positive coupling is shown to alleviate the well-known cosmological coincidence problem.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21993号 / 医博第4507号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 竹内 理, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(生命科学) / 乙第13281号 / 論生博第19号 / 新制||生||55(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 井垣 達吏, 教授 垣塚 彰, 教授 藤田 尚志 / 学位規則第4条第2項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

This dissertation deals with the dynamics of interacting quantum and classical spin models and the question of whether and to which degree the dynamics of these models agree with each other. For this purpose, XXZ models are studied on different lattice geometries of finite size, ranging from one-dimensional chains and quasi-one-dimensional ladders to two-dimensional square lattices. Particular attention is paid to the high-temperature analysis of the temporal behavior of autocorrelation functions for both the local density of magnetization (spin) and energy, which are closely related to transport properties of the considered models. Due to the conservation of total energy and total magnetization, the dynamics of such densities are expected to exhibit hydrodynamic behavior for long times, which manifests itself in a power-law tail of the autocorrelation function in time. From a quantum mechanical point of view, the calculation of these autocorrelation functions requires solving the linear Schrödinger equation, while classically Hamilton’s equations of motion need to be solved. An efficient numerical pure-state approach based on the concept of typicality enables circumventing the costly numerical method of exact diagonalization and to treat quantum autocorrelation functions with up to N = 36 lattice sites in total. While, in full generality, a quantitative agreement between quantum and classical dy- namics can not be expected, contrarily, based on large-scale numerical results, it is demonstrated that the dynamics of the quantum S = 1/2 and classical spins coincide, not only qualitatively, but even quantitatively, to a remarkably high level of accuracy for all considered lattice geometries. The agreement particularly is found to be best in the case of nonintegrable quantum models (quasi-one-dimensional and two-dimensional lattice), but still satisfactory in the case of integrable chains, at least if transport properties are not dominated by the extensive number of conservation laws. Additionally, in the context of disordered spin chains, such an agreement of the dynamics is found to hold even in the presence of small values of disorder, while at strong disorder the agreement is pronounced most for larger spin quantum numbers. Finally, it is shown that a putative many-body localization transition within the one- dimensional spin chain is shifted to stronger values of disorder with increasing spin quantum number. It is concluded that classical or semiclassical simulations might provide a meaningful strategy to investigate the quantum dynamics of strongly interacting quantum spin models, even if the spin quantum number is small and far from the classical limit.