Displacement fields from point-like defects are investigated by x-ray diffraction. The atomic volume changes in the interstitial compounds using crystallographic information has been found to correlate with the size of filled octahedral sites. Systematic correlations enable estimates to be made of the components of the dipole tensor for interstitials in octahedral sites for binary systems containing N, C, and 0 in V, Nb, Ta, Cr, Mo, W, and Fe lattices. X-ray diffraction analysis of the concentration and residual stress gradients in N implanted Mo crystals and Nb films show that the dominant source of internal strain arises from N located in octahedral sites. For Nb implanted at LNT, these distortion centers are aligned equally along three mutually perpendicular directions to maintain cubic symmetry. Large biaxial residual strains are developed after a 5at% implantation of N into Nb and Mo. Radiation damage is present as small vacancy and interstitial loops. A method was developed to obtain the orientation function for samples containing a fiber texture. A slit correction is included and the final results from this simplified approach are compared with the pole figure measured by direct x-scanning. Knowing the orientation function allows one to correct the integrated intensities to that for an ideal powder, thereby allowing thermal and static displacements to be obtained from textured samples. Anisotropic displacements about coherent Be rich GP zones were investigated in a Cull-at%Be alloy. The results indicate that the attenuation factor 2M which determines the relative integrated intensities of Bragg, quasiline, and static diffuse scattering can be expressed in a simplified form. Experimental data of 2M for aged Cu-Be samples show an anisotropy. The anisotropy increases with increasing aging time when the equiaxed-GP zones formed in the early stage collapse into platelike GP zones. / Ph. D.

Die MYST-HAT Sas2 in Saccharomyces cerevisiae acetyliert Histon H4 an Lysin 16 (H4 K16Ac), was die Heterochromatinausbreitung an Telomeren begrenzt. Sas2 interagiert mit den Histonchaperonen Asf1 und CAF-1. Da CAF-1 während der DNA-Replikation in der S-Phase aktiv ist, ergab sich die Hypothese, dass Sas2-katalysiertes H4 K16Ac genomweit während der S-Phase ins Chromatin eingebaut wird. Durch Aktivierung von Sas2 stieg die Menge von H4 K16Ac in der S-Phase, aber nicht in der G1-Phase, in Abhängigkeit von Asf1 und CAF-1 an. Dieses H4 K16Ac wurde jedoch nicht ins Chromatin eingebaut. Dies deutete auf die Existenz eines H4 K16Ac-Pools hin. Sas2-katalysiertes H4 K16Ac hat auch eine genomweite Funktion, da das H4 K16Ac-Niveau an ORFs in sas2D Zellen vermindert ist. Eine Hypothese ist, dass H4 K16Ac euchromatische Gene vor SIR-vermittelter transkriptioneller Stilllegung schützt. Entsprechend ist das H4 K16Ac-Niveau an schwach transkribierten Genen hoch und an stark transkribierten Genen niedrig. Wir konnten zeigen, dass sich H4 K16Ac an GAL-Genen während deren Repression anreichert. Dieser H4 K16Ac-Einbau ist abhängig vom Histonchaperon Spt6. In spt6-1004 Zellen war das H4 K16Ac-Niveau an stark sowie an schwach transkribierten Genen höher als im Wildtyp, während die H4-Menge an diesen Genen reduziert war. Dies weist auf einen indirekten Effekt von Spt6 hin, indem es das H4 K16Ac-Niveau durch den Einbau von K16-unacetyliertem H4 während der Transkription reguliert. Die Abwesenheit anderer Histonchaperone (Asf1, CAF-1, HIR, Rtt106) hatte keinen Einfluss auf den repressionsgekoppelten H4 K16Ac-Einbau. Weiterhin konnten wir zeigen, dass H4 K16Ac nicht notwendig ist, um die Bindung des SIR-Komplexes an euchromatischen Genen zu verhindern, da das verminderte H4 K16Ac-Niveau an ORFs in sas2D Zellen nicht auf Deacetylierung durch Sir2 zurückzuführen war. Daher verhindert Sas2-katalysiertes H4 K16Ac die SIR-Bindung nur an subtelomerischen Loci, jedoch nicht in genomweitem Maßstab. / In Saccharomyces cerevisiae, the MYST HAT Sas2 acetylates histone H4 lysine 16 (H4 K16Ac), which prevents the spreading of heterochromatin at telomeres. Sas2 interacts with the histone chaperones Asf1 and CAF-1, the latter of which is active during DNA replication in S-phase, suggesting a genome-wide incorporation of Sas2-mediated H4 K16Ac during S-phase. Upon activation of Sas2, H4 K16Ac on bulk histone H4 increased during S-phase, but not G1-phase, in an Asf1- and CAF-1-dependent manner. Unexpectedly, H4 K16Ac was not incorporated into chromatin during S-phase following its acetylation, which suggested the existence of a nuclear pool of H4 K16Ac. Moreover, Sas2-mediated H4 K16Ac is suggested to have a genome-wide function, since in sas2D cells, H4 K16Ac is decreased at ORFs. One hypothesis is that Sas2-mediated H4 K16Ac might protect euchromatic genes from being spuriously silenced by SIR proteins. Accordingly, H4 K16Ac is highly enriched at poorly transcribed genes, but not at highly expressed genes. In this study, we found that H4 K16Ac became enriched at GAL genes upon repression. Importantly, this H4 K16Ac incorporation required the histone chaperone Spt6. In spt6-1004 cells, H4 K16Ac levels were higher at highly and poorly transcribed genes compared to wild type, whereas H4 occupancy was lower than in wild type. The data suggested an indirect effect of Spt6 in that it regulates H4 K16Ac levels by the incorporation of K16-unacetylated histone H4 during transcription. In contrast, the absence of other histone chaperones (Asf1, CAF-1, HIR, Rtt106) had no effect on H4 K16Ac enrichment upon gene repression. Moreover, we could show that H4 K16Ac was not necessary to prevent the erroneous binding of the SIR complex in euchromatic regions. The decrease of H4 K16Ac at ORFs in sas2∆ cells was not caused by an activity of the HDAC Sir2. Thus, Sas2-mediated H4 K16Ac prevents the binding of the SIR complex only at subtelomeric loci, but not on a genome-wide scale.

We analyse in a Footloose Capital productive public services provided by a central government aiming at reducing regional disparities. Two countervailing effects occur - one upon productivity and another upon local demand - the relative strength of which depends upon the financing scheme. Only if the "rich" region contributes sufficiently to the financing of the public services in the "poor" region, the poor region will actually gain. In studying these questions we pay particular attention to the dynamic adjustment processes and to the role of trade freeness. / Series: Department of Economics Working Paper Series

Hepatitis C (HCV) infection is associated with high rates of mortality and morbidity. Interferon alpha based treatment for HCV offers a good rate of viral clearance, however the associated neuropsychiatric side effects increase the risk of treatment interruption and disease progression. The HIV/HCV coinfection is of particular interest due to association with higher rates of HCV treatment side effects and earlier treatment discontinuation when compared with HCV mono-infection. Therefore, the aim of the thesis was to further explore the effect of coinfection on mood and cognition and how HCV interferon based treatment influences neuropsychiatric side effects in mono and co-infected samples. Firstly a meta-analysis was performed to explore cognitive impairment and depression in HIV HCV co-infection. The results suggested that there was consistent literature indicating that the coinfected group were more cognitively impaired and more likely to be depressed than the HCV and HIV monoinfected groups. Secondly empirical studies were conducted to analyse the profile of depression during interferon-based treatment, and explore potential risk factors, such as gender and immune profile. Co-infected patients appeared less vulnerable to the emergence of depressive symptoms during HCV treatment than HCV mono-infected patients. Additionally, neither female gender nor immune response were associated with increased vulnerability to depression. Finally, a longitudinal study investigating cognitive performance during interferon-based treatment was conducted. A significant effect of treatment on information processing speed level of executive function was observed. Overall the research reported in this thesis further clarifies the nature of interferon induced depression and cognitive effects differences between mono and coinfected groups. Having identified a neurovegetative symptom profile and speed of processing impairment of executive function during HCV treatment, the discussion considers the potential of targeted interventions via psychotropic medication and cognitive interventions to minimise the impact of these treatment effects and optimise outcomes in this clinical group.

The fundamental building blocks of chromatin are the nucleosomes. Each such unit is composed of about 200 bp of DNA, the well-conserved core histones (H2A, H2B, H3 and H4) and a linker histone (H1). The DNA is wound around two dimers of H2A–H2B and a tetramer comprising two molecules each of H3 and H4, and there is approximately one linker histone molecule positioned on the exterior of the DNA–protein octamer complex. The nucleosome directs the various structural transitions in chromatin that are needed for proper transcriptional regulation during differentiation and development of the organism in question. The gene activity can be regulated by different histone variants, DNA–protein interactions, and protein–protein interactions, all of which are influenced by the enormous amounts of post-translational modifications that occur in the histone tails. The research underlying this thesis focused on different aspects of post-translational modifications during aging, differentiation, and progression of the cell cycle, and also on expression of linker histone variants and linker histone-chromatin interactions in a variety of cells and tissues. The present results are the first to show that H4 can be trimethylated at lysine 20 in mammalian cells. The trimethylated H4K20 was found in rat kidney and liver at levels that rose with increasing age of the nimals, and it was also detected in trace amounts in human cell lines. Furthermore, in differentiating MEL cells, trimethylated H4K20 was localized to heterochromatin, and levels of trimethylated H4K20 increased during the course of cell differentiation and were correlated with the increasing compaction of the chromatin. The chromatin of terminally differentiated chicken and frog erythrocytes is highly condensed, and the linker histone variants it contains vary between the two species. Cytofluorometric analyses revealed that the linker histones in the chicken erythrocytes exhibited higher affinity for chromatin than did those in the frog erythrocytes. Characterization of the H1° in frog erythrocytes proved it to be the H1°-2 subvariant. Other experiments demonstrated that normal human B lymphocytes expressed the linker histone variants H1.2, H1.3, H1.4, and H1.5, and that B cells from patients with B-CLL expressed the same variants although in different amounts. The most striking dissimilarity was that amounts of H1.3 in the cells were decreased or undetectable in some samples. Sequencing did not discern any defects in the H1.3 gene, and thus the absence of H1.3 is probably regulated at the post-translational level. It was also observed that the levels of linker histone phosphorylation in EBV-transformed B lymphocytes were already increased in the G1 phase of the cell cycle, which is earlier than previously thought. This increase in phosphorylation is probably responsible for the lower affinity of linker histones for chromatin in EBV-transformed cells in the G1 phase of the cell cycle.

[Truncated abstract] Protein phosphorylation, one of the most important forms of post-translational modification, has been demonstrated to play crucial roles in regulation of cell function. Phosphorylation of protein serine, threonine and tyrosine residues has been the most thoroughly investigated, taking advantage of the acid-stable character of these phosphohydroxyamino acids. Whereas, the cellular occurrence of acid-labile phosphoamino acids, such as phosphohistidine, phosphoarginine and phospholysine was often underestimated due to the acid treatments employed by most of the traditional phosphoamino acid analysis methods. The biological roles of histidine kinases (HKs) in prokaryotes are well understood in contrast to those of HKs in eukaryotes, especially in mammalian cells. However, the evidence has shown that phosphohistidine comprised 6% of phosphoamino acids of the basic nuclear proteins in eukaryotes (Matthews, 1995) and there was more phosphohistidine than phosphoserine in rat liver mitochondria (Bieber and Boyer, 1966). More significantly, phosphohistidine was revealed to be the major phosphoamino acid in phosphorylated histone H4 in regenerating liver in vivo (Chen et al., 1974) and the Walker-256 carcinosarcoma cells in vitro (Smith et al., 1974). Recently, the histone H4 histidine kinase (HHK) activity of human hepatocellular carcinoma (HCC) tumour tissue was measured to be 400 times higher than the normal liver tissue surrounding the tumour. HepG2 cells (HCC cell line) and PIL-2 cells (a p53 knockout mouse tumorigenic liver progenitor cell line) also displayed high HHK activity (Tan et al., 2004). The above observations suggested that HKs and HHKs are playing important roles in both prokaryotes and eukaryotes, including mammals. One major obstacle in the study of HHK study has been the lack of knowledge of the amino acid sequence of an HHK. Attempts at purifying and identifying the HHK from yeast led to the partial purification of a yeast HHK protein(s) at 32kDa (Huang et al., 1991). However, the amino acid sequence of the HHK has not yet been established. ... The success of the separation was demonstrated by the MALDI-TOF-MS and/or ESI-MS spectra of the RP-HPLC fractions. These achievements suggested that it is possible to detect phosphohistidyl histone H4 in vivo using MS under experimental conditions where phosphohistidine is relatively stable. The study in this thesis represents the progression of HHK research in various aspects, including the yeast HHK purification and identification, mammalian HHK partial purification and the methodological developments in detecting histone H4 histidine phosphorylation using MS. Furthermore, new information regarding the physical characteristics of yeast HHKs and its potential role in cellular biology have been documented. It is anticipated that knowledge generated in these studies will contribute to the insight and the understanding of the biological significance of HHK in yeast and mammalian cells.

This thesis attempts to provide an historicised account of excuse-making strategies in sixteenth- and seventeenth-century literature. This issue is considered, broadly, in the light of the pervasive influence of rhetoric in early modem culture at large, and specifically, as an aspect of the rhetorical construction of moral ambiguity in Shakespearean drama. Its chief concern is with the intractable ambiguity of 'favourable interpretations' or 'charitable constructions' of actions or events, the apparent desirability of which seems beyond doubt. Chapter I uses the 'generosity' often regarded as Shakespeare's own trademark as a way into exploring the aims of the thesis. Its central section focuses more closely on the ambiguity inherent in a 'female rhetoric' of mitigation, apology and extenuation. Where these chapters concentrate on 'covert' excuse-making strategies. Chapter V, by contrast, begins with an exploration of the early modern transformation (or domestication) of classical, female orators into decent, modest, seventeenth-century women. The thesis concludes with an account of Shakespeare's suppliant women, a group of petitioners who are repeatedly represented 'between men'. The persistence of this pattern, I argue, stresses the extent to which excuse-making is gendered, and might be read, as well, as the playwright's own attempt to 'contain' the radical moral ambiguity (radical because as difficult to condone as to condemn) generated by such 'female' excuse-making.

An efficient numerical method to simulate a subpicosecond semiconductor optical switch is developed in this research. The problem under studying involves both electromagnetic wave propagation and semiconductor dynamic transport, which is a nonlinear phenomenon. Finite difference time domain (FDTD) technique is used to approximate the time dependent Maxwell's equations for full-wave analysis of the wave propagation. The dynamic transport is handled by solving the balance equations using the energy and momentum relaxation time approximation. Based on the structure of the device, a physical semi-analytical model is also developed for preliminary analysis. Simulation results in the device's subpicosecond responses including nonlinearity and overshoot. The validity of the method is verified by comparing the simulation with the published experimental results. The method can be extended to other devices as well. / Ph. D.

With the rapid and ubiquitous deployment of mobile communications in recent years, cochannel interference has become a critical problem because of its impact on system capacity and quality of service. The conventional approach to minimizing interference is through better cell planning and design. Digital Signal Processing COSP) based interference rejection techniques provide an alternative approach to minimize interference and improve system capacity. Single channel adaptive interference rejection techniques have long been used for enhancing digitally modulated signals. However these techniques are not well suited for analog mobile phone system (AMPS) and narrowband AMPS (NAMPS) signals because of the large spectral overlap of the signals of interest with interfering signals and because of the lack of a well defined signal structure that can be used to separate the signals. Our research has created novel interference rejection techniques based on time-dependent filtering which exploit spectral correlation characteristics exhibited by AMPS and NAMPS signals. A mathematical analysis of the cyclostationary features of AMPS and NAMPS signals is presented to help explain and analyze these techniques. Their performance is investigated using both simulated and digitized data. The impact of these new techniques on AMPS system capacity is also studied. The adaptive algorithms and structures are refined to be robust in various channel environments and to be computationally efficient. / Ph. D.

5 Abstract Neuroblastoma is one of the most common cancer diseases diagnosed in children. This rapidly growing solid tumor is usually formed by hypoxic areas which arise as a consequence of inefficient and disorganized neovascularization. The cells stressed by hypoxia triggers transcription of many genes necessary for their survival, and conversely stop the production of proteins which are not necessarily needed for the survival in these severe conditions. The adaptation of cells to hypoxic conditions may appear due to the epigenetic regulation of metabolism associated with chromatin remodeling which involves the DNA methylation and also the posttranslational modifications of histones. Among the most important of these, there is the acetylation of lysine residues of histones associated with the DNA strands loosening, facilitated binding of transcription factors and the activation of gene expression. Thus, the first part of this study is concerned with changes in the acetylation of histones H3 and H4 of human neuroblastoma cell lines UKF-NB-3, UKF-NB-4, SH-SY5Y and SK-N-AS, cultured in parallel under standard culture conditions and in the absence of oxygen (hypoxia, 1% O2) for 24 hours, which are studied by Western blot analysis. Thereupon, the activity of histone deacetylases and histonacetyltransferases,...