Business cycles, long waves, and company langevity in Birmingham area metal industries 1780-1980

This doctoral thesis originates from an observational incongruence between the perennial aims and aspirations of economic endeavour and actually recorded outcomes, which frequently seem contrary to those intended and of a recurrent, cyclical type. The research hypothesizes parallel movement between unstable business environments through time, as expressed by periodically fluctuating levels of economic activity, and the precipitation rates of industrial production companies. A major problem arose from the need to provide theoretical and empirical cohesion from the conflicting, partial and fragmented interpretations of several hundred historians and economists, without which the research question would remain unanswerable. An attempt to discover a master cycle, or superimposition theorem, failed, but was replaced by minute analysis of both the concept of cycles and their underlying data-bases. A novel technique of congregational analysis emerged, resulting in an integrated matrix of numerical history. Two centuries of industrial revolution history in England and Wales was then explored and recomposed for the first time in a single account of change, thereby providing a factual basis for the matrix. The accompanying history of the Birmingham area provided the context of research into the failure rates and longevities of firms in the city's staple metal industries. Sample specific results are obtained for company longevities in the Birmingham area. Some novel presentational forms are deployed for results of a postal questionnaire to surviving firms. Practical demonstration of the new index of national economic activity (INEA) in relation to company insolvencies leads to conclusions and suggestions for further applications of research into the tempo of change, substantial Appendices support the thesis and provide a compendium of information covering immediately contiguous domains.

Antitumour imidazotetrazines: probes for the major groove of DNA

The antitumour imidazotetrazinones are believed to act as prodrugs for the triazene series of alkylating agents, showing a marked pteference for the alkylation of the middle guanine residue in a run of three or more contiguous guanines. However, the. exact nature of the interactions of imidazotetrazinones within the micro~environment of DNA are; as yet unknown. In order to examine such interactions a three pronged approach involving molecular modelling, synthetic chemistry and biological analysis has been undertaken during the course of this project. . Molecular modelling studies have shown that for the 8-carboxamido substituted imidazotetrazinones antitumour activity is dependent upon the. presence of a free NH group which can be involved in the formation of both intramolecular and intermolecular hydrogen bonds, and the presence of a non-bulky substituent with a small negative potential . volume. Modelling studies involving the docking of .mitozolomide into the major groove of DNA in the region of a triguanine sequence has shown that a number of hydrogen bonding interactions are feasible. A series of 8-substituted carboxamide derivatives of mitozolomide have been synthesised via the 8-acid chloride and 8-carboxylic acid derivatives including a number of peptide analogues. The peptide derivatives were based upon the key structural features of the helix-turn-helix motif of DNA-binding proteins with a view to developing agents that are capable of binding to DNA with greater selectivity. An examination of the importance of intramolecular hydrogen bonding in influencing the antitumour activity:of :the imidazotetrazinones has led to the synthesis of the novel pyrimido[4',5' :4,3]pyrazolo[5,1-d]-1,2,3,5-tetrazine ring system. In general, in vitro cytotoxicity assays showed that the new derivatives were less active against the TLX5 lymphoma cell line. than the parent compound mitozolomide despite an increased potential for hydrogen bonding interactions. Due to the high reactivity of the: tetrazinone ring system it is difficult to study the interactions between the imidazotetrazinones and DNA. Consequently a number of structural analogues that are stable under physiological conditions have been. prepared based upon the 1,2,3 triazin-4(3H)-one ring system fused with both benzene and pyrazole rings. Although the 3-methylbenzotriazinones failed to antagonise the cytotoxic activity of temozolomide encouraging results with a 3-methylpyrazolotriazinone may suggest the existence of an imidazotetrazinone receptor site within DNA. The potential of guanine rich sequences to promote the alkylating selectivity of imidazotetrazinones by acting as a catalyst for ring cleavage and thereby generation of the alkylating agent was examined. Experiments involving the monitoring: of the rate of breakdown of mitozolomide incubated in the presence of synthetic oIigonucleotides did not reveal any catalytic effect resulting from the DNA. However, it was noted that the breakdown of mitozolomide was dependent upon the type of buffer used in the incubations and this may indeed mask any catalysis by the oligonucleotides.

Contrast summation across eyes and space is revealed along the entire dipper function by a "Swiss cheese" stimulus.

Previous contrast discrimination experiments have shown that luminance contrast is summed across ocular (T. S. Meese, M. A. Georgeson, & D. H. Baker, 2006) and spatial (T. S. Meese & R. J. Summers, 2007) dimensions at threshold and above. However, is this process sufficiently general to operate across the conjunction of eyes and space? Here we used a "Swiss cheese" stimulus where the blurred "holes" in sine-wave carriers were of equal area to the blurred target ("cheese") regions. The locations of the target regions in the monocular image pairs were interdigitated across eyes such that their binocular sum was a uniform grating. When pedestal contrasts were above threshold, the monocular neural images contained strong evidence that the high-contrast regions in the two eyes did not overlap. Nevertheless, sensitivity to dual contrast increments (i.e., to contrast increments in different locations in the two eyes) was a factor of ∼1.7 greater than to single increments (i.e., increments in a single eye), comparable with conventional binocular summation. This provides evidence for a contiguous area summation process that operates at all contrasts and is influenced little, if at all, by eye of origin. A three-stage model of contrast gain control fitted the results and possessed the properties of ocularity invariance and area invariance owing to its cascade of normalization stages. The implications for a population code for pattern size are discussed.

The development of the visual system in pre-term infants as assessed by electrophysiological techniques

In an endeavour to provide further insight into the maturation of the human visual system, the contiguous development of the pattern reversal VEP, flash VEP and flash ERG was studied in a group of neurologically normal pre-term infants, born between 28 and 35 weeks gestation. Maturational changes were observed in all the evoked electrophysiological responses recorded, these were mainly characterised by an increase in the complexity of the waveform and a shortening in the latency of the response. Initially the ERG was seen to consist of a broad b-wave only, with the a-wave emerging at an average age of 40 weeks PMA. The a-wave showed only a slight reduction in latency and a modest increase in amplitude as the infant grows older, whereas the changes seen in the ERG b-wave were much more dramatic. Pattern reversal VEPs were successfully recorded for the first time during the pre-term period. Flash VEPs were also recorded for comparison. The neonatal pattern reversal VEP consistently showed a major positive component (P1) of long latency. As the infant grew older, the latency of the P1 component decreased and was found to be negatively correlated with PMA at recording. The appearance of the N1 and N2 components became more frequent as the infant matured. The majority of infants were found to be myopic at birth and refractive error was correlated with PMA, with emmetropisation occurring at about 45 weeks PMA. The pattern reversal VEP in response to 2o checks was apparently unaffected by refractive error.

A multivariate spatial analysis of vowel formants in American English

This paper presents the results of a multivariate spatial analysis of 38 vowel formant variables in the language of 402 informants from 236 cities from across the contiguous United States, based on the acoustic data from the Atlas of North American English (Labov, Ash & Boberg, 2006). The results of the analysis both confirm and challenge the results of the Atlas. Most notably, while the analysis identifies similar patterns as the Atlas in the West and the Southeast, the analysis finds that the Midwest and the Northeast are distinct dialect regions that are considerably stronger than the traditional Midland and Northern dialect region indentified in the Atlas. The analysis also finds evidence that a western vowel shift is actively shaping the language of the Western United States.

Codon-precise, synthetic, antibody fragment libraries built using automated hexamer codon additions and validated through next generation sequencing

We have previously described ProxiMAX, a technology that enables the fabrication of precise, combinatorial gene libraries via codon-by-codon saturation mutagenesis. ProxiMAX was originally performed using manual, enzymatic transfer of codons via blunt-end ligation. Here we present Colibra™: an automated, proprietary version of ProxiMAX used specifically for antibody library generation, in which double-codon hexamers are transferred during the saturation cycling process. The reduction in process complexity, resulting library quality and an unprecedented saturation of up to 24 contiguous codons are described. Utility of the method is demonstrated via fabrication of complementarity determining regions (CDR) in antibody fragment libraries and next generation sequencing (NGS) analysis of their quality and diversity.

Concurrent codes:a holographic-type encoding robust against noise and loss

Concurrent coding is an encoding scheme with 'holographic' type properties that are shown here to be robust against a significant amount of noise and signal loss. This single encoding scheme is able to correct for random errors and burst errors simultaneously, but does not rely on cyclic codes. A simple and practical scheme has been tested that displays perfect decoding when the signal to noise ratio is of order -18dB. The same scheme also displays perfect reconstruction when a contiguous block of 40% of the transmission is missing. In addition this scheme is 50% more efficient in terms of transmitted power requirements than equivalent cyclic codes. A simple model is presented that describes the process of decoding and can determine the computational load that would be expected, as well as describing the critical levels of noise and missing data at which false messages begin to be generated.