The Articulatory Basis of the Alphabet

The origin of the alphabet has long been a subject for research, speculation and myths. How to explain its survival and effectiveness over thousands of years? One approach is in terms of the practical problems faced by the originator of the alphabet: another would examine the archaeological record; a third might focus on the perceptual process by which the alphabet makes rapid reading possible. It is proposed that the alphabet originated in an intellectual sequence similar to that followed by Alexander Bell and Henry Sweet in constructing their Visible and Organic Alphabets.The originator of the alphabet used the same kind of introspective analysis of his own speech sounds and of the manner in which they were articulated. This was the vital step. The next step was to represent the articulatory differences in terms of visual patterns. One way to understand what might have been involved is to attempt to replicate the process oneself

THE CHILD AND THE WORLD: How Children acquire Language

HOW CHILDREN ACQUIRE LANGUAGE Over the last few decades research into child language acquisition has been revolutionized by the use of ingenious new techniques which allow one to investigate what in fact infants (that is children not yet able to speak) can perceive when exposed to a stream of speech sound, the discriminations they can make between different speech sounds, differentspeech sound sequences and different words. However on the central features of the mystery, the extraordinarily rapid acquisition of lexicon and complex syntactic structures, little solid progress has been made. The questions being researched are how infants acquire and produce the speech sounds (phonemes) of the community language; how infants find words in the stream of speech; and how they link words to perceived objects or action, that is, discover meanings. In a recent general review in Nature of children's language acquisition, Patricia Kuhl also asked why we do not learn new languages as easily at 50 as at 5 and why computers have not cracked the human linguistic code. The motor theory of language function and origin makes possible a plausible account of child language acquisition generally from which answers can be derived also to these further questions. Why computers so far have been unable to 'crack' the language problem becomes apparent in the light of the motor theory account: computers can have no natural relation between words and their meanings; they have no conceptual store to which the network of words is linked nor do they have the innate aspects of language functioning - represented by function words; computers have no direct links between speech sounds and movement patterns and they do not have the instantly integrated neural patterning underlying thought - they necessarily operate serially and hierarchically. Adults find the acquisition of a new language much more difficult than children do because they are already neurally committed to the link between the words of their first language and the elements in their conceptual store. A second language being acquired by an adult is in direct competition for neural space with the network structures established for the first language

Factors influencing the downstream transport of sediment in the Lough Feeagh catchment, Burrishoole, Co. Mayo, Ireland

Research laboratories in the Burrishoole catchment have been the focus of salmonid research since 1955. One aspect of the research has been to monitor the number of salmon and sea trout migrating to sea as smolts and returning to the catchment as adults. In the early 1990s it became clear that the smolt output from the catchment had declined over the previous two decades. At about the same time the presence of fine particles of peat silt in the hatchery became increasingly apparent and led to a higher incidence of mortality of young fry. These observations and management difficulties led to a study of silt transport in the surface waters of the catchment, which is described in this article. The authors describe geology, soils, climate and hydrology of Burrishoole before examining the sediment deposition in Lough Feeagh

The development of nuclear receptor imaging agents

Positron emission tomography (PET) is a molecular imaging technique which allows visualisation and quantification of biomarkers by administering a positron-emitting molecular probe. The steroid hormone receptors for estrogen and progesterone are over-expressed in hormone-dependent cancers of the breast and ovary. Endocrine therapies targeting estrogen receptor (ER) such as Tamoxifen, a selective estrogen receptor modulator (SERM), are among the frontline treatments for these cancers. Currently patient stratification for ER therapy is carried out using immunohistochemical (IHC) assays from biopsy samples; however, this invasive technique is unsuitable for assessing metastatic lesions (multiple and difficult biopsy sampling required). IHC assays are also prone to errors arising from discordance in methodology for assessment of results and also the effect of tumour heterogeneity. Progesterone receptor (PR) expression is regulated by ER and can therefore serve as a surrogate treatment response biomarker for endocrine therapy as PR expression reports on modulation of the ER pathway even if the receptor is saturated with tamoxifen. The use of PET for quantitative interrogation of breast tumour response to endocrine therapy has been reported with steroidal PR ligand, [¹⁸F]FFNP using an in vivo breast cancer rodent model. Correlation between PR expression and tracer uptake has been evaluated in a clinical trial.A focused library of non-steroidal PR imaging agents has been synthesised, based on the benzoxazinthione core structure of tanaproget, a well-established non-steroidal PR agonist. Novel synthetic methodology for accessing thio-carbamate Tanaproget derivatives was developed to avoid the use of Lawesson’s reagent. This thesis reports the first synthesis of a 1,2,3-triazole containing PR ligand which exhibited nanomolar potency in T47D cells.This project aimed to develop surface plasmon resonance (SPR) methodology to assess ligand-receptor binding kinetics to aid lead candidate selection for radiolabelling. The development of an assay to assess ligand binding between progesterone (used as a known PR ligand) and captured PR-ligand binding domain proved to be unsuccessful even though the receptor was able to bind anti-PR monoclonal antibody (mAb). A reduction in temperature and introducing a chaotropic agent to denature the receptor were unsuccessful attempts at getting the receptor to bind to progesterone. The dependence of ligand binding on chaperone proteins like heat shock protein-90 (HSP90) was realised and a PR-HSP90 complex receptor was captured to try and facilitate ligand binding. These receptors proved to be unsuccessful at facilitating ligand binding. Compound libraries were evaluated for potency using the T47D alkaline phosphatase assay in live cells; lead candidates were selected using this data.Radiochemical methodology was developed to label lead candidates with fluorine-18. Two lead candidates were selected from the potency data of cold compounds in the breast cancer cell line T47D; these compounds were compound 26 (EC₅₀ = 4.7 nM) and 32 (EC₅₀ = 47.6 nM). Initial steps to access compound [¹⁸F]26 were developed by radiolabelling dibromopyridine precursors as a prosthetic group; however, this radiosynthesis was not completed. The radiosynthesis of [¹⁸F]32 was achieved by one-step methodology with a fluoride incorporation of 75 – 78 % in a 15 min reaction time. Work towards developing conditions to purify [¹⁸F]32 allowed some compound to be isolated and specific activity determined (0.027 GBq/μmol). Future work will involve improving the purification method to [¹⁸F]32 in anticipation of isolating compound with higher specific activity to evaluate the compound with in vitro cell uptake studies and in vivo biodistribution in an animal model