Traditionally, drug discovery programs have focused on prioritising compounds by their affinity to a specific target in isolation, which was hypothesised to be the cause of a particular disease. Through chemical inhibition, the disease could, thus, be prevented or at the very least, controlled. These hypotheses require significant validation before drug screening can begin which relates to lengthy and expensive programs. Furthermore, drug screening against a single target in isolation is not a realistic model of cellular behaviour and is not appropriately tailored to more complex diseases such as cancer. Phenotypic drug discovery, on the other hand, bypasses any involvement of known targets, instead focusing on the desired outcome – the phenotype. In this way, drugs are biased by their potency on the phenotype and not against any particular targets. The molecular mechanism of action need not be known at all, however, it can be useful to later reveal the target(s) involved by various deconvolution methods. This thesis describes a cooperative ligand based phenotypic drug discovery approach, undertaken in order to develop more suitable small molecule drugs for cancer treatment. For this purpose, the promiscuous pyrazolopyrimidine inhibitor PP1 was chosen as a starting model compound. Modification of PP1 on the N1 position allowed a series of water solubilising groups to be incorporated into the pyrazolopyrimidine scaffold which created an initial 12-membered library. Testing against MCF7 breast cancer cells and looking at phenotypic end points such as cell proliferation, cell mobility and cell cycle, generated early target-agnostic structure/anti-proliferative activity relationships. These early results, along with compounds published in recent literature, were used to generate further libraries. Profiling lead compounds against a selection of 18 kinases known to be targeted by PP1, showed the compounds were inhibiting either SRC family or mTOR kinases which enabled the creation of two, structure specific, groups of inhibitors. Further lead optimisation led to the rapid discovery of preclinical candidates with excellent drug-like properties and potencies in both cellular assays and against their respective targets. Compounds also showed improved selectivity profiles compared to PP1 and commonly known inhibitors of SRC and mTOR kinases. Reported, herein, is the discovery of the first sub-nanomolar SRC inhibitor which does not inhibit the kinase ABL and shows excellent properties suitable for further preclinical development.

Phenotypic plasticity is the ability of the single genotype to pruduce multiple phenotypes in response to evironmental conditions. There are many factors affecting phenotypic plasticity. The aim of this thesis is to summarize the current knowledge of phenotypic plasticity of aquatic insects with emphasis on the role of temperature and food availability. The review is complemented by a laboratory experiments designed to investigate the effect of temperature and food availability on growth and development rate of diving beetle Acilius canaliculatus (Coleoptera: Dytiscidae). The results are discussed in the light of the ecological concepts of temperature-size rule and developmental isomorphy.

Phenotypic plasticity is the ability of the single genotype to pruduce multiple phenotypes in response to evironmental conditions. There are many factors affecting phenotypic plasticity. The aim of this thesis is to summarize the current knowledge of phenotypic plasticity of aquatic insects with emphasis on the role of temperature and food availability. The review is complemented by a laboratory experiments designed to investigate the effect of temperature and food availability on growth and development rate of diving beetle Acilius canaliculatus (Coleoptera: Dytiscidae). The results are discussed in the light of the ecological concepts of temperature-size rule and developmental isomorphy.

Abstract Plants have evolved various adaptive strategies for balancing the benefits and costs of having a high affinity for resources, plasticity of growth allocation and mycorrhizal symbiosis. The relative growth rates of mycorrhizal and non-mycorrhizal plants were modelled for stable and variable nutrient availability. Mycorrhizal plants had higher growth rates at low and non-mycorrhizal plants at high nutrient availability. Variation in nutrient availability reduced the growth rate of mycorrhizal plants due to a high affinity for nutrients. However, mycorrhizal plants may be able to buffer against external fluctuations and therefore experience less environmental variation than non-mycorrhizal plants. Non-mycorrhizal plants may even benefit from variation. The optimal allocation of growth between shoot and roots depends on the availability of energy and nutrients. The optimisation model predicted that the requirement for phenotypic plasticity of shoot/root allocation is greatest in environments with low resource availability. Plants with a high affinity for resources required more plasticity in order to tolerate variation than plants with a low affinity. The model predicted a trade-off between the ability to deplete resources and the ability to tolerate resource fluctuations. Changes in the availability and ratio of resources lead to changes in the structure and composition of vegetation during primary succession. The field study of the forested phases of the land uplift island Hailuoto showed a successional change in the vegetation from the dominance of bryophytes and deciduous dwarf shrubs to dominance by lichens and evergreen dwarf shrubs. The humus layer became thinner and the availability of nutrients declined, while the C/N ratio of soil organic matter increased during succession indicating a decline in the quality of organic matter. The increased soil respiration rate indicates a successional increase in the energetic costs of decomposing organic matter. Nutrients mediate both direct and indirect trophic interactions. Indirect interactions of nutrient cycling are not explicit in continuous time models. A transformation to a discrete time model was shown to make the indirect interactions explicit as transition probabilities and allowed their dynamic contribution to be evaluated with an elasticity analysis. The importance of indirect interactions was greater in tundra than temperate forest and increased with the rate of nutrient cycling.

Evolution of adaptation requires both generation of novel phenotypic variation and retention of a locally beneficial subset of this variation. Such retention can be facilitated by genetic assimilation, the accumulation of genetic and molecular mechanisms that stabilize induced phenotypes and assume progressively greater control over their reliable production. A particularly strong inference into genetic assimilation as an evolutionary process requires a system where it is possible to directly evaluate the extent to which an induced phenotype is progressively incorporated into preexisting developmental pathways. Evolution of diet-dependent pigmentation in birds-where external carotenoids are coopted into internal metabolism to a variable degree before being integrated with a feather's developmental processes-provides such an opportunity. Here we combine a metabolic network view of carotenoid evolution with detailed empirical study of feather modifications to show that the effect of physical properties of carotenoids on feather structure depends on their metabolic modification, their environmental recurrence, and biochemical redundancy, as predicted by the genetic assimilation hypothesis. Metabolized carotenoids caused less stochastic variation in feather structure and were more closely integrated with feather growth than were dietary carotenoids of the same molecular weight. These patterns were driven by the recurrence of organism-carotenoid associations: commonly used dietary carotenoids and biochemically redundant derived carotenoids caused less stochastic variation in feather structure than did rarely used or biochemically unique compounds. We discuss implications of genetic assimilation processes for the evolutionary diversification of diet-dependent animal coloration.

Background Recurrence and predictability of evolution are thought to reflect the correspondence between genomic and phenotypic dimensions of organisms, and the connectivity in deterministic networks within these dimensions. Direct examination of the correspondence between opportunities for diversification imbedded in such networks and realized diversity is illuminating, but is empirically challenging because both the deterministic networks and phenotypic diversity are modified in the course of evolution. Here we overcome this problem by directly comparing the structure of a “global” carotenoid network – comprising of all known enzymatic reactions among naturally occurring carotenoids – with the patterns of evolutionary diversification in carotenoid-producing metabolic networks utilized by birds. Results We found that phenotypic diversification in carotenoid networks across 250 species was closely associated with enzymatic connectivity of the underlying biochemical network – compounds with greater connectivity occurred the most frequently across species and were the hotspots of metabolic pathway diversification. In contrast, we found no evidence for diversification along the metabolic pathways, corroborating findings that the utilization of the global carotenoid network was not strongly influenced by history in avian evolution. Conclusions The finding that the diversification in species-specific carotenoid networks is qualitatively predictable from the connectivity of the underlying enzymatic network points to significant structural determinism in phenotypic evolution.

Thesis (M.Sc. (Zoology) --University of Limpopo, 2014 / Refer to the document / The Department of Biodiversity at the University of Limpopo, and the National Research Foundation (NRF)

Native fowl populations in South Africa were characterized genetically and phenotypically. Four South African native populations, two dual-purpose breeds, and two populations from Mozambique and Botswana were included for genetic analysis. For phenotypic characterization, two commercial lines were also included as a benchmark. Twenty-three micro satellite markers were selected and tested to obtain genetic data for estimation of genetic variability and distance. Growth (weight gain) and egg production were included for phenotypic characterization. A relatively high (53% ¬64%) genetic variation was found among the populations, which suggests conservation as a genetic resource for future use. The lowest genetic variation (53%) was found for the Koekoek and Australorp populations, which are the two populations that were subjected to formal selection, while the highest variation was observed in the Naked Neck population (64%). The New Hampshire has often been included in upgrading programs and this is evident from the close relationship with both the Lebowa- Venda and Naked Neck fowls. Phenotypic trials indicated significant differences among the populations included for growth, carcass and egg production traits. The Koekoek and New Hampshire populations had the best performance for egg production and growth (weight gain) in the study. Genetic and phenotypic differences indicate that the populations can be distinguished as different breeds or groups of fowl. The results of this study may contribute to selection for improved performance for household food production, as well as conservation of the populations as a genetic resource. / Thesis (PhD)--University of Pretoria, 2001. / Animal and Wildlife Sciences / unrestricted

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第22481号 / 農博第2385号 / 新制||農||1075(附属図書館) / 学位論文||R2||N5261(農学部図書室) / 京都大学大学院農学研究科地域環境科学専攻 / (主査)教授 縄田 栄治, 教授 北山 兼弘, 教授 冨永 達 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

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