Large-Scale Networks in the Human Brain revealed by Functional Connectivity MRI

The human brain is composed of distributed networks that connect a disproportionately large neocortex to the brainstem, cerebellum and other subcortical structures. New methods for analyzing non-invasive imaging data have begun to reveal new insights into human brain organization. These methods permit characterization of functional interactions within and across brain networks, and allow us to appreciate points of departure between the human brain and non-human primates.Psycholog

Multiscale Geometric Methods for Isolating Exercise Induced Morphological Adaptations in the Proximal Femur

The importance of skeletal bone in the functioning of the human body is well-established and acknowledged. Less pervasive among the populace, is the understanding of bone as an adaptive tissue which modulates itself to achieve the most construction sufficient for the role it is habituated to. These mechanisms are more pronounced in the long load bearing bones such as the femur. The proximal femur especially, functions under significant loads and does so with high degree of articulation, making it critical to mobility. Thus, exercising to buttress health and reinforce tissue quality is just as applicable to bone as it is to muscles. However, the efficiency of the adaptive (modelling/remodelling) processes is subdued after maturity, which makes the understanding of its potential even more important. Classically, studies have translated the evaluation of strength in terms of its material and morphology. While the morphology of the femur is constrained within a particular phenotype, minor variations can have a significant bearing on its capability to withstand loads. Morphology has been studied at different scales and dimensions wherein parameters quantified as lengths, areas, volumes and curvatures in two and three dimensions contribute towards characterising strength. The challenge has been to isolate the regions that show response to habitual loads. This thesis seeks to build on the principles of computational anatomy and develop procedures to study the distribution of mechanically relevant parameters. Methods are presented that increase the spatial resolution of traditional cross-sectional studies and develop a conformal mapping procedure for proximal femur shape matching. In addition, prevalent methods in cross-sectional analyses and finite element simulations are employed to analyse the morphology of the unique dataset. The results present the spatial heterogeneity and a multi-scale understanding of the adaptive response in the proximal femur morphology to habitual exercise loading

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)