<p dir="ltr">The beautiful complexity of our world is manifested in how macro- and even planetary-scale processes are essentially completely determined and regulated by chemical and physical transformations happening at the micro- and nanoscale. The introduction and subsequent development of optical microscopy methods have provided us with a unique opportunity to visualize, probe, and sometimes even control these processes that are too small to be seen by the human eye by their nature.</p><p dir="ltr">Among the great variety of truly impressive advances in microscopy instrumentation, two techniques stand out in their widespread and usefulness. First of them, fluorescence imaging has completely revolutionized the study of biological specimens and living systems due to its unprecedented single-molecule sensitivity and resolution combined with video-rate imaging capability. On the other hand, chemical imaging in the mid-infrared region provides an unmatched amount of chemical information enabling label-free mapping of the spatial distribution of various classes of biological molecules. However, each of these techniques falls short where the other excels. For example, despite its high resolution and sensitivity, fluorescence imaging does not carry direct chemical information and relies on labeling specificity, while infrared microscopy is diffraction-limited at the resolution of several micrometers and suffers from low penetration depth in aqueous solutions.</p><p dir="ltr">This dissertation introduces a novel imaging method designed to combine the advantages of fluorescence imaging and infrared spectroscopy. Fluorescence-detected photothermal mid-IR (F-PTIR) microscopy is presented in <b>chapter 1</b> as a technique enabling sub-diffraction chemically-specific microscopy by detecting local temperature-induced fluctuations in fluorescence intensity to inform on localized mid-infrared absorption. F-PTIR applications in targeted biological microspectroscopy (<b>chapter 1</b>) and pharmaceutical materials (<b>chapters 2 and 3</b>) analysis are demonstrated to highlight the potential of this new method. Furthermore, instrumentation developments relying on modern radiation sources such as dual-comb quantum cascade laser and synchrotron infrared radiation are shown to improve spectral acquisition speed (<b>chapter 4</b>) and spectral coverage (<b>chapter 5</b>), respectively, to extend the application range of F-PTIR.</p>

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This dissertation examines the history of the creation and development of the concept of anticipation, a pattern of heredity found in several diseases (e.g. Huntington’s disease and myotonic dystrophy), in which an illness manifests itself earlier and often more severely in successive generations. It reconstructs major arguments in twentieth-century debates about anticipation and analyzes the relations between different research communities and schools of thought. Developments in cutting-edge medicine, biology, and genetics are analyzed; many of these developments were centered in Britain, but saw significant contributions by people working in France, Germany, Switzerland, the Netherlands and North America. Chapter one traces precursor notions in psychiatric and hereditarian thought from 1840 to the coining of the term ‘anticipation’ by the ophthalmologist Edward Nettleship in 1905. Key roles in the following chapters are played by several figures. Prior to World War II, these include: the neuropathologist F.W. Mott, whose advocacy during 1911- 1927 led to anticipation being called “Mott’s law”; the biometrician and eugenicist Karl Pearson, who opposed Mott on methodological and political grounds; and two politically and theoretically opposed Germans – Ernst Rüdin, a leading psychiatrist and eugenicist who came to reject anticipation, and Richard Goldschmidt, a geneticist who offered a peculiar Mendelian explanation. The British psychiatrist and human geneticist, Lionel Penrose, makes a first interwar appearance, but becomes crucial to the story after World War II due to his systematic dismissal of anticipation, which discredited the notion on orthodox Mendelian grounds. The final chapters highlight the contributions of Dutch neurologist Christiaan Höweler, whose 1980s work demonstrated a major hole in Penrose’s reasoning, and British geneticist Peter Harper, whose research helped demonstrate that expanding trinucleotide repeats accounted for the transgenerational worsening without contradicting Mendel and resurrected anticipation as scientifically legitimate. Reception of the concept of anticipation is traced across the century through the examination of textbooks used in different fields. This dissertation argues against established positions regarding the history of the concept, including claims that anticipation’s association with eugenics adequately explains the rejection of the notion after 1945. Rejected, in fact, by many eugenicists from 1912, anticipation was used by physicians until the 1960s.

The basal ganglia (BG) are a group of brain nuclei situated deep in the cerebral hemispheres. While BG were primarily associated with motor functions, in recent years there has been an increasing evidence that BG are also significantly involved in a wide range of non-motor functions. This work focused on some of the non-motor symptoms associated with two typical basal ganglia disorders: Parkinson's disease (PD) and Huntington's disease (HD). The first study concerned spatial navigation impairment in patients with HD. Their spatial navigation skills were tested using the Blue Velvet Arena, technique evaluating spatial navigation in real space, capable to selectively differentiate between two components of spatial navigation - allocentric (environment-oriented) and egocentric (self-oriented). Allocentric navigation is linked to hippocampal function, whereas egocentric navigation is usually associated with striatum, a structure predominantly affected in HD. We found that spatial navigation is not significantly affected in the early stages of HD and that in more advanced stages, when spatial navigation is already impaired, there is no significant difference between allocentric and egocentric navigation impairment. We speculate that the striatal involvement does not contribute to the impairment of the...

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Neurological disorders affect more than 14% of the population worldwide and together with traumatic brain and spinal cord injuries represent major health, public and economic burden of the society. Incidence of inherited and idiopathic neurodegenerative disorders and acute CNS injuries is growing globally while neuroscience society is being challenged by numerous unanswered questions. Therefore, research of the CNS disorders is essential. Since animal models of the CNS diseases and injuries represent the key step in the conversion of the basic research to the clinics, we focused our work on generation of new animal models and on their use in pre-clinical research. We generated and characterized transgenic minipig model of Huntington's disease (HD) which represents the only successful establishment of a transgenic model of HD in minipig which should be valuable for testing of long term safety of HD therapeutics. Next, we crossed the well characterized R6/2 mouse HD model with the gad mouse model which lacks the expression of UCHL1 which led to results that support the theory of "protective" role of mutant huntingtin aggregates and suggest that UCHL1 function(s) may be affected in HD disturbing certain branches of Ubiquitin Proteasome System. Traumatic spinal cord injury and Amyotrophic Lateral...