The use of OLEDs (organic light-emitting diodes) in display screens has become increasingly popular due to their improved energy efficiency, relatively low cost, and minimized generation of heat. For these devices, emitters with high photostabilities are desired and efforts in developing molecules of this caliber are increasing rapidly. In the work presented, treatment of an aryl-bridged, bis(N-heterocyclic thione) (NHT) pincer ligand precursor with [PdCl2(CH3CN)2] or PtCl2 yielded 6,6used ring, SCS-NHT Pd and Pt pincer complexes, which are stable in the presence of air. These complexes were found to have excellent photostabilities of 96 % and 93% retention of emission intensity, which make these complexes good candidates for uses in OLEDs. X-ray crystallography of the complexes, computational studies, and the catalytic activity of the SCS-NHT Pd complex are also reported. With advancements in photoluminescent compounds such as these, more energy-efficient display screens can be developed, reducing electricity costs world-wide.

Clinical trials are currently exploring the combinations of P ARP inhibitors and immunotherapies in the treatment of ovarian cancer, but their effects on the ovarian tumour microenvironment (TME) remain unclear. Here, we investigate how olaparib, PD-L1 monoclonal antibodies and their combination can influence TME composition and survival of tumour-bearing mice. We further explored how BRCA mutations can influence the response to therapy. Olaparib and combination therapies similarly improved the median survival of Brca1- and Brca2-deficient tumour-bearing mice. Anti-PD-L1 monotherapy improved the survival of mice with Brca1-null tumours, but not Brca2-null tumours. A detailed analysis of the TME revealed that the olaparib monotherapy resulted in a large number of immunosuppressive and immunomodulatory effects in the more inflamed Brca1-deficient TME but not Brca2-deficient tumours. Anti-PD-L1 treatment was mostly immunosuppressive, resulting in a systemic reduction of cytokines and a compensatory increase of PD-L1. The results of the combination therapy generally resembled the effects of one or both of the monotherapies, along with unique changes observed in certain immune populations. In-silico analysis of RNA-seq also revealed numerous differences between Brca-mutated tumour models. In summary, these findings shed light on the influence of novel therapeutics and BRCA mutations on the ovarian TME.

<p>Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by pathological features that include the selective loss of dopaminergic (DA) neurons in the substantia nigra (SN) region of the midbrain and the presence of intraneuronal Lewy body and Lewy neurite inclusions primarily comprised of fibrillar forms of the pre-synaptic protein alpha-synuclein (aSyn).  aSyn aggregation has been implicated as a critical event in PD pathogenesis, and mutant forms of aSyn are associated with familial, early-onset forms of the disease. PD presents clinically as a movement disorder through appearance of its cardinal motor symptoms of bradykinesia, rigidity, postural instability, and resting tremor. However, upon manifestation of these clinical symptoms, over 50% of the DA nigral neurons have been lost, suggesting that PD neuropathology likely begins 10-15 years prior to the clinical onset. Current PD treatment is focused on symptomatic therapy through dopamine replacement strategies, and there are currently no medications available to prevent or slow disease progression. </p> <p>A major hurdle to developing disease-modifying therapies for PD is a lack of knowledge of the molecular phenomena responsible for the death of DA neurons in the SN. Multiple cellular pathways that are dysregulated in PD include protein clearance systems and oxidative stress responses. Changes in these systems by environmental or genetic perturbations cause increased aSyn aggregation, which in turn leads to increased oxidative and proteasomal stress, thereby generating a vicious cycle culminating in the death of nigral DA neurons. Therefore, strategies to activate these protective pathways have the potential to reduce aSyn aggregation and halt neurodegeneration. One such mechanism is through the activation of the stress-induced transcription factor, Nfe2L1. Nfe2L1 is a cap ‘n’ collar basic leucine zipper (CNC-bZIP) transcription factor that forms heterodimers with small Maf proteins. In turn, the heterodimers bind to antioxidant response element (ARE) sequences in the promoter regions of cytoprotective genes, such as genes encoding proteasome subunits and proteins involved in the glutathione synthesis pathway. In the studies summarized in Chapter 2, we have characterized a pre-clinical <em>in vivo</em> model of PD involving aSyn overexpression in rat SN and used this model to investigate whether Nfe2L1 co-expression could alleviate aSyn neurotoxicity by reducing cytosolic aSyn levels via proteasome activation. Using unbiased stereology to determine nigral DA neuron cell counts, we found that Nfe2L1 may have a protective effect against aSyn-mediated nigral DA neurodegeneration. Surprisingly, we observed no increase in proteasome subunit expression through quantitative PCR or immunoblotting. However, by using a single-neuron analysis approach, we observed a significant increase in PSMC1 subunit expression, suggesting that Nfe2L1 expression could indeed lead to an upregulation of proteasome subunits and an increase in proteasome function. Future experiments will be aimed at determining whether Nfe2L1 expression results in an increase in proteasome activity, an enhancement of aSyn degradation, and a decrease in the burden of proteinase K-resistant (Lewy-like) aSyn aggregates in rat SN. </p> <p>The ability to detect PD in the pre-symptomatic stage is necessary for the development of novel therapies to enable treatment prior to irreversible neuronal loss. Biomarkers with high sensitivity and specificity are critical for early PD detection. aSyn levels have been measured in human biofluids, such as blood and CSF, as a potential biomarker for PD diagnosis and for monitoring disease progression. aSyn can undergo a number of post-translational modifications (PTMs), and a particular form of the protein phosphorylated at serine 129 (pS129-aSyn) is enriched in Lewy bodies, making it an attractive candidate for biomarker studies. Although there are several antibodies targeting pS129, little is known about the influence of PTMs close to pS129 on the antibodies’ affinity for the pS129 epitope, or how these neighboring PTMs could affect assays developed to quantify pS129-aSyn in biofluids. In the studies summarized in Chapter 3, we characterized the impact of PTMs near pS129 on the affinity of currently available pS129-aSyn antibodies for their target antigen using biolayer interferometry (BLI). BLI analysis of the D1R1R pS129-aSyn antibody (Cell Signaling Technology) revealed that tyrosine phosphorylation or nitration at Y133 greatly reduced antibody affinity. In contrast, the MJF-R13 pS129-aSyn antibody (Abcam) was found to have reduced affinity for peptide targets nitrated or phosphorylated on Y125 or phosphorylated on Y133. </p> <p>While aSyn is typically investigated as it relates to PD and other neurodegenerative disorders, recently reported evidence suggests that aSyn downregulation could be linked to an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD).  ASD is a complex neurodevelopmental disorder that presents with characteristic behavioral symptoms of social and communication impairments and restricted, repetitive behaviors. Diagnosis of ASD is based on the presentation of these behavioral symptoms, typically appearing at ~12 months of age, yet individuals don’t receive a diagnosis until the age of five. Early identification and early treatment are regarded as two of the most important factors for improving patient outcomes. SNCA gene deletions and loss-of-function duplications have been found in individuals with intellectual disability, developmental delay, and/or ASD, leading to the idea that reduced aSyn expression may be a biomarker for early ASD diagnosis and may play a role in ASD neuronal dysfunction. In the studies summarized in Chapter 4, we evaluated salivary aSyn as a potential biomarker for early ASD diagnosis and examined SNCA-/- iPSC-derived cortical neurons for indications of ASD-related neuronal anomalies. Our preliminary results suggest that salivary aSyn is reduced in individuals with neurodevelopmental disorders such as ASD and Fragile X Syndrome (FXS), a result consistent with findings of reduced aSyn in serum and plasma from ASD individuals. Furthermore, SNCA-/- iPSC-derived cortical neurons depleted of aSyn expression had increased soma size, a characteristic of iPSC-derived cortical neurons with ASD-associated mutations in the genes encoding MECP2 and TSC1/2 These results suggest that SNCA gene disruptions play a role in ASD-related neuronal anomalies and dysfunction. </p> <p>Overall, the results presented in this thesis support a role for targeting aSyn protein expression in neurodegenerative and neurodevelopmental disorders, and they underscore the importance of designing aSyn biomarker immunoassays that faithfully report on each of these syndromes. Our data suggesting that Nfe2L1 could protect against nigral neurodegeneration by stimulating proteasome-mediated aSyn clearance imply that strategies to increase Nfe2L1-dependent transcriptional activity (e.g., using small molecule activators or gene therapy) could ameliorate pathological aspects of PD. The results presented here also highlight the need for sensitive and specific biomarker assays targeting multiple aSyn proteoforms, and they suggest that aSyn could be a viable biomarker for early ASD diagnosis. Finally, our findings provide the first evidence that aSyn down-regulation contributes to neuronal anomalies associated with ASD, in turn suggesting that strategies to increase cytosolic aSyn by preventing its degradation or through gene therapy could potentially mitigate ASD neuronal dysfunction. </p>

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The development of autoimmune diseases is frequently linked to exposure to environmental factors such as chemicals, drugs or infections. In the experimental model of metal-induced autoimmunity, administration of subtoxic doses of mercury (a common environmental pollutant) to genetically susceptible mice induces an autoimmune syndrome with rapid anti-nucleolar antibody production and immune system activation. Regulatory components of the innate immune system such as the costimulatory molecules PD-1, CTLA-4 and their ligands PD-L1, PD-L2, B7-1 and B7-2 can also modulate the autoimmune process. We examined the interplay among environmental chemicals and these costimulatory molecules in the regulation of autoimmunity. Additionally, we studied PD-1, CTLA-4 and its ligands in a tolerance model where pre-administration of a low dose of mercury in the steady state renders animals tolerant to metal-induced autoimmunity. Overall, PD-1/CTLA-4 blockade by blocking antibodies enhanced the manifestations of metal-induced autoimmunity. Although we expected that the blockade of both PD-1 ligands would mimic blocking the receptor, blocking the ligands resulted in the opposite effect when co-injected with mercury, reducing the manifestations of metal-induced autoimmunity. Individual PD-1 ligands differed in their ability to enhance the mercury treatment, with PD-L1 being the major regulator in the model. Likewise, we showed that PD-L1 is essential to keep the recall response to mercury at check. Our data suggest that these effects could be mediated by the modification of cytokine profiles, B cells and T cell subpopulations numbers. / Microbiology and Immunology

Alzheimer's Disease (AD) is an irreversible, age-related neurodegenerative disorder which causes cognitive impairment and a wide variety of neuropsychiatric and behavioral disturbances. Acetylcholinesterase inhibitors (AChEI) are the mainstay for the treatment of AD. Acetylcholinesterase (AChE) catalyzes the hydrolysis of acylcholinesters with a relative specificity for acetylcholine (ACh). Observation of a deficiency of cholinergic neurotransmission in AD led to the development of AChEI as the first approved treatment for dementia symptoms. Tacrine (9-amino-1,2,3,4-tetrahydroacridine) is a reversible inhibitor of AChE. It was the first drug approved by the FDA for the treatment of cognitive symptoms of AD. Tacrine is now rarely prescribed as a drug for the treatment of AD due to its high hepatotoxicity in almost 50% of the patients. However, tacrine derivatives have considerable potential for the palliative treatment of AD. Synthesis of various bivalent tacrines led to the improvement in inhibitory potency and selectivity towards inhibition of AChE. Heptylene-linked bis-tacrine has especially shown immense promise to be an ideal AChEI. Thus dimerization of a lead compound seemed to be an ideal strategy where the compound can bind to both catalytic anionic site (CAS) and peripheral anionic site (PAS) on the AChE enzyme. However synthesis of N-alkyl derivatives of expanded tacrines like 12-chloro-2-methyl-6,7,8,9,10,11-hexahydrocycloocta[b]quinoline by the standard SNAr methods was unsuccessful and thus alternatives needed to be developed to synthesize N-alkylated and bivalent 12-chloro-2-methyl-6,7,8,9,10,11-hexahydrocycloocta[b]quinoline. Upon exploring the alternatives, N-arylation by Pd-catalysis seemed to be the most mild and convenient alternative over the standard SNAr procedures. / Master of Science

I present a detailed study of the magnetic propertie of electron-beam evaporated Pdo.4Nio.6 alloy thin films by means of ferromagnetic resonance measurements on extended films of varying thickness and anisotropic magnetoresistance measurements lithographically patterned high aspect-ratio ferromagnetic electrodes, respectively. The results reveal that the direction of the magnetization with respect to the film plane strongly depends on the electrode lateral dimensions, transitioning from in-plane magnetization for extended films to out of the plane magnetization for electrode width below 2-3 microns, reaching ~58 degrees for electrode widths of about 100nm (nanowires). This behavior arises from a competition between the film demagnetizing vector, which leads to in-plane magnetization for extended films , and an intrinsic uniaxial anisotropy, which overcomes the magnetostatic energy for laterally constrained films, pulling the magnetization off plane.

The determination of lending (credit) risk is one of the most important fields of bank activities. This thesis discusses the IRB approach under Basel II. This approach includes the LGD, EAD and PD parameters. All parameters are individually modelled by the bank using regulator approved models. Parameter PD is the most focused one in this thesis. Theory for this parameter is of interest in many papers. However, at present the need for modelling of PD parameter over more years is appearing. Parameter LGD is also discussed in this thesis. The parameter EAD is only briefly presented. The thesis begins with the IRB approach, regression models and evaluation indicators, and then it focuses on the above parameters.