Trends in Intellectual Property Rights to Genetically Modified Agricultural Products (exemplified by legislation of Ukraine)

Genetically modified agricultural products (hereinafter-GMAPs) are produced based on genetic resources (hereinafter - GRs), which could be treated as valuable ecological (for functioning of the ecosystem) and economic (for social development) resources. They are identified as part of the environment and commercialized particles/processes of nature with implementation of the UN Convention on Biological Diversity, 1992 (hereinafter - CBD), and the Agreement on Trade Related Aspects of Intellectual Property Rights of the World Trade Organization, 1994 (hereinafter - TRIPS), respectively. The international community faces new challenges in establishing legal regimes for GMAPs, based on the principles of fairness, equality, ensuring of private property, and precautionary principle. This thesis examines implementation of CBD and TRIPS (as regards IPRs to GMPs) in developing countries (Ukraine is taken as an example). The legal framework on IPRs to GMAPs in Ukraine is analyzed together with socio-economic factors that affect its efficiency. The thesis also investigates legal nature and social functions of patenting as one of the disputable types of IPRs to GMAPs. Finally, consideration is given to the potential of GR management at the national level. Theoretical approach is combined with practical examples of genetic resource management. That combination helps to identify obstacles in the development of genetic resource management, analyze the effectiveness of the existing legal rules, and understand the trends in IPRs to GMAPs. Some recommendations to improve the legal regime of IPRs to GMAPs in Ukraine are formulated. This master thesis employs the method of qualitative analysis, investigating the general issues on environmental and trade regimes of GRs, and the conditions of compliance of Ukraine with appropriate international and European requirements. Discourse analysis is used to identify points of view and issues which shape debates about IPRs to GMAPs. An interview clarifies the Russian legal perspective on GRs.M-IE

Identifying genetic determinants of progression in Parkinson's disease

Parkinson’s disease (PD) is a progressive neurodegenerative condition for which there are currently no treatments to stop or slow disease progression. A number of genome-wide association studies (GWASs) of PD patients compared to controls have identified genetic variants associated with disease risk, however these cannot inform us about the genetic factors and biology underpinning progression. The aim of this PhD is to identify genetic variants associated with disease progression. I first examined the frequency and baseline clinical features of patients carrying rare pathogenic Mendelian mutations (including variants in LRRK2, SNCA, Parkin, and PINK1) in the Tracking Parkinson’s cohort. I showed that Parkin and PINK1 carriers had better cognition than other early-onset patients at baseline despite having longer disease duration, suggesting slower progression. In analysis of longitudinal data, I also showed that GBA carriers appeared to have more rapid motor and cognitive progression than non-carriers. Prior to conducting GWASs, I sought to understand the clinical predictors of progression and showed that age at onset and gender were associated with progression to clinical milestones. Following a new method from the Huntington’s disease progression GWAS, I used principal components analysis (PCA) to combine multiple motor and cognitive scales in PD to create composite progression scores. I showed that APOE ε4 was strongly associated with cognitive progression, and identified a novel signal in ATP8B2 which was nominally associated with motor progression. Finally, I conducted large-scale GWASs of survival to clinical milestones: mortality, Hoehn and Yahr stage 3, and dementia, using data from Tracking Parkinson’s, Oxford Discovery, Parkinson’s Progression Markers Initiative, Queen Square Brain Bank, UK Biobank, and Calypso studies. I identified loci in or near APOE, ADRA2A, and SH3GL2 which were nominally associated with progression to mortality. I also showed that the APOE ε4 variant, rs429358, was strongly associated with progression to dementia

Variation of echolocation pulse source levels and detection distances for bat assemblages across an environmental gradient: “a test of the acoustic adaptation hypothesis”

The use of multiple microphone arrays to measure echolocation pulse source levels of free-flying bats does not allow one to determine the species of the bat being recorded. However, the echolocation pulses can be assigned to species based on pulse parameters used in conjunction with a reference library of pulses, the distribution records of bat species and the identification of captured individuals sampled in the area of recording (Chapter 2). Echolocation pulses were recorded as bats emerged from their own roosts, using the multiple microphone array system. Several parameters were measured from pulses within each echolocation sequence to identify a representative pulse type for each species. These initial species assignations were confirmed through multivariate analyses so that source level of echolocation pulses could be assigned to species. Source levels used by bats impacts on the distance at which bats perceive their targets like prey in their habitats. Habitat and prevailing climatic conditions present different challenges for echolocation systems, and so the quality and content of information derived from echolocation pulse reflects these environmental challenges. Hence, echolocation pulses within or between species may vary from one habitat to the next due to variable selection pressure, resulting in local adaptation as formalised in the Acoustic Adaptation Hypothesis, which proposes that acoustic properties of the environment influence sound propagation and ultimately the evolution of echolocation pulses. To test the Acoustic Adaptation Hypothesis, I used multiple microphone arrays to measure the source levels of echolocation pulses of fourteen bat species in several bat assemblages across seven sites in different biomes in South Africa. Source levels generated from echolocation pulses, together with frequency and weather parameters were used to calculate detection distances (Chapter 3). In Chapter 4, detection distances were calculated using long-term climate data of 40 years, which is the same data used to assess whether predictive models could explain detection distances. In both chapters, the resultant detection distances were used to test the predictions of the Acoustic Adaptation Hypothesis. Results show that bats in the same assemblage used different echolocation pulse source levels and frequencies resulting to different detection distances, which differ among bat assemblages occupying different sites. Detection distance is species-specific and remained similar within species between assemblages, hence species is a better predictor of detection distances than site as indicated by Miniopterus natalensis across sites in biomes (Chapter 3). Results in Chapter 4 show that bats belonging to the same assemblage used different echolocation pulse source levels and frequencies resulting to different detection distances, which differ among bat assemblages occupying different sites under the prevailing climatic conditions. Detection distances between sites were different only in some sites, suggesting that the AAH was partially supported. Detection distance is species-specific and remained similar within species between assemblages, hence species is a better predictor of detection distances than climatic conditions as indicated by Miniopterus natalensis across sites. Detection distances for bat assemblages were correlated with temperature and longitude, whereas for Miniopterus natalensis, they were correlated with longitude, providing partial support for the Acoustic Adaptation Hypothesis. Detection distances were however not correlated with relative humidity, atmospheric pressure and latitude. Because temperature may change at different longitudes owing to diverse geographical features that affect atmospheric circulation, it suggests that temperature is the most important climatic variables that impacts echolocation and any human induced climate change that results in changes in temperature are likely to impact the survival of bats

Genetic and molecular biomarkers of Alzheimer's disease

[eng] Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Research in the past decade has led to major progress in understanding the genetic etiology of the disease; since I started my PhD (2019), nearly 20 genetic risk factors have been associated with late onset AD. Among them, the Ԑ4 allele of the APOE gene was the first identified, and remains the major genetic risk factor for AD. Despite extensive genetic research, a large part of the disease heritability remains elusive, the disease mechanisms incomprehensible, and targeted preventive interventions or pharmacological treatments for AD unavailable at the time. In this context, the overarching aim of the studies included in this thesis was to contribute to the knowledge of AD identifying new genetic risk factors and to better understand the role played by the APOE gene in the development of the disease. Such information would allow us to gain new insights into the molecular and biological mechanisms underlaying the disease and ultimately find new targets for treatment. This thesis provides evidence of the possible effectiveness of the use of a polygenic risk scores in a clinical setting for diagnosis of AD and actively improves the knowledge of the genetic factors associated with AD through genome-wide association studies

05. 2014 IMSAloquium Student Investigation Showcase

https://digitalcommons.imsa.edu/class_of_2015/1003/thumbnail.jp

2014 IMSAloquium, Student Investigation Showcase

The ability to work with professionals is a life-changing experience for our students. Working with world-class scholars and advisors, students have contributed to advances in a variety of fields from science, technology, engineering and mathematics, to the performing arts and history.https://digitalcommons.imsa.edu/archives_sir/1006/thumbnail.jp

Obesity and prostate cancer: epidemiology, genetics and molecular and cellular mechanisms

Doutoramento em Ciências BiomédicasDoctoral Degree in Biomedical Science

Statistical co-analysis of high-dimensional association studies

Modern medical practice and science involve complex phenotypic definitions. Understanding patterns of association across this range of phenotypes requires co-analysis of high-dimensional association studies in order to characterise shared and distinct elements. In this thesis I address several problems in this area, with a general linking aim of making more efficient use of available data. The main application of these methods is in the analysis of genome-wide association studies (GWAS) and similar studies. Firstly, I developed methodology for a Bayesian conditional false discovery rate (cFDR) for levering GWAS results using summary statistics from a related disease. I extended an existing method to enable a shared control design, increasing power and applicability, and developed an approximate bound on false-discovery rate (FDR) for the procedure. Using the new method I identified several new variant-disease associations. I then developed a second application of shared control design in the context of study replication, enabling improvement in power at the cost of changing the spectrum of sensitivity to systematic errors in study cohorts. This has application in studies on rare diseases or in between-case analyses. I then developed a method for partially characterising heterogeneity within a disease by modelling the bivariate distribution of case-control and within-case effect sizes. Using an adaptation of a likelihood-ratio test, this allows an assessment to be made of whether disease heterogeneity corresponds to differences in disease pathology. I applied this method to a range of simulated and real datasets, enabling insight into the cause of heterogeneity in autoantibody positivity in type 1 diabetes (T1D). Finally, I investigated the relation of subtypes of juvenile idiopathic arthritis (JIA) to adult diseases, using modified genetic risk scores and linear discriminants in a penalised regression framework. The contribution of this thesis is in a range of methodological developments in the analysis of high-dimensional association study comparison. Methods such as these will have wide application in the analysis of GWAS and similar areas, particularly in the development of stratified medicine.I was supported by a grant from the NIHR Cambridge BR

Non-Canonical Odor Coding Ensures Robust Mosquito Attraction to Humans

Aedes aegypti mosquitoes spread deadly diseases, including dengue, Zika, yellow fever, and chikungunya. Only female mosquitoes bite, and they do so because they require a blood-meal for reproduction. Aedes aegypti prefer to bite human hosts, which contributes to their effectiveness as a deadly disease vector. Mosquitoes rely heavily on chemosensory cues, including carbon dioxide (CO2) emitted from breath and human body odor, which is a mixture of more than 200 different individual odorants. Although the exact odor profile of people varies considerably, Aedes aegypti are incredibly reliable in finding humans to bite, despite widespread efforts to by humans to mask our odor. Even mosquitoes with genetic mutations that eliminate entire families of chemosensory receptors are still able to find and bite humans. It remains unknown how the mosquito olfactory system is seemingly infallible in its ability to detect humans for taking a blood meal. In the well-studied olfactory systems of Drosophila melanogaster and Mus musculus, individual olfactory sensory neurons express a single type of olfactory receptor and project their axons to discrete regions, called glomeruli, in the antennal lobe or olfactory bulb, respectively. This organization is believed to be a widespread motif in olfactory systems and has been established dogma since the mid-2000s and is hypothesized to permit the brain to parse which subpopulation of olfactory neurons is activated by a given odor. To understand how human odor is encoded in the mosquito olfactory system, we developed a CRISPR-Cas9-based genetic knock-in strategy in Aedes aegypti and generated a suite of transgenic mosquito strains that label populations of olfactory sensory neurons. Surprisingly, we find that the olfactory system of Aedes aegypti does not have the expected “one-receptor-to-one-neuron-to-oneglomerulus” organization seen in other insects. Rather, there are many more receptors than glomeruli. We frequently observe co-expression of multiple chemosensory receptors within individual olfactory sensory neurons and individual glomeruli are commonly innervated by olfactory sensory neurons expressing different receptors. What is the functional consequence of this unconventional organization? To understand how co-expression of multiple chemosensory families affects human odor detection by mosquitoes, we examined a minimal mixture that drives host seeking behavior. Mosquitoes are attracted to the combination of the two human-derived, cues CO2 and lactic acid. We found that the same neurons that sense CO2 also sense volatile amines, including triethyl amine. These amines are detected by separate chemosensory receptor genes and we discovered that these cues can be interchanged to drive attraction in the presence of lactic acid. This sensory organization, in which multiple receptors that respond to very different types of chemicals are co-expressed, suggests a redundancy in the odor code at the level of the olfactory sensory neurons for cues that signal the presence of a human to bite. We speculate that this design supports the robust human host-seeking seen in this olfactory specialist

RNA-Seq Reveals Transcriptomic Program Associated with Stemness in Taxane Resistant Prostate Cancer

There is no cure for advanced prostate cancer (PCa), and taxane chemotherapy is the only treatment option once other therapies have failed. However, this is problematic since all patients eventually develop chemoresistance. Emerging treatments for advanced PCa have shown promise at the benchside, but clinical trials have not resulted in newly approved drugs due in part to redundant survival pathways utilized by prostate tumor cells to maintain therapy-resistance. Using RNAsequencing—an innovative approach for quantifying gene expression changes—this dissertation sought to elucidate chemoresistance-associated molecular pathways as a catalyst to develop new therapeutic targets. Results revealed a differential upregulation of stemness-associated genes in PCa cells selected for chemoresistance. In addition, chemoresistant cells formed robust stem cell prostaspheres compared to chemosensitive cells, and expressed other markers of cancer stem cells. Overall, these findings support the hypothesis that PCa chemoresistance is driven by cancer stem cells