A Québec mystery unveiled : the quest to understand hereditary sensory and autonomic neuropathy type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Single-Cell Transcriptome Analysis of Olfactory Sensory Neurons

Olfactory sensory neurons (OSNs), which detect a myriad of odorants, are known to express one allele of one olfactory receptor (OR) gene (Olfr) from the largest gene family in the mammalian genome. The OSNs expressing the same OR project their axons to the main olfactory bulb where they converge to form glomeruli. This “One neuron-one receptor rule” makes the olfactory epithelium (OE), which consists of a vast number of OSNs expressing unique ORs, one of the most heterogeneous cell populations. However, the mechanism of how the single OR allele is chosen remains unclear along with the question of whether one OSN only expresses a single OR gene, a hypothesis that has not been rigorously verified while we performed the experiments. Moreover, failure of axonal targeting to single glomerulus was observed in MeCP2 deficient OSNs where delayed development was proposed as an explanation for the phenotype. How Mecp2 mutation caused this aberrant targeting is not entirely understood.

In this dissertation, we explored the transcriptomes of single and mature OSNs by single-cell RNA-Seq to reveal their heterogeneity and further studied the OR gene expression from these isolated OSNs. The singularity of sequenced OSNs was ensured by the observation of monoallelic expression of X-linked genes from the hybrid samples from crosses between mice of different strains where strain-specific polymorphisms could be used to track the allelic origins of SNP-containing reads. The clustering of expression profiles from triplicates that originated from the same cell assured that the transcriptomic identities of OSNs were maintained through the experimental process. The average gene expression profiles of sequenced OSNs correlated well to the conventional transcriptome data of FACS-sorted Omp-positive cells, and the top-ranked expression of OR was conceded in the single-OSN transcriptomes. While exploring cellular diversity, in addition to OR genes, we revealed nearly 200 differentially expressed genes among the sequenced OSNs in this study. Among the 36 sequenced OSNs, eight cells (22.2%) showed multiple OR gene expression and the presences of additional ORs were not restricted to the neighbor loci that shared the transcriptional effect of the primary OR expression, suggesting that the “One neuron-one receptor rule” might not be strictly true at the transcription level. All of the inferable ORs, including additional co-expressed ORs, were shown to be monoallelic. Our sequencing of 21 Mecp2308 mutant OSNs, of which 62% expressed more than one OR genes, and the expression levels of the additional ORs were significantly higher than those in the wild-type, suggested that MeCP2 plays a role in the regulation of singular OR gene expression. Dual label in situ hybridization along with the sequence data revealed that dorsal and ventral ORs were co-expressed in the same Mecp2 mutant OSN, further implying that MeCP2 might be involved in regulation of OR territories in the OE. Our results suggested a new role of MeCP2 in OR gene choice and ratified that this multiple-OR expression caused by Mecp2 mutation did not accompany delayed OSN development that has been observed in the previous studies on the Mecp2 mutants.

The effects of centrally acting ACE inhibitors on the rate of cognitive and functional decline in dementia: a KDD approach

Alzheimer’s Disease and other dementias are one of the most challenging illnesses confronting countries with ageing populations. Treatment options for dementia are limited, and the costs are significant. There is a growing need to develop new treatments for dementia, especially for the elderly. There is also growing evidence that centrally acting angiotensin converting enzyme (ACE) inhibitors, which cross the blood-brain barrier, are associated with a reduced rate of cognitive and functional decline in dementia, especially in Alzheimer’s disease (AD). The aim of this research is to investigate the effects of centrally acting ACE inhibitors (CACE-Is) on the rate of cognitive and functional decline in dementia, using a three phased KDD process. KDD, as a scientific way to process and analysis clinical data, is used to find useful insights from a variety of clinical databases. The data used are from three clinic databases: Geriatric Assessment Tool (GAT), the Doxycycline and Rifampin for Alzheimer’s Disease (DARAD), and the Qmci validation databases, which were derived from several different geriatric clinics in Canada. This research involves patients diagnosed with AD, vascular or mixed dementia only. Patients were included if baseline and end-point (at least six months apart) Standardised Mini-Mental State Examination (SMMSE), Quick Mild Cognitive Impairment (Qmci) or Activities Daily Living (ADL) scores were available. Basically, the rates of change are compared between patients taking CACE-Is, and those not currently treated with CACE-Is. The results suggest that there is a statistically significant difference in the rate of decline in cognitive and functional scores between CACE-I and NoCACE-I patients. This research also validates that the Qmci, a new short assessment test, has potential to replace the current popular screening tests for cognition in the clinic and clinical trials.

A geographical perspective on the decline and extermination of the Irish wolf Canis lupus - an initial assessment

Wolves were a component of the Irish landscape until 1786 when the last one was killed. It had taken a concerted effort by Cromwell and his Government in Ireland to bring this about particularly through deforestation and landscape change, legislation, bounties and the efforts of a few professional wolf hunters. This paper estimates the wolf population in Ireland at three lime periods in the 1600s and examines how each of the forces already mentioned led to their eventual extermination. The 87 dated and documented wolf incidents which include wolf attacks on both animals and humans, wolf observations and the hunting and killing of wolves over the period 1560-1789 show both spatial and temporal variations.

A Québec mystery unveiled : the quest to understand hereditary sensory and autonomic neuropathy type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Effects of Altered Prenatal Sensory Stimulation on Postnatal Contingency Learning in Bobwhite Quail Neonates (Colinus Virginianus)

Preterm infants are exposed to high levels of modified early sensory experience in the Neonatal Intensive Care Unit (NICU). Reports that preterm infants show deficits in contingency detection and learning when compared to full-term infants (Gekoski, Fagen, & Pearlman, 1984; Haley, Weinberg, & Grunau, 2006) suggest that their exposure to atypical amounts or types of sensory stimulation might contribute to deficits in these critical skills. Experimental modifications of sensory experience are severely limited with human fetuses and preterm infants, and previous studies with precocial bird embryos that develop in ovo have proven useful to assess the effects of modified perinatal sensory experience on subsequent perceptual and cognitive development. In the current study, I assessed whether increasing amounts of prenatal auditory or visual stimulation can interfere with quail neonates’ contingency detection and contingency learning in the days following hatching. Results revealed that augmented prenatal visual stimulation prior to hatching does not disrupt the ability of bobwhite chicks to recognize and prefer information learned in a contingent fashion, whereas augmented prenatal auditory stimulation disrupted the ability of chicks to benefit from contingently presented information. These results suggest that specific types of augmented prenatal stimulation that embryos receive during late prenatal period can impair the ability to learn and remember contingently presented information. These results provide testable developmental hypotheses, with the goal of improving the developmental care and management of preterm neonates in the NICU setting.

First evidence of altered sensory quality in a shellfish exposed to decreased pH relevant to ocean acidification

Understanding how seafood will be influenced by coming environmental changes such as ocean acidification is a research priority. One major gap in knowledge relates to the fact that many experiments are not considering relevant end points related directly to production (e.g., size, survival) and product quality (e.g., sensory quality) that can have important repercussions for consumers and the seafood market. The aim of this experiment was to compare the survival and sensory quality of the adult northern shrimp (Pandalus borealis) exposed for 3 wk to a temperature at the extreme of its thermal tolerance (11°C) and 2 pH treatments: pH 8.0 (the current average pH at the sampling site) and pH 7.5 (which is out of the current natural variability and relevant to near-future ocean acidification). Results show that decreased pH increased mortality significantly, by 63%. Sensory quality was assessed through semiqualitative scoring by a panel of 30 local connoisseurs. They were asked to rate 4 shrimp (2 from each pH treatment) for 3 parameters: appearance, texture and taste. Decreased pH reduced the score significantly for appearance and taste, but not texture. As a consequence, shrimp maintained in pH8.0 had a 3.4 times increased probability to be scored as the best shrimp on the plate, whereas shrimp from the pH 7.5 treatment had a 2.6 times more chance to be scored as the least desirable shrimp on the plate. These results help to prove the concept that ocean acidification can modulate sensory quality of the northern shrimp P. borealis. More research is now needed to evaluate impacts on other seafood species, socioeconomic consequences, and potential options.

Cape Breton Provides Pointers for the Adjustment Programs Required by the Decline of the Old Economy (Working Paper 14)

The Cape Breton Development Corporation need not, should not, be dying in the way it is. “Devco” has been widely represented as a failure dragged out too long. In fact it had for a time considerable success in a role too difficult to be often attempted. The main failure was in the political will to stick to its purpose. This commentary is in three parts. The first, major section discusses the purpose of Devco and the policies that served the purpose quite well but were maintained for little more than a decade. It suggests that the benefits would have been greater if Devco had been started earlier in the period of postwar prosperity. The second section comments on the enfeeblement of Devco in the 1980s. The removal of its development function also weakened, and has eventually led to the abandonment of, Devco’s social purpose in the operation of coal mining. Third, a short epilogue pointing out that, while the Cape Breton case is extreme, there will be increasing need to moderate the socially disruptive consequences of accelerating economic change. There are lessons from the Devco experience: the longer remedial action is delayed, the more difficult and expensive it becomes, and the more necessary for its effectiveness is a steady political will.

Deep Decline

Thesis (Ph.D.)--University of Washington, 2016-08

Functions of the SLC36 transporter Pathetic in growth control of Drosophila sensory neurons

Thesis (Ph.D.)--University of Washington, 2016-08