50140 research outputs found
Sort by
Different Responses to Altered Auditory Feedback in Younger and Older Adults Reflect Differences in Lexical Bias.
No full textPrevious work has found that both young and older adults exhibit a lexical bias in categorizing speech stimuli. In young adults, this has been argued to be an automatic influence of the lexicon on perceptual category boundaries. Older adults exhibit more top-down biases than younger adults, including an increased lexical bias. We investigated the nature of the increased lexical bias using a sensorimotor adaptation task designed to evaluate whether automatic processes drive this bias in older adults. Method A group of older adults (n = 27) and younger adults (n = 35) participated in an altered auditory feedback production task. Participants produced target words and nonwords under altered feedback that affected the 1st formant of the vowel. There were 2 feedback conditions that affected the lexical status of the target, such that target words were shifted to sound more like nonwords (e.g., less-liss) and target nonwords to sound more like words (e.g., kess-kiss). Results A mixed-effects linear regression was used to investigate the magnitude of compensation to altered auditory feedback between age groups and lexical conditions. [...
Insecurity about getting old: age-contingent self-worth, attentional bias, and well-being
No full textObjectives: Older adulthood has often been recognized as a time of increased well-being and positive cognitive biases. However, older adults can also experience many social and identity challenges. We sought to investigate which older adults might be most vulnerable to these difficulties. [...]Conclusions: These findings demonstrate that older adults who are insecure about aging may have lower well-being and negatively biased social cognitive patterns. Negatively biased attentional patterns may play a key role in maintaining feelings of insecurity. Importantly, our research sheds light on those older adults who may not experience a positivity effect
Shaping the Body Politic: Mass Media Fat-Shaming Affects Implicit Anti-Fat Attitudes
No full textObjectives: Older adulthood has often been recognized as a time of increased well-being and positive cognitive biases. However, older adults can also experience many social and identity challenges. We sought to investigate which older adults might be most vulnerable to these difficulties. [...]Conclusions: These findings demonstrate that older adults who are insecure about aging may have lower well-being and negatively biased social cognitive patterns. Negatively biased attentional patterns may play a key role in maintaining feelings of insecurity. Importantly, our research sheds light on those older adults who may not experience a positivity effect
Opaque Transparency: How Material Affordances Shape Intermediary Work
No full textHow do the material aspects of intermediary work affect regulators, targets, and beneficiaries? To shed light on this question, we studied an information intermediary in the form of a website and the organizations who founded it. Specifically, we analyzed FracFocus, a self‐regulatory initiative with strong industry ties, charged with disclosing data pertaining to the chemicals used in oil and gas wells completed using hydraulic fracturing technology (fracking) in the United States and Canada. We found that between 2010 and mid‐2017, the vast majority of legislation in states and provinces where fracking actively occurred was updated to mandate or encourage disclosure via FracFocus, meaning that it had a considerable effect on the trajectory of official regulation on fracking disclosure. We also found that FracFocus disclosed important data but did so in a manner that limited accessibility and reduced the comprehensibility of environmental and public health risks to beneficiaries. Our analysis suggests that the public's experience of such a device is one of opaque transparency, in which the line between official and non‐official regulation is blurred. We traced these outcomes to the material affordances created by FracFocus
On the Properties of the Arctic Halocline and Deep Water Masses of the Canada Basin from Nitrate Isotope Ratios
No full textNitrogen is a limiting nutrient for primary production in the western Arctic Ocean.Measurements of the nitrogen (15N/14N) and oxygen (18O/16O) isotope ratios of nitrate in thesoutheastern Beaufort Sea provide insight into biogeochemical cycling of nitrogen in the western ArcticOcean. Nitrate O isotope ratios in the Pacific halocline evidence a highly regenerated reservoir. Coincidentpeaks in nutrient concentrations and reduced dissolved oxygen concentrations suggest that nitrateaccrues from organic matter remineralization in bottom waters of the Chukchi shelf and that theseventilate the basin predominantly in summer, when isolated from the atmosphere. Preformed nitrate inPacific Winter Water lacks 18O/16O elevation from nitrate assimilation, contrasting with preformed nitratein other ocean regions. A reactive N deficit and elevated nitrate N isotope ratios in the Pacific haloclinefurther indicate substantial N loss to coupled nitrification-denitrification in shelf sediments upstream. Inthe Atlantic Water below, nitrate isotope ratios identify two distinct waters entering the Arctic at FramStrait, from (1) the surface West Spitsbergen Current, bearing isotopic signatures akin to North Atlanticwaters, and (2) deeper inflows of waters ventilated in the Nordic Seas, transporting nitrate O isotoperatios indicative of regenerated nitrate
Anodized Aluminum with Nanoholes Impregnated with Quaternary Ammonium Compunds can kill pathogenic bacteria within seconds of contact
No full textBacterial contamination of surfaces results in the spread of pathogens in public spaces such as hospitals and public transport. The development of antibacterial surfaces that rapidly kill bacteria is therefore highly desirable. Here, we investigate the antibacterial efficacy of a novel anodized aluminum surface featuring nanoholes impregnated with quaternary ammonium compounds, referred to as A3S. The antimicrobial activity of A3S was assessed using both Gram-positive and Gram-negative bacteria in a novel assay which simulates pathogen transfer from a contaminated "finger" to a clean finger in a real-world scenario. Enumeration of colony-forming units shows that the number of viable bacteria on the second "finger" contacting A3S is significantly reduced compared to a control surface. Furthermore, bacterial contact with the A3S material results in compromised cell membranes in less than 1 min, and a kill zone assay shows that an exposure time as short as 5 s is sufficient to kill pathogenic bacteria. The rapid antimicrobial action of A3S was particularly evident against Gram-positive bacteria, that account for more than 70% of nosocomial infections. Taken together, these findings demonstrate that A3S is a promising candidate for the fabrication of antibacterial surfaces that can be used in a wide range of clinical and commercial applications to stop the spread of harmful bacteria
Measuring enzyme kinetics using isothermal titration calorimetry
No full textEnzymes play a central role in virtually all biological processes. Consequently, mutations that lead to alterations in enzyme activity can result in diseased states. Modern drug discovery is primarily based on developing small molecule inhibitors of biological macromolecules, in order to correct their function and restore regular physiology. The properties of inhibitors are tested throughout the drug development process to help guide structural optimization making rapid approaches for quantifying enzyme activity in the presence of inhibitors imperative. There are various techniques for measuring enzyme kinetics including isothermal titration calorimetry (ITC) which works by directly measuring heat flow, a near universal feature of chemical reactions. By measuring heat flow ITC is able to perform measurements under conditions which would be inaccessible using other techniques. In addition, ITCs have become a standard instrument in biochemistry laboratories. In this thesis, we present several novel methods for measuring enzyme kinetics using isothermal titration calorimetry. In chapter 2 we demonstrate that isothermal titration calorimeters (ITCs) are capable of measuring heat flow with sub-second precision and develop a technique for quantitatively modelling rapid time-scale kinetics. Importantly, this approach is implemented into the techniques described in chapters 3 and 4 allowing for quantitative modelling of rapid kinetics throughout the thesis. Chapter 3 describes a technique for extracting both the strength and mode of enzyme inhibitors in a single experiment. In chapter 4 we present a pair of complementary techniques capable of rapidly measuring association and dissociation kinetics as well the strength of enzyme-inhibitor interactions. Importantly, all of the methods presented here are time/sample efficient and possess all of the inherent advantages of ITC.Les enzymes jouent un rôle principal dans pratiquement tous les processus biologiques. Par conséquent, les mutations qui mènent à des changements par rapport à l'action des enzymes peuvent entraîner des conditions de maladies. La production de médicaments actuels est principalement basée sur le développement d'inhibiteurs à petites molécules de macromolécules biologiques afin de corriger leur fonction et de rétablir la physiologie normale. Les propriétés des inhibiteurs sont testées tout au long du processus de développement du médicament afin de guider l'optimisation structurale, rendant impératif des méthodes rapides pour quantifier l'activité enzymatique en présence d'inhibiteurs. Il existe diverses techniques de mesure de cinétique enzymatique, y compris la Titration Calorimétrique Isotherme (TCI) qui fonctionne en mesurant directement le flux de chaleur, une caractéristique quasi-universelle des réactions chimiques. En mesurant le flux de chaleur, la TCI dispose alors de la capacité d'effectuer des mesures dans des conditions qui seraient inaccessibles en utilisant d'autres techniques. De plus, la TCI est devenue une méthode standard dans les laboratoires de biochimie. Dans cette thèse, nous présentons plusieurs nouvelles méthodes pour mesurer la cinétique enzymatique en utilisant la Titration Calorimétrique Isotherme. Au chapitre 2, nous démontrons que la TCI permet de mesurer le flux de chaleur avec une précision sous la seconde et développons une technique de modélisation quantitative d'échelle de temps de la cinétique à taux rapide. Étant importante, cette approche est implantée dans les techniques décrites dans les chapitres 3 et 4, impliquant la modélisation quantitative de la cinétique à taux rapide tout au long de la thèse. Le chapitre 3 décrit une technique pour déterminer le mode et la force des inhibiteurs d'enzymes dans une seule expérience. Dans le chapitre 4, nous présentons deux techniques complémentaires permettant de mesurer rapidement la cinétique d'association et de dissociation, ainsi que la force des interactions d'inhibiteurs d'enzymes. Toutes les méthodes présentées ici sont efficaces en matière de temps et d'échantillonnage, et disposent de tous les avantages inhérents à la TCI
Mechanisms of novel Hsp70 inhibitors and the co-chaperone Hsp110
No full textHsp70 is a ubiquitously expressed molecular chaperone and required for maintaining protein homeostasis. Hsp70 is also highly upregulated in many cancer cells and important for their survival. Therefore, small molecule inhibitors are being developed for clinical use. Of those that are available currently, most, if not all, have poor potency, specificity or off-target effects. Thus, there is a need for specific Hsp70 inhibitors. Our collaborators developed a novel inhibitor of Hsp70 called YK5 (YK-series), which was effective at killing cancer cells. YK5 interacts with an allosteric interaction site which contains a cysteine residue where it binds covalently. I established a cellular assay for the Hsp70-mediated protein folding and solubilization and show that YK5 indeed disrupts the core biochemical functions of Hsp70. Hsp70 is an ATP-dependent molecular chaperone with a cycle that requires an ATPase stimulating DNAJ protein and a nucleotide exchange factor, NEF, to displace ADP. These changes in the nucleotide state in the nucleotide-binding domain drive the conformational changes in the substrate-binding domain. In the ATP-bound state, Hsp70 does not bind substrate, whereas in the ADP or apo-state, it does. Understanding how the YK inhibitors affect Hsp70 is important, especially when using them as tools to study biological functions of Hsp70. I show that the reversible analog of YK5, 17l, increases peptide binding to Hsc70 and Hsp70 in the core ATPase cycle. The effects are on the kinetics of substrate release, but also for Hsc70 in the equilibrium between substrate free and bound states. However, with the NEF Hsp110 present in the cycle, peptide binding to Hsc70 and Hsp70 decreases due to faster dissociation of Hsp110 caused by 17l. In both cases, there is a disruption of the ATPase cycle, which affects the ability of the Hsp70s to fold and solubilize substrate, an effect we observed in cells. The mechanistic effects of 17l on substrate interaction suggested the importance of the Hsp70 chaperone complex, as a whole, specifically with Hsp110. First, I show that Hsp110 is indeed important for folding and solubilization of substrate in cells and cannot be substituted by the Bag family of NEFs. I specifically addressed the importance of the Hsp70-Hsp110 interaction by designing a mutant of Hsp70 predicted to lose interaction with Hsp110; Hsp70-R301E. With this mutant, I show the first direct evidence for the importance of this interaction for folding and solubilization of substrate by Hsp70 in cells. I then show that the disaggregation of a mutant implicated in amyotrophic lateral sclerosis, SOD1-G85R, is dependent on a mechanism involving Hsp70 and Hsp110. Overall, this work demonstrates the direct importance of the Hsp70-Hsp110 interaction in cells for Hsp70 chaperoning functions.Hsp70 est un chaperon moléculaire exprimé ubiquiteusement et nécessaire au maintien de l'homéostasie des protéines. Hsp70 est également régulé à la hausse dans plusieures des cellules cancéreuses et important pour leur survie. C'est pourquoi des petites molécules inhibitrices sont en développement pour une utilisation clinique. La quasi-totalité de ces inhibiteurs disponibles à ce jour ont une activité et spécificité très basse et ont des effets non-ciblés. C'est pourquoi il y a un besoin d'inhibiteurs spécifiques de Hsp70. Nos collaborateurs ont développé un nouvel inhibiteur de Hsp70; YK5 (série YK) qui s'est avéré être efficace à tuer des cellules cancéreuses. YK5 interagit en se liant d'une manière covalente au résidu cystéine d'un site allostérique. J'ai établi un test cellulaire de pliage et de solubilisation des agrégats protéique (les deux dépendant de Hsp70) et j'ai démontré que YK5 perturbe en effet les fonctions biochimiques essentielles de Hsp70. Hsp70 est un chaperon moléculaire qui dépend de l'ATP et qui nécessite la protéine DNAJ (qui stimule l'ATPase) ainsi que le facteur d'échange de nucléotides NEF, pour déloger l'ADP. Ces changements de nucléotide dans le domaine de liaison de nucléotides entraînent les changements conformationnels du domaine de liaison du substrat. Dans son état de liaison avec l'ATP, Hsp70 ne se lie pas à un substrat tandis que dans l'état de liaison avec l'ADP ou l'état-apo il se lie à un substrat. La compréhension du mécanisme par lequel les inhibiteurs YK affectent Hsp70 est importante, surtout dans le contexte de leur utilisation comme des outils moléculaires pour l'étude des fonctions biologiques de Hsp70. Je démontre que l'analogue réversible de YK5, 171, augmente la liaison du peptide à Hsc70 et à Hsp70 dans le cœur du cycle de l'ATPase. Les effets sont dûs à la cinétique de la libération du substrat, mais également, pour Hsc70, à l'équilibre entre les états de substrat libre et de substrat lié. Par contre, avec le NEF Hsp110 présent dans le cycle, la liaison du peptide avec Hsc70 et Hsp70 diminue en conséquence de la dissociation plus rapide de Hsp110 causé par 171. Dans les deux cas, il y a perturbation du cycle de l'ATPase, ce qui affecte la capacité des Hsp70s à plier et solubiliser le substrat, un effet observable dans les cellules. Les effets mécanistiques de 171 sur l'interaction avec le substrat suggéraient l'importance du complexe chaperon Hsp70, dans son entièreté, spécifiquement en conjonction avec Hsp110. Premièrement, je démontre que Hsp110 est en effet important pour le pliage et la solubilisation du substrat dans les cellules et ne peut être substitué par la famille BAG des NEFs. J'ai spécifiquement adressé l'importance de l'interaction Hsp70-Hsp110 en produisant un mutant de Hsp70 conçu pour perdre l'interaction avec Hsp110; Hsp70-R301E. Avec ce mutant je démontre la toute première preuve directe de l'importance de cette interaction pour le pliage et la solubilisation du substrat par Hsp70 dans les cellules. Par la suite, je démontre que la désagrégation du mutant SOD1-G85R, qui est impliqué dans la sclérose amyotropique latérale, est dépendante d'un méchanisme qui implique Hsp70 et Hsp110. Dans son ensemble, mon travail démontre l'importance directe de l'intéraction Hsp70-Hsp110 pour les fonctions cellulaires de chaperon de Hsp70
Exploring dynamic hamiltonian Monte Carlo for bayesian neural networks
No full textNeural network models have seen tremendous success in predictive tasks in machine learning and artificial intelligence, with some attributing their success to implicit use of Bayesian inference. Stan is a state-of-the-art software for Bayesian statistical computing used mainly in the statistical community, however, it is not optimized for use with neural network models. In this thesis, we replicated much of Stan's No U-Turn sampler in PyTorch and explored its use for sampling from Bayesian neural network models. We were able to explore different samplers, model structures and their sampling and predictive performances on a benchmark classification task. We found that Bayesian inference gives more robust predictive performance compared to their frequentist counterparts in general, but care is needed with the choice of prior and the MCMC sampler.Neural network models have seen tremendous success in predictive tasks in machine learning and artificial intelligence, with some attributing their success to implicit use of Bayesian inference. Stan is a state-of-the-art software for Bayesian statistical computing used mainly in the statistical community, however, it is not optimized for use with neural network models. In this thesis, we replicated much of Stan's No U-Turn sampler in PyTorch and explored its use for sampling from Bayesian neural network models. We were able to explore different samplers, model structures and their sampling and predictive performances on a benchmark classification task. We found that Bayesian inference gives more robust predictive performance compared to their frequentist counterparts in general, but care is needed with the choice of prior and the MCMC sampler
Determinants of trophic structure in ecological communities
No full textEcological communities are complex, and this complexity can obscure their underlying patterns and natural laws. One way to understand communities is to summarize their most important characteristics using consistent measures. Community structure is a set of measures of composition, abundance, distribution, and interaction that describe an ecological community over space and time. Trophic structure is an important aspect of community structure, and relates to energy and nutrient flow, especially the distribution of organisms across trophic levels. Trophic level is the energetic distance of an organism from the base of production – its average position in the food chains to which it belongs. Due to energetic inefficiencies, we generally predict that organisms decrease in number and biomass with trophic level, forming trophic pyramids (known as "pyramids of numbers" and "pyramids of biomass", respectively). Other, non-pyramidal trophic structures are also common, and trophic structure is affected by variables at multiple ecological scales. The objective of this thesis is to investigate determinants of trophic and community structure, including latitude, ecosystem type, biome transition, community composition, and body size. While pyramids of numbers and pyramids of biomass are well-studied, few have investigated the trophic distribution of diversity. Using a meta-analysis approach, I found that, on average, large published food webs form pyramids of species richness, with a decrease in number of species as trophic level increased. Trophic diversity structure was correlated to centrality, latitude, ecosystem type, and study identity.Community structure varies spatially, as can be seen even by a casual observer at interfaces between biomes. I studied how macroinvertebrate and soil prokaryote communities changed latitudinally along the forest-tundra biome transition in the Yukon, and how the communities responded to other environmental variables. I found that the communities differed between sites, changed along the latitudinal transect, and responded to environmental variables at multiple scales, including active layer depth, lichen cover, and road proximity. Loss of predators can have profound effects on community structure. I used an experimental approach to investigate the effect of spider assemblage composition and diversity on prey consumption. I hypothesized that diverse assemblages would consume more prey due to niche complementarity and sampling effects. I found, however, that the spiders were generalist and intraguild predators, and that the one-species assemblage consumed the most prey. Spider body size affects its trophic niche, energy requirements, and interspecific interactions, and as a result, body size mediates the relationship between spider assemblage composition and prey consumption. The body size of an organism affects how it interacts with other organisms and its biological rates. I used a meta-analytic approach to test several prediction regarding the relationship between body mass and trophic properties of terrestrial vertebrate predators: Accipitridae (hawks, eagles, and their relatives), Felidae (cats), and Serpentes (snakes). I found that the predators chose prey smaller than themselves, within a predictable mass range. Prey taxonomic diversity increased with Serpentes mass. Counter to theory, Felidae trophic level decreased with body mass, and Felidae and Accipitridae predator-prey body mass ratio increased with trophic level. We currently live in the Anthropocene, an epoch characterized by anthropogenic geological, atmospheric, and biological change. These changes are affecting community structure, which in turn is affecting human access to the benefits provided by nature. Therefore, it is important that we continue to study community structure and the variables that affect it, so that we can predict and respond to ecological change in the Anthropocene.Les communautés écologiques sont complexes, et cette complexité peut masquer leurs modèles et leurs lois naturelles. Il possible de tenter de comprendre les communautés en résumant leurs caractéristiques les plus importantes avec des mesures reproductibles. La structure communautaire consiste en l'ensemble des mesures de la composition, de l'abondance, de la distribution et des interactions qui décrivent une communauté écologique dans l'espace et dans le temps. La structure trophique est un aspect important de la structure communautaire et concerne la circulation de l'énergie et des nutriments, en particulier la distribution des organismes entre les niveaux trophiques. Le niveau trophique est la distance énergétique entre un organisme et la base de la production - sa position moyenne dans les chaînes alimentaires auxquelles il appartient. En raison des inefficiences énergétiques, nous prédisons généralement que le nombre et la biomasse des organismes diminuent avec le niveau trophique, formant des pyramides trophiques (appelées respectivement « pyramides des nombres » et « pyramides des biomasses »). D'autres structures trophiques non-pyramidales sont également fréquentes, et la structure trophique est affectée par de multiples variables à différentes échelles écologiques. L'objectif de cette thèse est d'étudier les déterminants de la structure trophique et communautaire, incluant la latitude, le type d'écosystème, la transition du biome, la composition de la communauté et la taille du corps. En utilisant une méta-analyse, j'ai constaté qu'en moyenne, les grands réseaux trophiques publiés forment des pyramides de la richesse spécifique; le nombre d'espèces diminue avec le niveau trophique. La structure de diversité trophique corrélait à la centralité, la latitude, le type d'écosystème et l'identité de l'étude. J'ai étudié comment les communautés de macroinvertébrés et de procaryotes du sol changeaient le long de l'écotone entre la toundra et la forêt au Yukon, et comment les communautés réagissaient à d'autres variables environnementales. J'ai constaté que les communautés étaient différentes entre les sites, qu'elles changeaient le long du transect latitudinal et réagissaient aux variables environnementales à de multiples échelles. J'ai utilisé une approche expérimentale pour étudier l'effet de la diversité et de la composition d'assemblages d'araignées sur la consommation de proies. J'ai posé l'hypothèse que les assemblages les plus divers consommeraient plus de proies en raison de la complémentarité des niches et des effets d'échantillonnage. La taille du corps de l'araignée affecte sa niche trophique, ses besoins en énergie et ses interactions interspécifiques et, par conséquent, la taille du corps sert de médiateur entre la composition de l'assemblage d'araignées et la consommation de proies. J'ai utilisé une approche méta-analytique pour tester plusieurs hypothèses concernant la relation entre la masse corporelle et les propriétés trophiques des prédateurs vertébrés terrestres : Accipitridae (faucons, aigles et leurs parents), Felidae (chats) et Serpentes (serpents). J'ai découvert que les prédateurs choisissaient des proies plus petites qu'eux, dans une fourchette de masse prévisible. Contrairement à la théorie, le niveau trophique de Felidae diminuait avec la masse corporelle, et le ratio des masses prédateurs-proies de Felidae et Accipitridae augmentait avec le niveau trophique. Nous vivons actuellement dans l'Anthropocène, une époque caractérisée par des changements géologiques, atmosphériques et biologiques anthropiques. Ces changements affectent la structure de la communauté, qui à son tour affecte l'accès humain aux richesses fournies par la nature. Il est donc important que nous continuions à étudier la structure des communautés et les variables qui l'affectent, afin de pouvoir prédire et répondre aux changements écologiques de l'Anthropocène