82837 research outputs found
Sort by
Supplementary File 2 Comparison of proteins with significantly altered stability from the BONCAT pulse‑chase proteomics dataset to curated lists of known Hsp90 and Ahsa1 interactors
No full textHsp90 is an essential molecular chaperone that plays a key role in maintaining protein homeostasis by assisting the folding, activation, and maturation of diverse client proteins. Hsp90 functions through a dynamic conformational cycle that is coupled to ATP hydrolysis. Its ATP driven conformational cycle is finely regulated by post translational modifications and a network of co chaperones. Among these regulators, Accelerator of Hsp90 ATPase 1 (Ahsa1) is the most potent stimulator of Hsp90 ATPase activity, yet its mechanistic role in metazoans, and its potential Hsp90 independent functions, remain incompletely understood. This thesis dissects the biochemical and cellular functions of a conserved 20-residue N-terminal segment of Ahsa1, termed the intrinsic chaperone domain (ICD), and evaluates Ahsa1-dependent proteome turnover. Quantitative ATPase assays, structure guided mutagenesis, and cell based co immunoprecipitation revealed that removing the ICD accelerates Hsp90 ATPase activity in vitro and impairs stable Ahsa1–Hsp90 recruitment in cells. Surprisingly, this region has also recently been shown to contribute to an Hsp90-independent chaperone role. The work here also demonstrates that the NxNNWHW motif is also essential in the mammalian protein function, revealing key differences and similarities in yeast and metazoan protein. To probe cellular roles of Ahsa1, a novel proteome wide bioorthogonal non-canonical amino acid tagging (BONCAT) pulse chase workflow was performed to measure in cell protein degradation kinetics. BONCAT profiling showed that Ahsa1 knock down modestly destabilises a select set of proteins, whereas over expression, especially of the ICD deleted variant, reshapes the half lives of hundreds of proteins, including factors beyond the canonical Hsp90 client repertoire. These data, coupled with in vitro holdase assays, support dual Hsp90 dependent and autonomous activities for Ahsa1. The study has also uncovered previously unappreciated roles for Ahsa1 in signalling and innate immune pathways. Together, these findings expand the current understanding of co-chaperone function by revealing new structural and functional roles for Ahsa1 in proteome maintenance. This work introduces BONCAT pulse chase proteomics as a powerful tool for studying chaperone mediated proteome dynamics and advancing understanding of co chaperone biology
Coupled Heat Transfer, Phase Transformations and Oxide Layer Effects during Accelerated Cooling
No full textIn thermo-mechanically controlled processing (TMCP) of high-strength low-alloy (HSLA) steels, the final microstructure is highly sensitive to the cooling conditions applied during the run-out table (ROT) stage. Accurately predicting the transformation behavior under industrial cooling conditions is thus essential for controlling mechanical properties.
This thesis aims to model the ROT cooling process by coupling heat transfer phenomena with phase transformation kinetics, and to evaluate the impact of oxide scale on cooling and microstructure evolution. A multi-step methodology was developed, combining finite element simulations on COMSOL Multiphysics, analytical heat transfer models, a Python-implemented phase transformation model based on the additivity rule, and dilatometric data fitting. Experimental austenite decomposition curves under constant cooling rates were used to calibrate and validate the transformation model.
The model accurately predicted the transformation behavior under both constant and non-constant cooling rates. However, surface temperature rebounds required a specific treatment, as the developed approach does not account for reheating phenomena. Modified versions of the JMAK equation were used to describe the kinetics of phase transformations, and the predicted fractions of ferrite and acicular ferrite across the plate thickness show good agreement with EBSD observations.
The presence of scale on the steel surface was shown to increase the final temperature and to modify the partitioning between ferrite and acicular ferrite, particularly near the surface. Predictions indicate that the fraction of acicular ferrite at the surface is higher in the presence of scale. In addition, scale disturbs the heat transfer, resulting in an increased peak cooling rate at the steel–scale interface compared to a scale-free surface during water cooling. This higher cooling rate is also associated with a shift in the temperature at which the maximum cooling occurs, potentially promoting the formation of additional phases\nsuch as bainite and martensite. Together, these effects of scale can lead to the development of local hard zones at the steel surface, exhibiting higher hardness than the corresponding scale-free regions.
The lack of temperature uniformity previously observed on the steel surface using an infrared camera was found to be attributable to the presence of scale. Analytical modeling and COMSOL simulations demonstrated that non-uniform scale thicknesses induce surface temperature gradients that closely match the IR camera measurements. By making assumptions regarding the thermal conductivity of scale, the scale thickness at the steel surface can be estimated.
This work demonstrates that accurately coupling latent heat effects, realistic cooling conditions, and oxide scale properties is crucial for predicting microstructure evolution in TMCP-processed steels
Acupuncture and Children with Autism Spectrum Disorder
No full textBackground: Autism is characterized by persistent difficulties in communication and social interaction, and repetitive, stereotyped behaviours, interests and activities (Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)). There is no standard, single, most effective treatment, nor is there a cure for autism. An estimated 81% of parents have tried complementary therapies for their children with autism. Research involving acupuncture for autism shows promise, but fear of needles may be a barrier for many children. Since laser stimulation of acupuncture points is less invasive and potentially more acceptable to children and families, a systematic review was conducted to summarize the evidence on laser acupuncture for pediatric autism. A qualitative study explored healthcare provider awareness and views of acupuncture and laser acupuncture for children with autism. Methods: The first study was a systematic review of the efficacy and safety of laser acupuncture on children with autism. The second study was an interpretive descriptive qualitative study with conventional healthcare providers in disciplines that provide services for children with autism. We collected data on: (1) knowledge and views about acupuncture, including laser acupuncture, and (2) perceived reasons why ⅱhealthcare providers may or may not recommend acupuncture for children with autism. Results: A total of 13 healthcare providers from Alberta, Canada - physicians, occupational therapists, psychologists, speech-language pathologists and physiotherapists - participated in the qualitative study. Most professionals had not considered acupuncture due to a lack of awareness and knowledge, but had a positive and open attitude in exploring its use and evidence as an adjunct therapy and to help meet existing therapeutic gaps. The systematic review identified only two small randomized controlled trials (RCTs), both of which reported positive effects, however, the quality of evidence for all outcomes was low to very low due to the small number of studies and methodological limitations. Both RCTs reported no adverse effects from laser acupuncture. The systematic review concluded there was inadequate evidence to confirm or refute the efficacy or safety of laser acupuncture at this time.
Conclusion: Healthcare professionals in Alberta are open and curious about acupuncture, particularly laser acupuncture, and its evidence for children with autism. Research on laser acupuncture is in its infancy, and it is premature to support or refute its use at this time. Larger, more rigorous studies would help inform health care providers who are interested in laser acupuncture for children with autism.
ABSTRACT
Background: Autism is characterized by persistent difficulties in communication and social interaction, and repetitive, stereotyped behaviours, interests and activities (Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)). There is no standard, single, most effective treatment, nor is there a cure for autism. An estimated 81% of parents have tried complementary therapies for their children with autism. Research involving acupuncture for autism shows promise, but fear of needles may be a barrier for many children. Since laser stimulation of acupuncture points is less invasive and potentially more acceptable to children and families, a systematic review was conducted to summarize the evidence on laser acupuncture for pediatric autism. A qualitative study explored healthcare provider awareness and views of acupuncture and laser acupuncture for children with autism. Methods: The first study was a systematic review of the efficacy and safety of laser acupuncture on children with autism. The second study was an interpretive descriptive qualitative study with conventional healthcare providers in disciplines that provide services for children with autism. We collected data on: (1) knowledge and views about acupuncture, including laser acupuncture, and (2) perceived reasons why ⅱhealthcare providers may or may not recommend acupuncture for children with autism. Results: A total of 13 healthcare providers from Alberta, Canada - physicians, occupational therapists, psychologists, speech-language pathologists and physiotherapists - participated in the qualitative study. Most professionals had not considered acupuncture due to a lack of awareness and knowledge, but had a positive and open attitude in exploring its use and evidence as an adjunct therapy and to help meet existing therapeutic gaps. The systematic review identified only two small randomized controlled trials (RCTs), both of which reported positive effects, however, the quality of evidence for all outcomes was low to very low due to the small number of studies and methodological limitations. Both RCTs reported no adverse effects from laser acupuncture. The systematic review concluded there was inadequate evidence to confirm or refute the efficacy or safety of laser acupuncture at this time.
Conclusion: Healthcare professionals in Alberta are open and curious about acupuncture, particularly laser acupuncture, and its evidence for children with autism. Research on laser acupuncture is in its infancy, and it is premature to support or refute its use at this time. Larger, more rigorous studies would help inform health care providers who are interested in laser acupuncture for children with autism
The Role of Ketones in Regulating Inflammation
No full textSepsis is a life-threatening condition characterized by a strong immune response to infection, often leading to multi-organ failure. While clinical studies suggest that female patients have better sepsis outcomes than males, the mechanisms underlying this sex difference remain unclear. Recent studies indicate that ketone bodies, particularly β-hydroxybutyrate (βHB), possess anti-inflammatory properties and may contribute to sex-based differences in immune resilience. However, whether ketones play a role in modulating the different sex-mediated inflammatory responses during sepsis remains unknown.
This study investigated sex differences in the inflammatory response to lipopolysaccharide (LPS)-induced sepsis and the role of ketones in immune regulation. Using a mouse model, we found that female mice exhibited significantly higher circulating βHB levels in fed, fasted, and post-LPS states compared to males. This was associated with fewer behavioral impairments, improved renal function, and reduced expression of pro-inflammatory cytokines in the heart and brain. To determine whether circulating ketone levels are necessary for coordinating a normal inflammatory response, we generated liver-specific Hmgcs2 knockout mice, thereby abolishing liver-derived ketone production. In opposition to our hypothesis, the decrease in circulating βHB levels resulting from decreased hepatic ketogenesis did not significantly exacerbate inflammation or organ dysfunction following LPS administration. Instead, female Hmgcs2 knockout mice responded similarly to WT littermates, while knockout males showed a mild yet consistent reduction in inflammatory cytokine expression in vital organs, suggesting a sex-dependent role of ketone metabolism in immune regulation.
The findings from our studies provide novel insights into the intersection of ketone levels, ketone-mediated signalling, sex differences, and immune function. While ketones are widely regarded as anti-inflammatory, they may also play an underappreciated role in supporting function of the pro-inflammatory response, with context-dependent effects. Despite the ambiguity of our findings, ketone therapy remains a promising and attractive intervention for many inflammatory diseases
The Cell Must Go On: Agar.io for Continual Reinforcement Learning
No full textContinual reinforcement learning (RL) focuses on agents that learn and adapt incrementally over time rather than converging to a fixed policy solely for evaluation. This learning paradigm is particularly well suited to environments that agents perceive as changing in which static policies become suboptimal. The few simulators explicitly designed for empirical research in continual RL are often limited in scope or complexity, and it is now common for researchers to modify episodic RL environments by artificially incorporating abrupt task changes during interaction. In this thesis, I introduce AgarCL, a continual RL research platform inspired by the game Agar.io. AgarCL presents a non-episodic, high-dimensional problem featuring stochastic, ever-evolving dynamics, continuous actions, and partial observability. By enabling a natural progression of increasingly sophisticated and adaptive behaviors, AgarCL offers a challenging testbed for evaluating and advancing continual RL research. Additionally, I provide benchmark results reporting the performance of DQN, PPO, and SAC in both the primary, challenging continual RL problem and across a suite of smaller tasks within AgarCL, each designed to isolate and characterize the different challenges posed by different facets of the environment. These evaluations demonstrate the difficulty of the domain and highlight important directions for future continual RL research
Organ injury and metabolic abnormalities in Ebolavirus disease: retrospective review of cases from the 2018-2020 outbreak in the Democratic Republic of the Congo
No full textEbola virus disease (EVD) is a lethal multi-system infection. Patients require intensive care, with frequent laboratory monitoring. However, outbreaks frequently occur in low-resource settings where advanced medical management may be challenging. The present thesis examines a cohort of 426 patients admitted to EVD treatment units in the DRC in 2019, during a large epidemic. In Chapter 1, we provide an introduction and review of the literature on EVD. In Chapter 2, we provide a general description of the methods used in subsequent chapters. Chapter 3 focuses on skeletal muscle injury and its downstream effects on the kidney. Chapter 4 examines the frequency of hypoglycemia and hyperglycemia in this critically ill cohort, and the association of these metabolic abnormalities with mortality. Chapter 5 examines acute kidney injury and associated electrolyte imbalances. Key findings were as follows. Rhabdomyolysis was common (61% of patients) and was associated with increased risk of AKI (odds ratio (OR) 2.2, 95%CI 1.2-3.8) and death (OR 1.7, 95%CI 1.03-2.9). Severe hypoglycemia (≤2.2 mmol/L) occurred in 25% of patients and periods of severe hypoglycemia were associated with an elevated hazard of death (adjusted hazard ratio (aHR) 6.2, 95%CI 3.2-12). Acute kidney injury was present at admission in 49% of patients and each doubling of creatinine was associated with a 1.9-fold (1.6-2.3) higher hazard of death. Our findings are instructive for the clinical care of EVD patients and call attention to priorities for laboratory monitoring. Our results also highlight opportunities for improved clinical care in the EVD treatment unit (e.g., enhanced glucose monitoring) as well as advanced therapies that should be contemplated, though they would be challenging (e.g., dialysis). It is hoped that these data from a large EVD outbreak will inform guidelines for the use of laboratory data in future EVD epidemics
Habits of highly effective worms: brachiopod host preferences of North American Devonian microconchids and cornulitids: Appendix 1
No full textThe appendix for the manuscript: Habits of highly effective worms: brachiopod host preferences of North American Devonian microconchids and cornulitids. Currently in press in the journal Lethaia
Get out of Hair: Black Girls’ Experiences of School Hair Grooming Policies in Jamaica
No full textThis research aims to shed light on the experiences of Black girls who wear natural hair in a predominantly Black high school in Jamaica. I employ a Black feminist methodology, utilizing conversations and observations to investigate how school hair grooming policies, under the directives of the Ministry of Education, impact Black girls’ schooling experiences. Using an anti-colonial lens, I examine the stories of six female students at Sankofa High School (pseudonym) and the racialized and gendered logics embedded in the school’s hair grooming regulations. I utilize Bacchi’s “What’s the Problem Represented to Be?” (WPR) approach to critically interrogate how Black hair is problematized within policy discourse and institutional practices. The research determined that although Sankofa High School’s written policy does not prohibit any particular hairstyle, its enforcement reveals anti-Black sentiments on the part of teachers and administrators. Afrocentric hairstyles and those linked to anti-colonial resistance movements are often flagged as “inappropriate” for school, while straight hair is deemed “neat” and “well-groomed.” Additionally, a texture-based hierarchy exists, in which kinkier hair types are more likely to be labelled “untidy” and in need of correction. The rationales used to judge hair reflect colonial logics that deemed Eurocentric features as the epitome of beauty and femininity, and Black hair as primitive and unfeminine. Although some students feel compelled to alter their hair texture through heat or chemicals, others actively resist them through everyday acts of defiance, critical questioning, and a desire to reconnect with their African identity. The study intervenes in the academic literature about race, beauty, aesthetics, and belonging in Jamaica and the wider Caribbean. Moreover, it contributes to public conversations about anti-Blackness in Jamaican institutions – which are predominantly led by Black people – and calls for educational policies that affirm and not regulate Black hair
Impact of the COVID-19 pandemic on tuberculosis program performance in Alberta, Canada, A population-based evaluation
No full textINTRODUCTION: The COVID-19 pandemic imposed major disruptions to essential
tuberculosis (TB) services globally. We evaluated the performance of the TB program in
Alberta, Canada by comparing two periods - before and during the pandemic - to estimate the
local impact of those disruptions.
METHODS: Ten program performance indicators and their related targets were applied and
compared by period. These include a measure of decline in the age- and sex-adjusted
incidence by population group, proportion of recently-arrived immigrants screened on time,
five case management and three close contact management indicators. Performance targets
were measured by time period and clinic type – outpatient vs virtual. The latter did not see
patients face-to-face. An interrupted time series analysis estimated the COVID-19 impact on
timeliness of immigrant screening.
RESULTS: The rate of disease by population group was not remarkably different,
pre-pandemic vs pandemic. Over a more extended period of time, the rate in the
Canadian-born but not the foreign-born, declined. Local program performance was not
negatively affected by COVID-19 in general, but there was a large reduction in immigration
and in turn the number of immigrants referred for screening (37.6%) and contacts identified
for assessment (71.8%) during the pandemic, resulting in improvements to the proportion of
referrals assessed (91.7% vs 96.6%, relative risk and 95% confidence interval 0.949
(0.936-0.962)), contacts assessed (81.7% vs 90.0%, 0.908 (0.875-0.943)), and contacts
completing treatment of infection (90.4% vs 97.1%, 0.931 (0.886-0.979)). Among patients
with TB disease, monitoring of treatment response was suboptimal while other targets were
met or nearly met. Virtual clinic performance tended to be worse during the pandemic.
INTERPRETATION: COVID-19 related disruptions were not as significant in the Alberta
TB program as elsewhere with multiple likely explanations
Decision Support System (DSS) for sustainability-oriented contractor selection in Integrated Project Delivery (IPD)
No full textContractor selection is a key aspect of construction project management, traditionally based on factors like cost, experience, quality, and past performance. With growing emphasis on environmental and social responsibility, the process now incorporates sustainability considerations. Sustainability in this context reflects a balanced integration of economic, social, environmental, and technical factors aimed at maximizing value and minimizing negative impacts. Despite growing interest, there is still a lack of comprehensive multi-criteria models that fully integrate these dimensions in contractor selection. Additionally, while the Integrated Project Delivery (IPD) method is acknowledged for its potential to enhance sustainability, its role in contractor selection remains underexplored. This research seeks to fill these gaps by developing a robust Multi-Criteria Decision-Making (MCDM) framework for evaluating sustainable contractors, incorporating insights from both academic experts and industry professionals. The study aims to expand sustainability theory by recognizing technical sustainability as a core component, alongside environmental, economic, and social aspects. It also demonstrates the effectiveness of MCDM tools such as Fuzzy AHP and Fuzzy VIKOR in facilitating sustainable contractor selection. Moreover, the research evaluates IPD as a delivery method that supports improved project outcomes through enhanced stakeholder collaboration. The research centers on the selection of sustainable contractors for a proposed multi-purpose banquet facility, using expert input and best practices from the industry. The case study illustrates the practical application of the proposed Decision Support System (DSS), showcasing its effectiveness in supporting sustainability-oriented contractor assessments within the IPD framework. Sustainability sub-criteria are refined through an extensive review of existing literature and feedback from both academia and industry. Applying MCDM techniques, particularly Fuzzy AHP and Fuzzy VIKOR, the study focuses on developing selection criteria and a decision-making framework, without delving into actual project execution or management. By addressing the current gap in sustainability-focused contractor selection and integrating IPD principles, this research introduces a comprehensive and practical framework that serves both industry professionals and academic researchers. From an academic standpoint, the study contributes an innovative, integrated MCDM model set in a fuzzy environment to combine quantitative data with qualitative expert opinions, enhancing the methodological depth of sustainability-related decision-making. It illustrates how expert-assigned weights to sub-criteria influence contractor rankings, offering insights into stakeholder-driven evaluation dynamics. From an industry perspective, the DSS presents a versatile and practical tool that brings greater consistency, transparency, and objectivity to contractor selection within IPD contexts. Its use in the banquet center case study validates its real-world applicability and showcases its potential to promote more sustainable construction practices