82837 research outputs found
Sort by
The rise and fall of the Wagner Group: from a “black cat in the dark room” to Russia`s geopolitical tool (2014 – 2023).
No full textThis thesis discusses the development of Russia’s mercenary industry through the lens of history. Given complexity and multifaceted nature of the phenomenon in question, the author decided to use the Wagner Group, Russias notorious and, arguably, best known Private Military Company (PMC) and its activities in selected worlds regions. Specifically, the thesis analyzes activities of the PMC in Ukraine, Syria, Libya and parts of Sub Sharan Africa, where – depending on differences in the landscape (both physical and cultural) and priorities of the Russian state – the Wagner Group has employed different tactics and showcased various qualities. This thesis aims to address two misconceptions about the Wagner Group specifically and, by extension, the whole mercenary industry in Russia. First, that this PMC, its emergence, organization and operations derived from a private initiative of Yevgeny Prigozhin and his close associates. Secondly, that the raise of the Wagner Group became a derivative of Russias geopolitical “adventures” in Ukraine and the Middle East. As I argue in this thesis and support my point of view by historical evidence, the history of state-sponsored mercenary in Russia (in different interims of its history) has had a very long and complex pedigree and, despite changing appearance, has preserved its core qualities through various historical epochs. From methodological point of view, this thesis primarily relies on a combination of primary and secondary sources, including statements of representatives of Russian military-political and diplomatic elite, statements and opinions of leaders of the Wagner Group and other mercenary formations. In order to increase reliability and maintain objectivity of the study, this research employs a broad range of sources in Russian, English, Ukrainian, French, and Portuguese languages. This approach offers a benefit of assessment and analysis of diverse opinions offered by subject experts, practitioners, policymakers and members of academia coming from various parts of the world. The main conclusions offered by this thesis should be outlined in the following way. First, emergence and the raise of the Wagner Group was not a coincidence but a logical continuation of Russias previous historical experiences. The use of mercenaries for solving specific geo-economic and geopolitical objectives has been integral to Russias (and in many ways Soviet) military-political thinking. Second, while the Wagner Group offers some benefits to the end user and commissioner of its services (the Russian state), its use poses challenges to its creators (as clearly demonstrated by the unsuccessful mutiny of Yevgeny Prigozhin in 2023). Furthermore, mercenary formations, while offering the benefit of “plausible deniability”, are not always incapable of solving complex objectives. Third, the use of the Wagner Group (and similar formations) is not always confined to (para)military functions. As demonstrated in this thesis, informational confrontation, psychological operations and participation in youth militarization are other tasks that can be performed by entities like the Wagner Group. Finally, the thesis also provides reflections about implication of Russias de-facto unpunished use of mercenary formations that challenge the basic principles of International Humanitarian Law and the Law of Armed Conflicts. Those implications could be in turn broken down on global, regional and domestic (Russia-specific) aspects. Most crucially, however, this thesis argues that Russias defiance of international law is likely to have an invigorating effect on both state- and non-state actors that will choose to employ mercenary formations and other types of militarized irregulars for solving their specific objectives
Identification of protease cleavage sites using chemical and enzymatic N-terminomics
Get PDFProteolysis is an important protein modification by which a peptide bond in a substrate is hydrolyzed by a class of enzymes called proteases. Proteases are key regulators of vital biological processes, such as apoptosis, cell differentiation, viral infection and neurodegeneration. To understand the role of proteases in health and disease, identifying their substrates is a useful step in uncovering their biological functions.
This thesis focuses on the application and optimization of several labeling strategies to characterize proteolytic cleavage events in cell differentiation and neurodegenerative diseases. In Chapter 2, I present the successful application of the subtiligase-based N-terminomics for caspase substrate identification. We investigated the non-apoptotic role of caspases in a mouse myoblast model during the time course of differentiation into myotubes using proteomics and forward degradomics. We also identified direct caspase-3 substrates at the beginning of the differentiation process using reverse-degradomics. Chapter 3 covers a forward degradomic approach in the mouse brain to describe proteolytic events in this tissue. To study the cleavage events in the prion protein, a combination of enzymatic and in-gel chemical labeling approaches were applied using immunoprecipitated material for the complete characterization of this complex fragmentation. In Chapter 4, I include a variation to the enzymatic labeling protocol to improve proteomic coverage of the cleavage sites identified by this technique. Additionally, I present an expanded panel of chemical reactions for in-gel modification of purified material.
These findings highlight how complex proteolytic processing could generate a diverse degradome that requires a combination of several N-terminomic strategies to be fully characterized. Our findings add on the current N-terminomic technologies toolbox available to define cleavage sites in biological systems
Numerical investigation of winglets for horizontal-axis wind turbines
No full textWind power plays a pivotal role in reducing the global greenhouse emissions. To meet the increasing demands for clean and sustainable energy production, improvements in wind turbine efficiency are required. This research work explores the impact of bio-inspired wingtip modifications on wind turbine performance, focusing on aerodynamic efficiency and wake recovery of a 10-MW horizontal axis wind turbine. Using computational fluid dynamics, a reference baseline wind turbine with no winglet was modeled using Reynolds-Averaged Navier-Stokes (RANS) equations. The study first validated the model against published data and was then used to model two winglet configurations, one with an equivalent swept area and one with a 2% increase in radius. Results demonstrated that both extended and shortened winglets improved power production by 10% and 4% on average, respectively. The first set of results indicated that wake recovery was also improved, highlighting the potential of wingtip modifications to enhance wind turbine performance and mitigate velocity deficits in wind farm operations.
A time-resolved study using Unsteady Reynolds-Averaged Navier-Stokes (URANS) and Detached Eddy Simulations (DES) models was then conducted to more accurately model the effects of the winglet on the performance of the wind turbine. Both methods produced similar results for power and force measurements, but DES revealed more detailed transient turbulence structures in the wake. The turbine modifications using winglets reduced vorticity and induced drag, contributing to a 5-6% increase in power output and a 2-3% increase in axial loading. A detailed investigation of wake evolution using DES further revealed that the addition of the winglet altered the flow dynamics in the near vicinity of the turbine and in the mid-wake. The winglet increased the velocity deficit in the near wake while reducing turbulence intensity in this region. The vortex ring originating from the blade tips decayed faster in the wingletted turbine, resulting in reduced vorticity and increased turbulent convection in the far wake. The study also noted a 4.5% increase in power production and a 1.5% increase in thrust for the wingletted turbine, with approximately 10% lower power fluctuation.
In conclusion, while wingtip modifications affect the near- and mid-wake regions, their influence diminishes in the far wake. The addition of winglets has the potential to increase the power output of wind turbines while having negligible effects on the structural loading and velocity deficit of the wake
PET imaging of fibrosis using Ga-68 labeled collagen binding peptides and allysine targeting small molecules
No full textPositron emission tomography (PET) imaging of fibrotic diseases has been previously achieved
using collagen-binding peptides such as CBP81
that binds the collagen triple helix and allysinebinding molecules such as [
68Ga]Ga-NODAGA-indole that reacts with allysine overexpressed
during fibrogenesis.
2 Here we report the synthesis, Ga-68 labeling, and analysis of four (three
collagen binding peptides and one allysine binding molecule) fibrosis targeting radiotracers.
Three collagen binding peptides were synthesized based on a modified sequence of the CBP8
peptide. [
68Ga]Ga-NOTA-CG-CBP-C-N is a disulfide cyclized, N-terminal NOTA modified
peptide synthesized at a 68% total chemical yield and labeled with Ga-68 at decay corrected
radiochemical yield (RCY) of 41% with a >97% purity. [68Ga]Ga-DOTAGA-CG-CBP-LD and
[
68Ga]Ga-DOTA-CG-CBP-ML are modified with novel, bifunctional linchpin molecules that
contain cyclization and chelator moieties for peptide cyclization and chelator introduction.
[
68Ga]Ga-DOTAGA-CG-CBP-LD was synthesized at a 26% total chemical yield yield and labeled
with Ga-68 at RCY of 73% with a >85% purity. [68Ga]Ga-DOTA-CG-CBP-ML was synthesized
at a 46% total chemical yield and labeled with Ga-68 at RCY of 24% with a >95% purity.
The pharmacokinetics of each peptide was studied in a bleomycin-induced lung fibrosis mouse
model. [68Ga]Ga-DOTA-CG-C-N and [68Ga]Ga-DOTA-CG-CBP-ML displayed similar lung
tissue retention and clearance similar to [
68Ga]Ga-CBP8 with clearance predominately through the
kidneys. [
68Ga]Ga-DOTAGA-CG-CBP-LD displayed a prolonged lung tissue retention and
clearance dominated by the hepatobiliary system. The clearance patterns and tissue retentions of
the peptide derivatives highlight the impact peptide modifications can have on pharmacokinetics
patterns.
The allysine binding molecule, [68Ga]Ga-NOTA-CG-PEG3-OA-D, was synthesized with a NOTA
chelator attached to an allysine reactive oxyamine group containing a short polyethylene glycol
(PEG) linker. The small molecule was synthesized at a yield of 93% and labeled with Ga-68 at a
RCY of 17%. The pharmacokinetics of the allysine binding molecule matched that of other
published allysine binding molecules, characterized by a rapid uptake into lung tissues followed
by a clearance (dominated by the renal system). The development radiotracer that can detect
changes in fibrotic tissues remains an important field of research to monitor disease development
and progression
A comparison of eNOS-based platelet subpopulations in acute myocardial infarction patients versus age- and sex-matched controls
No full textBackground: Coronary artery disease continues to be one of the main causes of mortality around the world, and despite current antiplatelet therapies, incidence and mortality of coronary artery disease remains high. Acute coronary syndromes encompass a broad spectrum of diseases characterized by atherosclerotic plaque disruption or erosion leading to myocardial ischemia. Atherosclerotic plaque disruption can occur by multiple mechanisms all leading to exposure of subendothelial matrix triggering platelet activation, aggregation and thrombus formation. Many mechanisms are involved in the homeostasis of platelets, with a delicate balance between pro- and anti-aggregating stimuli. Prostacyclin and nitric oxide are recognized to be key mediators of inhibitory pathways limiting platelet aggregation. Nitric oxide is synthesized by endothelial and many other cells. However, platelets are also capable of producing nitric oxide through the endothelial nitric oxide synthase (eNOS) present in the platelet plasma membrane. Recently it has been described that different eNOS platelet subpopulations exist. One subpopulation is incapable of producing nitric oxide due to the absence of the eNOS (eNOSneg/low), which accounts for 20% of the total circulating platelets, while another platelet subpopulation is capable of producing nitric oxide due to the presence of the eNOS (eNOSpos/high) and accounts for the remaining percentage of platelets. Therefore, we aimed to determine whether there is a change in the ratio of eNOSneg/low to eNOSpos/high platelet subpopulations in patients with acute coronary syndromes — ST-segment elevation acute myocardial infarction (STEMI) and non-ST-segment elevation acute myocardial infarction (NSTEMI)— and compare it to age- and sex-matched controls.
Methods: Blood samples were collected from STEMI and NSTEMI patients and age and sex matched controls. Washed platelets were prepared to further assess the ratios in eNOS-based platelet subpopulations using a monoclonal antibody that recognize the N-terminus of the eNOS (6H2) and an antibody that recognize GPIbα (anti-CD42b-PE) as a platelet marker. The inhibitory effect of nitric oxide in platelet function was investigated with the use of a novel method that allows the assessment of platelet aggregation under flowing conditions at nanogram levels of mass change. This novel method utilizes the quartz crystal microbalance with energy dissipation (QSense). It can assess platelet microaggregate formation and the resulting stiffness of aggregates attached to a collagen-coated QSense sensor. In addition, confocal microscopy was used to visualize eNOS-based platelet subpopulations based on eNOS fluorescence and platelet adhesion to QSense sensors. Furthermore, plasma concentration of nitric oxide metabolites (nitrite/nitrate) was assessed using Griess assay. Lastly, plasma concentrations of pro-inflammatory and anti-inflammatory cytokines known to regulate eNOS expression were measured using (ELISA).
Results: An increase of eNOSneg/low and a decrease in eNOSpos/high platelet subpopulations was found in STEMI and in NSTEMI groups compared to age- and sex-matched controls. Interestingly, no change in eNOSneg/low and eNOSpos/high platelet subpopulations was observed between males and females within the same groups of study participants. Furthermore, reduced nitrate/nitrite concentrations were found in plasma samples from acute myocardial infarction patients compared to age- and sex-matched controls. Platelets from acute myocardial infarction patients showed a trend towards a higher aggregatory response compared to age- and sex-matched controls evidenced as measured by QSense assessment. In addition, assessment of QSense sensors using confocal microscopy following aggregation showed decreased eNOS fluorescence in acute myocardial infarction patients compared to age- and sex-matched controls, and higher platelet adhesion to QSense sensors by platelets of acute myocardial infarction patients compared to age- and sex-matched controls. Overall, there were no significant differences in plasma cytokine concentrations (Interferon-γ, IL-1β, IL-6 and IL-10) between groups.
Conclusion: The increase in eNOSneg/low and a decrease in eNOSpos/high platelet subpopulations found in acute myocardial infarction patients compared to age- and sex-matched controls could explain the trend towards increased aggregation in acute myocardial infarction patients versus age- and sex-matched controls. Furthermore, these results are concordant with a decreased eNOS fluorescence and an increased aggregation by platelets obtained from MI patients as measured by confocal microscopy. As well, these results are concordant with the lower plasma nitrate/nitrite concentrations found in STEMI patients and a trend towards reduced plasma nitrate/nitrite concentration in NSTEMI
System based approach to the evaluation of group effect factors for timber connections
No full textMany timber design codes around the world use so-called ‘group effect’ factors to reduce the design strength of multiple fastener connections, though the basis for the factors is inconsistent and the original conceptual model is not relevant to many modern connections. This work expands on other recent studies that have observed reduced variability in larger connection groups, leading to higher design resistances, and proposes a function to define the group effect and three sub-factors related to the changes with respect to the number of fasteners in the reliability, strength variability, and mean strength.
To evaluate the reliability sub-factor a process was developed for calibrating material resistance factors for timber connections, which included collecting data on load distributions in Canada, selecting a target reliability index, and processing the results from first order reliability method (FORM) analyses. The process was developed for the case of axial withdrawal of self-tapping screws using resistance data collected from past studies across Canada and resulted in a resistance factor of 0.7. The process was applied using a generic Weibull distribution to illustrate the relationship between the reliability sub-factor and inverse of the Weibull shape factor, which was used to represent the strength variability. Decreasing strength variability in larger groups tended to result in higher values for the reliability sub-factor, which tended to increase the factored design resistance except when the single fastener strength variability was low.
Tests on axially loaded self-tapping screws in withdrawal demonstrated no change in the mean strength for up to 12 screws, with the screws widely spaced at 10 times the nominal screw diameter. The variability in ultimate strength decreased as the group size increased, supporting the assertion in the literature that there is a ‘balancing’ effect in large groups, and approximating the rate obtained from application of the central limit theorem. The combined effect of both sub-factors resulted in an increase of 25% in the design withdrawal resistance for 12 screws. Simulations were then carried out for connections with inclined self-tapping screws and steel side plates using input load-displacement data obtained through testing. The mean strength was sensitive to the way displacements were applied to each column of fasteners: negligible change when the displacement was uniformly applied across all fasteners, producing results similar to the test results for axially loaded screws in withdrawal; significantly decreasing in large groups, especially with more columns and a higher ratio of connector stiffness to axial stiffness of the connected members. In the latter case, premature failures produced an increase in ultimate strength variability. The general trend of lower variability resulting in higher specified design strength increased the factored design resistance an average of 10% for less than 30 screws; larger screws were highly dependent on the manner of load distribution.
The results of the study demonstrate that the factored design strength per fastener of a connection group may be greater than the factored design strength of a single fastener. Future experimental work is needed to develop specific factors for a range of connection configurations and failure modes
It Matters Where You Live: An Examination of Type 2 Diabetes Management Across Alberta’s Rural-Urban Continuum
No full textPurpose
Health services and outcomes research in diabetes often concludes that individuals living in rural areas are at an increased risk of poorer health outcomes due to a lack of healthcare access. While access to care is an indisputable barrier to rural-dwelling individuals, it is hypothesized that there are also additional factors that must be considered. The interactions occurring between providers and patients, encompassing the broader process of care, is often overlooked when assessing the quality of healthcare according to residence. Existing diabetes research rarely considers rurality as an independent predictor of management strategies and is often absent in drug utilization studies. Therefore, this thesis aims to examine the state of rural healthcare in Alberta with a focus on management strategies undertaken for the treatment of type 2 diabetes, compared to metropolitan areas. Implications of differential processes of care according to residence are also quantified.
Methods
This thesis utilized administrative data provided by Alberta Health and Alberta Health Services to conduct several analyses of individuals newly treated with metformin for type 2 diabetes between 2008 and 2023. Analytical models used throughout this thesis include multivariable logistic regression, Cox proportional hazard, and cause-specific hazard. In all models, exposure was defined as an individual’s place of residence along Alberta’s rural-urban continuum (rural/urban/metropolitan) and metropolitan was the reference category. Various outcomes were assessed including drug therapy utilization, laboratory monitoring, physical examination, cardiovascular complications, and all-cause mortality.
Results
The main findings in this thesis were:
1. Trends by location of residence along the rural-urban continuum in Alberta demonstrated a 4-year delay in the decline of sulfonylurea dispensations at first treatment intensification of type 2 diabetes in rural, compared with urban and metropolitan locations. After adjusting for potential confounders, people living in rural areas were statistically significantly more likely to start a sulfonylurea compared with residents of a metropolitan area (adjusted odds ratio [aOR] 1.34; 95% CI 1.29-1.39).
2. Guideline concordant management of type 2 diabetes varies according to residence along Alberta’s rural-urban continuum. Rural residents are less likely to have their cholesterol monitored (aOR 0.86; 95% CI 0.83-0.90) or have a statin dispensed (aOR 0.83; 95% CI 0.79-0.87) in the first year of type 2 diabetes management, compared to metropolitan residents. In contrast, rural residents were more likely to receive glycated hemoglobin A1C (aOR 1.14; 95% CI 1.08-1.21) and kidney function (aOR 1.17; 95% CI 1.11-1.24) monitoring.
3. Albertans rarely move after treatment initiation with metformin for type 2 diabetes (2.6% of individuals moved to a smaller centre [metropolitan to urban or rural, or urban to rural] and 3.1% moved to a larger centre [rural to urban or metropolitan, or urban to metropolitan]). Regardless of the method used to define residence along Alberta’s rural-urban continuum, the association between rural residence and all-cause mortality was consistent (adjusted hazard ratio [aHR] 1.18; 95% CI 1.12-1.24). Therefore, classifying place of residence in population-based cohort studies at baseline, 1-year prior to the index date is reasonable.
4. A geographic gradient in the rate of cardiovascular events is present with rural residents experiencing the highest rate, followed by urban, and then metropolitan. Cardiovascular event history modifies the effect of place of residence on future cardiovascular events whereby rural residents are at increased risk of primary cardiovascular events (aHR 1.16; 95% CI 1.11-1.20) and decreased risk of secondary events (aHR 0.84; 95% CI 0.78-0.91), compared to metropolitan residents.
Conclusions
This body of work demonstrated that rural residents, compared to metropolitan, experience gaps in the early management of their type 2 diabetes including the continued use of older antihyperglycemic drug therapies (sulfonylureas) when treatment intensification is required, limited dispensation of adjunct drug therapies (statins), and minimal cholesterol monitoring. This likely explains, in part, the reason for an increased rate of cardiovascular events in these rural areas and increased risk of all-cause mortality. This line of research may help in the development of targeted interventions of rural populations aiming to improve health outcomes in people with type 2 diabetes. Further research to answer why processes of care differ according to residence is warranted
Mechanical Environment and Morphological Adaptations of Cranial Sutures During Normal Growth
No full textThe cranial sutures, the fibrous connective tissues, bind together the separate bones of the skull to form the head and face shape. Besides physically joining the adjacent bones of the skull, the cranial sutures facilitate the growth of skull bones, and the cranial suture-bone interfaces are the main site of that intramembranous bone growth. The cranial suture-bone complex defined as the suture tissues and the surrounding bone front, biologically adapts to the applied loads by changing its size and shape, and collagenous fiber alignment. The intracranial pressure (ICP) driven by the rapid enlargement of the brain during the early development phase of mammals is believed to be one of the main causes of the rapid bone growth and adaptation at the suture-bone complex in neonates and infants. The structure of the cranial suture is generally linear butt-ended in neonates and later developed into a tortuous interdigitated structure.
Disorders that affect suture function/structure such as craniosynostosis are quite prevalent with around 1 case per 2500 live births. If left untreated, these disorders can lead to various complications including abnormal head or face shape, visual or hearing difficulties, obstruction of airways, and delayed or limited physical and intellectual development. The treatments for these complications often involve orthopedic devices that apply some sort of force directly or indirectly. However, the current understanding of suture mechanobiology, the effect of mechanical environment on biological adaptation, is limited, which in turn, prevents treatment planning to predict future growth/changes and response to treatment. Therefore, understanding the biological adaptations (bone growth and morphological changes) of the cranial suture-bone complex in response to the local mechanical state is essential for future development of the treatment and planning and evaluations.
The presented thesis investigates the morphometric changes of the coronal suture and the localized mechanical environment at the coronal suture-bone interface longitudinally in normally growing rats from young to adult age based on the in vivo micro-computed tomography (μCT) images and subject-specific finite element (FE) models. Furthermore, the mechanobiological relationships between the biological adaptation of the coronal suture-bone complex and the localized mechanical strains at the coronal suture-bone interface are established. The main finding of the presented thesis is that the coronal suture-bone complex grows and changes depending on the age of the animals and the localized mechanical strain state. In the case of normal growth, the morphometry of the rat coronal suture can be estimated based on the initial measurements and age. As for the effect of the localized mechanical state on the suture adaptation, the energy equivalent strain gradient and its interactions with other strain data from the earlier time point showed the highest correspondence and are able to explain about 33% of the variations of the bone growth at the coronal-suture bone interface.
The outcomes of the presented thesis demonstrate the practical development framework for the implementation of subject-specific and time point-specific FE models via a two-stage sub-modeling approach with a semi-automatic segmentation procedure of the complex geometries of cranial sutures from μCT data. The statistical models and quantified relationships from this thesis can be applied in the estimation of growth changes of suture-bone complex depending on the age and the mechanical environment, and in turn, could be applied in the treatment planning and evaluation steps of cranial malformations