The role of macrophage intracellular lipid partitioning in glucose and lipid homeostasis during obesity

Obesity-associated metabolic disorders are amongst the most prevalent causes of death worldwide. Understanding how obesity leads to the development of the Metabolic Syndrome (MetS) and cardiovascular disease (CVD) will enable the development of novel therapies that dissociate obesity from its cardiometabolic complications. Our laboratory views the functional capacity of white adipose tissue (WAT), the organ designed for safe lipid storage, as a key factor in the development of MetS and CVD. At a genetically-defined stage of the aberrant WAT expansion that occurs during obesity, adipocytes undergo a functional failure, resulting in an impaired control of serum free fatty acid (FFA) concentration. In such setting, FFAs and their metabolic derivatives accumulate in other organs, where they cause lipotoxicity, leading to the development of insulin resistance and CVD. We therefore aim to understand the pathophysiological mechanisms that induce adipocyte dysfunction. The past two decades of research have established the immune system as an important regulator of WAT function. The number of adipose tissue macrophages (ATMs), the most abundant immune cell type in WAT, increases during obesity, resulting in WAT inflammation. Multiple genetic and pharmacological intervention studies of murine models of obesity have assigned a causal link between ATM pro-inflammatory activation and WAT dysfunction. However, while the propagation of inflammation in ATMs during obesity has been extensively studied, factors triggering ATM inflammatory activation are less clear. Recently, our lab has observed lipid accumulation in the ATMs isolated from obese mice. Lipid-laden ATMs were pro-inflammatory, leading us to hypothesise that aberrant lipid build-up in macrophages triggers WAT inflammation during obesity. This thesis expands on the initial findings from our lab and describes two novel mechanisms that potentially contribute to lipid-induced inflammatory activation of ATMs. In chapter 3, the role of de novo phosphatidylcholine (PC) synthesis pathway during lipotoxicity in macrophages is addressed. The first part of the chapter demonstrates that lipotoxic environment increased de novo PC synthesis rate in bone marrow-derived macrophages (BMDMs) and ATMs, and that loss of rate-limiting enzyme in de novo PC synthesis pathway, CTP:phosphocholine cytidylyltransferase a (CCTa) diminished saturated FFA-induced inflammation in BMDMs. In the second part, I show that macrophage-specific CCTa deletion did not impact on the development of WAT inflammation or systemic insulin resistance, but had a minor benefitial effect on hepatic gene transcription during obesity. Chapter 4 develops on recent observations of interactions between sympathetic nerves and macrophages in WAT. In the first part of the chapter, I demonstrate that stimulating B2-adrenergic receptor (B2AR), the main receptor for sympathetic neurotransmitter norepinephrine in macrophages, enhanced intracellular triglyceride storage by up-regulating diacylglycerol O-acyltransferase 1 (Dgat1) gene expression in BMDMs. The second part of the chapter shows that macrophage-specific B2AR deletion did not modulate systemic glucose and lipid metabolism during obesity, but mice lacking B2ARs in macrophages demonstrated augmented hepatic glucose production on a chow diet. Furthermore, systemic B2AR blockade or macrophage-specific B2AR deletion in mice did not affect the thermogenic response to cold exposure. Chapter 5 includes the characterisation of B2AR stimulation-induced changes to the global cellular proteome of BMDMs, and a subsequent validation of the role of candidate transcription factors in regulating B2AR agonism-induced gene expression in BMDMs.Wellcome Trust 4 year PhD programm

Multiple outlier detection tests for parametric models

We propose a simple multiple outlier identification method for parametric location-scale and shape-scale models when the number of possible outliers is not specified. The method is based on a result giving asymptotic properties of extreme z-scores. Robust estimators of model parameters are used defining z-scores. An extensive simulation study was done for comparing of the proposed method with existing methods. For the normal family, the method is compared with the well known Davies-Gather, Rosner's, Hawking's and Bolshev's multiple outlier identification methods. The choice of an upper limit for the number of possible outliers in case of Rosner's test application is discussed. For other families, the proposed method is compared with a method generalizing Gather-Davies method. In most situations, the new method has the highest outlier identification power in terms of masking and swamping values. We also created R package outliersTests for proposed test

АНАЛИЗ И ОЦЕНКА ПОКАЗАТЕЛЕЙ КАЧЕСТВА АСФАЛЬТОБЕТОННЫХ ПОКРЫТИЙ АВТОМАГИСТРАЛЕЙ ЛИТВЫ

The quality of pavements is evaluated by the presence of such defects as: pot-holes, cracks, runs and others. An outward exhibition of defects is pavement evenness. The paper contains correlation dependences between evenness and defects. The critical pavement conditions when it is necessary to execute repair works are determined in the paper.Качество дорожных покрытий оценивается наличием дефектов: выбоин, трещин, колеи и др.Внешним проявлением дефектов является ровность покрытия. Установлены корреляционные   зависимости   между   ровностью   и   дефектностью.   Определены   критические состояния покрытий, при которых необходимо проводить ремонтные работы

Probabilistic Deep Learning for Electric-Vehicle Energy-Use Prediction

The continued spread of electric vehicles raises new challenges for the supporting digital infrastructure. For example, long-distance route planning for such vehicles relies on the prediction of both the expected travel time as well as energy use. We envision a two-tier architecture to produce such predictions. First, a routing and travel-time-prediction subsystem generates a suggested route and predicts how the speed will vary along the route. Next, the expected energy use is predicted from the speed profile and other contextual characteristics, such as weather information and slope. To this end, the paper proposes deep-learning models that are built from EV tracking data. First, as the speed profile of a route is one of the main predictors for energy use, different simple ways to build speed profiles are explored. Next, eight different deep-learning models for energy-use prediction are proposed. Four of the models are probabilistic in that they predict not a single-point estimate but parameters of a probability distribution of energy use on the route. This is particularly relevant when predicting EV energy use, which is highly sensitive to many input characteristics and, thus, can hardly be predicted precisely. Extensive experiments with two real-world EV tracking datasets validate the proposed methods. The code for this research has been made available on GitHub

Investigation of grain separation through straw layer over …

Straw walker is a separator that separates grain from straw, and limits the efficiency of combine-harvesters therefore special attention is devoted to the development and improvement of its design and technological parameters. The most important parameter of walker operation is Froude-number k that depends on the amplitude of the straw walker movement in vertical direction, i.e., walker sieve oscillation amplitude r and angular velocity ω. High speed camera used in the investigation tests helped to determine not only the behavior of the straw layers on the oscillating sieve of straw walker but also the duration of grain penetration (separation) through the straw. With estimation of these parameters the rational values of Froude-number k were substantiated. It has been determined that at various ω and r combinations when k=const. sieve vertical accelerations when the crankshaft is rotated at the same angle are equal, but speeds and displacements are varied. For this reason the duration of grain separation is different. The rational angular velocity of the crankshaft is 22.5 s-1 (r=0.05 m), as then the straw layer when the crankshaft is rotated at the angle 2π, raised from the walker surface (sieve) the most early and strokes with it latest, i.e. the duration of free movement of the straw is 1.5 times longer and the grain separation about 15% more intensive than when ω=21.5 s-1. The estimation of grain separation enabled to define critical value of crankshaft angular velocity equal to ω=23.5 s-1. When this value is exceeded the top straw layers receive only one stroke when the crankshaft is rotated at the angle 4π, therefore the increase of crankshaft angular velocity and, simultaneously, sieve oscillation intensity above the critical value is inexpedient

The effect of a diet with fructan-rich chicory roots on intestinal helminths and microbiota with special focus on Bifidobacteria and Campylobacter in piglets around weaning

The restrictions on the use of antibiotic and anthelmintic treatments in organic pig farming necessitate alternative non-medical control strategies. Therefore, the antibiotic and parasite-reducing effect of a fructan-rich (prebiotic) diet of dried chicory was investigated in free-ranging piglets. Approximately half of 67 piglets from 9 litters were experimentally infected with Ascaris suum and Trichuris suis in the suckling period (1 to 7 weeks of age) and 58 of the piglets were challenged daily with E. coli O138:F8 for 9 days after weaning to induce weaning diarrhoea. The litters were fed either chicory (30% DM) or a control diet. The effect of chicory on intestinal helminths, intestinal microbiota, especially Bifidobacteria and Campylobacter spp., and E. coli post-weaning diarrhoea was assessed. The weight gain of the piglets was not impaired significantly by chicory. The intestinal A. suum worm burden was reduced by 64% (P=0.034) in the chicory-fed piglets, whereas these same piglets had 63% more T. suis worms (P=0.016). Feeding with chicory elicited no changes among the main bacterial groups in ileum according to terminal restriction fragment length polymorphism (T-RFLP) analysis. However, the terminal-restriction fragment (T-RF) 208 bp, which may belong to Lachnospiraceae, was stimulated by the chicory feed (P=0.03), and T-RF 370 bp that matches Enterobacter belonging to the Enterobacteria was reduced (P=0.004). Additionally, chicory increased the level of Bifidobacteria (P=0.001) and the faecal Campylobacter excretion level was transitorily reduced in chicory-fed piglets at 7 weeks of age (P=0.029). Unfortunately, it was not possible to assess the effect of chicory on post-weaning diarrhoea as it did not develop. In conclusion, feeding piglets chicory around the time of weaning caused complex changes of the microbiota and parasite communities within the intestinal tract, and feeding piglets chicory may therefore serve as an animal-friendly strategy to control pathogens

Anthelmintic resistance in small ruminants in the Nordic-Baltic region

Gastrointestinal nematodes (GIN) in small ruminants result in production losses, and consequently economic losses, and are an animal welfare problem in most countries in the Nordic-Baltic region. Intensive use of anthelmintics to control helminth infections has led to anthelmintic resistance (AR), which has become a major issue in many European countries. Several studies have been performed in countries in the Nordic-Baltic region (e.g. Denmark, Sweden, Norway and Lithuania) showing increasing/emerging levels of AR. The aim of this paper is to provide an overview of the problem of AR on sheep and goat farms in the Nordic-Baltic region. This region has a limited number of registered anthelmintics. However, researchers in this area have discovered some surprising findings, such as ivermectin (IVM) resistance on a farm that had never used IVM. In Sweden there is evidence of macrocyclic lactone (ML)-resistant Haemonchus contortus being introduced with sheep imported from the Netherlands. As elsewhere in the world, the livestock trade appears to be contributing to the spread of AR in the region and isolated cases of multidrug-resistant cases have also been reported. This is surprising given that the frequency of treatments here is much lower than in other countries where sheep production is economically more important. The prevailing nematodes are Haemonchus, Teledorsagia and Trichostrongylus, while on some farms Haemonchus is dominant and clinical haemonchosis has increasingly been observed in recent decades. The reasons for this are unclear, but are probably related to this parasite's propensity to rapidly develop drug resistance and a general lack of awareness of the problem, possibly in combination with global warming and the increased livestock trade within the EU. In addition, domestic interactions through contacts with wildlife ruminants, alpacas may also be a contributing factor for transmission of AR

Investigation of grain separation through straw layer over …

Straw walker is a separator that separates grain from straw, and limits the efficiency of combine-harvesters therefore special attention is devoted to the development and improvement of its design and technological parameters. The most important parameter of walker operation is Froude-number k that depends on the amplitude of the straw walker movement in vertical direction, i.e., walker sieve oscillation amplitude r and angular velocity ω. High speed camera used in the investigation tests helped to determine not only the behavior of the straw layers on the oscillating sieve of straw walker but also the duration of grain penetration (separation) through the straw. With estimation of these parameters the rational values of Froude-number k were substantiated. It has been determined that at various ω and r combinations when k=const. sieve vertical accelerations when the crankshaft is rotated at the same angle are equal, but speeds and displacements are varied. For this reason the duration of grain separation is different. The rational angular velocity of the crankshaft is 22.5 s-1 (r=0.05 m), as then the straw layer when the crankshaft is rotated at the angle 2π, raised from the walker surface (sieve) the most early and strokes with it latest, i.e. the duration of free movement of the straw is 1.5 times longer and the grain separation about 15% more intensive than when ω=21.5 s-1. The estimation of grain separation enabled to define critical value of crankshaft angular velocity equal to ω=23.5 s-1. When this value is exceeded the top straw layers receive only one stroke when the crankshaft is rotated at the angle 4π, therefore the increase of crankshaft angular velocity and, simultaneously, sieve oscillation intensity above the critical value is inexpedient