Auto Warranty Data: Mean Cumulative Function

Стефанка Чукова, Хър Гуан Тео - В това изследване разглеждаме и разширяваме предишната ни работа по цензуриране, типично за авто гаранционни данни. За да разрешим проблема с непълната информация за километража, използваме линеен подход в непараметрични рамки. Оценяваме средните кумулативни гаранционни разходи (за превозно средство) и стандартната им грешка като функция на възрастта, на километража и на реалното (календарно) време.

Maximization of a Linear Utility Function over the Set of the Housing Market Short-Term Equilibria

AMS subject classification: 90C05, 90A14.

Optimal investment under stochastic volatility and power type utility function

2000 Mathematics Subject Classification: 37F21, 70H20, 37L40, 37C40, 91G80, 93E20.

Retinal vascular function and cardiovascular risk factors

The current platform of conventional cardiovascular risk assessments tends to forsake the importance of endothelial function - a key biological mechanism by which cardiovascular risk factors exert their propensity for adverse vascular events. Moreover, the presence and severity of endothelial dysfunction in ‘low-risk’ individuals suggests considerable variability in pre-clinical risk that could potentially be detected well before the onset of disease. The aim of the present thesis was to investigate the presence and impact of retinal vascular dysfunction, as a barometer of endothelial function, in otherwise healthy individuals with one or more cardiovascular risk factors, but low to moderate cardiovascular risk. Systemic circulatory influences on retinal vascular function were also evaluated. The principle sections and findings of this work are: 1. Ageing effect on retinal vascular function • In low-risk individuals, there are age differences in retinal vascular function throughout the entire functional response curve for arteries and veins. Gender differences mainly affect the dilatory phase and are only present in young individuals. 2. Retinal vascular function in healthy individuals with a family history of cardiovascular disease • In low-risk individuals with a family history of cardiovascular disease, impairments in microvascular function at the retinal level correlate with established plasma markers for cardiovascular risk. 3. Ethnic differences in retinal vascular function • When compared to age-matched White Europeans, in low-risk middle-aged South Asians, there are impairments in retinal vascular function that correlate with established cardiovascular risk indicators. 4. Systemic circulatory influences on retinalµvascular function • Systemic antioxidant capacity (redox index) and plasma markers for cardiovascular risk (lipids) influence retinal microvascular function at both arterial and venous levels. 5. Retinal vascular function in individuals with obstructive sleep apnoea: a preliminarystudy • Patients with moderate to severe sleep apnoea exhibit attenuated retinal vascular function.

The amyloid precursor protein (APP) binds the PIKfyve complex and modulates its function

Phosphoinositides are important components of eukaryotic membranes that are required for multiple forms of membrane dynamics. Phosphoinositides are involved in defining membrane identity, mediate cell signalling and control membrane trafficking events. Due to their pivotal role in membrane dynamics, phosphoinositide de-regulation contributes to various human diseases. In this review, we will focus on the newly emerging regulation of the PIKfyve complex, a phosphoinositide kinase that converts the endosomal phosphatidylinositol-3-phosphate [PI(3)P] to phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2)], a low abundance phosphoinositide of outstanding importance for neuronal integrity and function. Loss of PIKfyve function is well known to result in neurodegeneration in both mousemodels and human patients. Our recent work has surprisingly identified the amyloid precursor protein (APP), the central molecule in Alzheimer s disease aetiology, as a novel interaction partner of a subunit of the PIKfyve complex, Vac14. Furthermore, it has been shown that APP modulates PIKfyve function and PI(3,5)P2 dynamics, suggesting that the APP gene family functions as regulator of PI(3,5)P2 metabolism. The recent advances discussed in this review suggest a novel, unexpected, â-amyloid-independent mechanism for neurodegeneration in Alzheimer s disease.

A cell-permeable tool for analysing APP intracellular domain function and manipulation of PIKfyve activity

The mechanisms for regulating PIKfyve complex activity are currently emerging. The PIKfyve complex, consisting of the phosphoinositide kinase PIKfyve (also known as FAB1), VAC14 and FIG4, is required for the production of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2). PIKfyve function is required for homeostasis of the endo/lysosomal system and is crucially implicated in neuronal function and integrity, as loss of function mutations in the PIKfyve complex lead to neurodegeneration in mouse models and human patients. Our recent work has shown that the intracellular domain of the Amyloid Precursor Protein (APP), a molecule central to the aetiology of Alzheimer's disease binds to VAC14 and enhances PIKfyve function. Here we utilise this recent advance to create an easy-to-use tool for increasing PIKfyve activity in cells. We fused APP's intracellular domain (AICD) to the HIV TAT domain, a cell permeable peptide allowing proteins to penetrate cells. The resultant TAT-AICD fusion protein is cell permeable and triggers an increase of PI(3,5)P2. Using the PI(3,5)P2 specific GFP-ML1Nx2 probe we show that cell-permeable AICD alters PI(3,5)P2 dynamics. TAT-AICD also provides partial protection from pharmacological inhibition of PIKfyve. All three lines of evidence show that the APP intracellular domain activates the PIKfyve complex in cells, a finding that is important for our understanding of the mechanism of neurodegeneration in Alzheimer's disease.

Munkaszervezés a lean termelésben – mit magyaráznak a termelésmenedzsment koncepciók = Work organization in lean production – what production concepts explain

A tanulmány a lean termelés munkaszervezését három termelésmenedzsment koncepció segítségével vizsgálja. Az egyes koncepciók a szervezet eltérő metszeteit érintik: (1) a termék-folyamat mátrix (Hayes és Wheelwright, 1979) a termék és a folyamat jellemzőit helyezi középpontba. A lean hatására a szervezet a mátrixban a nagyobb választék és a folyamat alapú működés (nagyobb függőség) irányába mozdul el. Az elmozdulást üzemi szinten a magas elkötelezettségű munkavégzési rendszer gyakorlatainak bevezetése kíséri, mivel azok támogatják a rugalmas működést, a gyors kommunikációt és problémamegoldást. Az elmozdulás „minősége” és így a munkaszervezési gyakorlatok használata (mélyég, száma, munkavállalók bevonása) nagyban függ a termelési stratégiától és a lean érettségtől. (2) A termelési stratégia szakaszai (Wheelwright és Hayes, 1985) a termelés üzleti stratégiában játszott szerepét elemzik. A lean termelés összeegyeztethető a termelési stratégia harmadik szakaszának „command és control” szemléletmódjával. Az ilyen lean termelők költégfókuszúak, a hagyományos munkaerőképben gondolkodnak és körükben kevésbé jellemző az új emberi erőforrás gyakorlatok használata. A lean termelés adaptálása ösztönözheti a vállalatokat a termelési stratégia negyedik szintje felé. A negyedik szint a bevonásra, problémamegoldásra és tanulásra épít, amely megfelel a lean „emberek tisztelete” pillérének. (3) A lean érettségi modell (Hines és társai, 2004) a lean szervezeten belüli elmélyülését és terjedését mutatja be. A lean utazás során a vállalatok az eszköz alapú megközelítéstől a komplex értékrendszerben gondolkodó lean szervezet felé haladnak. A technikai tudásanyag egyre szélesebb körűvé válik, ami rávilágít a tudásátadás (személyek közöttire, de akár struktúrákba, folyamatokba építése is) képességének jelentőségére. Az emberi erőforrás gyakorlatok folyamatosan jelennek meg. De csak a legfejlettebb szakasz, a lean tanuló szervezet megjelenése teszi valóban szükségessé a munkavállalói kép újragondolását is. = This paper examines work organization in lean production with the help of three production concepts. These concepts embrace different dimensions of the organization: (1) the product-process matrix (Hayes and Wheelwright, 1979) is about product and process characteristics. Due to the lean the organization shifts within the matrix – towards higher variability and flow (higher level of interdependencies). On the shop floor the shift is accompanied by the introduction of high commitment work system’s practices, since those support flexible operations, fast communication and problem-solving. The „quality” of the shift and hence the application of these work practices (number of practices, their embeddeness, employee involvement) highly depends on manufacturing strategy and lean maturity. (2) The concept of stages of manufacturing strategy (Wheelwright and Hayes, 1985) analyzes the role of the manufacturing function in the business strategy. Lean production is compatible with the „command and control” approach of the third stage of manufacturing strategy. These lean producers are cost-driven, they have the traditional approach of employees and apply new work organization practices to a less extent. However, the implementation of lean production may drive these companies to the fourth stage. The fourth stage of manufacturing strategy is based on employee involvement, problem-solving and learning. This stage is in full accordance with the „respect for people” pillar of lean production. (3) Lean maturity (Hines et al., 2004) shows the path how lean management deepens and expands within an organization. During the lean journey, companies progress from the tool-based approach to the complex lean value system. The technical knowledge of lean becomes more and more comprehensive and it points out the crucial importance of knowledge conversion capabilities (intrapersonal or even how to build knowledge into structures, processes). Work organization practices constantly appear with the progress, but the review of the traditional approach of employees is only essential at the most advanced stage, when an organization becomes lean learning organization.

Estimation of Inequality Indices of the Cumulative Distribution Function

Date of Acceptance: 02/03/2015

Estimation of Inequality Indices of the Cumulative Distribution Function

Date of Acceptance: 02/03/2015

A bidirectional relationship between executive function and health behavior : evidence, implications, and future directions

This work was supported by a grant from the UK Economic and Social Research Council (ES/L010437/1).

Relational work in synchronous text-based CMC of virtual teams

Based on close examinations of instant message (IM) interactions, this chapter argues that an interactional sociolinguistic approach to computer-mediated language use could provide explanations for phenomena that previously could not be accounted for in computer-mediated discourse analysis (CMDA). Drawing on the theoretical framework of relational work (Locher, 2006), the analysis focuses on non-task oriented talk and its function in forming and establishing communication norms in the team, as well as micro-level phenomena, such as hesitation, backchannel signals and emoticons. The conclusions of this preliminary research suggest that the linguistic strategies used for substituting audio-visual signals are strategically used in discursive functions and have an important role in relational work

Has your work worked you too hard? Physically demanding work and disability in a sample of the older Irish population

There is a heightened need for the practitioner to be alert to the determinants of functional limitations and disabilities owing to the ageing workforce. This study investigated the association between work type and disability in older age in both the paid and the previously unexplored, unpaid worker (household labour).Data on demographic factors, physical measurements, work history and functional status were collected on three hundred and fifty seven 57-80-year-olds. Past or present work was identified as either physically demanding or not. Functional limitations and activities of daily living (ADL) disabilities were assessed using validated scales. Logistic regression was used to examine the relationship between the dependent variables and work type (physically demanding work or not physically demanding work).Over half of the sample reported doing physically demanding work. 20 % had complete function (n = 67), 65 % (n = 223) functional limitations and 15 % (n = 53) ADL disability. Physically demanding work was associated with functional limitations [OR 2.52 (1.41, 4.51), p = 0.01] and ADL disability [OR 2.10 (1.06, 4.17), p = 0.03] after adjustment for a measure of obesity and gender. When gender stratified, looking only at females, physically demanding work was associated with ADL disability [OR 2.79 (1.10, 7.07), p = 0.03] adjusted for a measure of obesity and household labour. Physically demanding work was related to functional limitations and ADL disability in older age. This is valuable information to inform practitioners in the treatment of older people with functional limitations and disabilities and in guiding interventions in the prevention of work related disability.

Metabolism Regulates the Fate and Function of T Lymphocytes

Proper balancing of the activities of metabolic pathways to meet the challenge of providing necessary products for biosynthetic and energy demands of the cell is a key requirement for maintaining cell viability and allowing for cell proliferation. Cell metabolism has been found to play a crucial role in numerous cell settings, including in the cells of the immune system, where a successful immune response requires rapid proliferation and successful clearance of dangerous pathogens followed by resolution of the immune response. Additionally, it is now well known that cell metabolism is markedly altered from normal cells in the setting of cancer, where tumor cells rapidly and persistently proliferate. In both settings, alterations to the metabolic profile of the cells play important roles in promoting cell proliferation and survival.

It has long been known that many types of tumor cells and actively proliferating immune cells adopt a metabolic phenotype of aerobic glycolysis, whereby the cell, even under normoxic conditions, imports large amounts of glucose and fluxes it through the glycolytic pathway and produces lactate. However, the metabolic programs utilized by various immune cell subsets have only recently begun to be explored in detail, and the metabolic features and pathways influencing cell metabolism in tumor cells in vivo have not been studied in detail. The work presented here examines the role of metabolism in regulating the function of an important subset of the immune system, the regulatory T cell (Treg) and the role and regulation of metabolism in the context of malignant T cell acute lymphoblastic leukemia (T-ALL). We show that Treg cells, in order to properly function to suppress auto-inflammatory disease, adopt a metabolic program that is characterized by oxidative metabolism and active suppression of anabolic signaling and metabolic pathways. We found that the transcription factor FoxP3, which is highly expressed in Treg cells, drives this phenotype. Perturbing the metabolic phenotype of Treg cells by enforcing increased glycolysis or driving proliferation and anabolic signaling through inflammatory signaling pathways results in a reduction in suppressive function of Tregs.

In our studies focused on the metabolism of T-ALL, we observed that while T-ALL cells use and require aerobic glycolysis, the glycolytic metabolism of T-ALL is restrained compared to that of an antigen activated T cell. The metabolism of T-ALL is instead balanced, with mitochondrial metabolism also being increased. We observed that the pro-anabolic growth mTORC1 signaling pathway was limited in primary T-ALL cells as a result of AMPK pathway activity. AMPK pathway signaling was elevated as a result of oncogene induced metabolic stress. AMPK played a key role in the regulation of T-ALL cell metabolism, as genetic deletion of AMPK in an in vivo murine model of T-ALL resulted in increased glycolysis and anabolic metabolism, yet paradoxically increased cell death and increased mouse survival time. AMPK acts to promote mitochondrial oxidative metabolism in T-ALL through the regulation of Complex I activity, and loss of AMPK reduced mitochondrial oxidative metabolism and resulted in increased metabolic stress. Confirming a role for mitochondrial metabolism in T-ALL, we observed that the direct pharmacological inhibition of Complex I also resulted in a rapid loss of T-ALL cell viability in vitro and in vivo. Taken together, this work establishes an important role for AMPK to both balance the metabolic pathways utilized by T-ALL to allow for cell proliferation and to also promote tumor cell viability by controlling metabolic stress.

Overall, this work demonstrates the importance of the proper coupling of metabolic pathway activity with the function needs of particular types of immune cells. We show that Treg cells, which mainly act to keep immune responses well regulated, adopt a metabolic program where glycolytic metabolism is actively repressed, while oxidative metabolism is promoted. In the setting of malignant T-ALL cells, metabolic activity is surprisingly balanced, with both glycolysis and mitochondrial oxidative metabolism being utilized. In both cases, altering the metabolic balance towards glycolytic metabolism results in negative outcomes for the cell, with decreased Treg functionality and increased metabolic stress in T-ALL. In both cases, this work has generated a new understanding of how metabolism couples to immune cell function, and may allow for selective targeting of immune cell subsets by the specific targeting of metabolic pathways.

MicroRNA expression and function in neonatal hypoxic ischaemic encephalopathy

Hypoxic ischaemic encephalopathy (HIE) is a devastating neonatal condition which affects 2-3 per 1000 infants annually. The current gold standard of treatment - induced hypothermia, has the ability to reduce neonatal mortality and improve neonatal morbidity. However, to be effective it needs to be initiated within the therapeutic window which exists following initial insult until approximately 6 hours after birth. Current methods of assessment which are relied upon to identify infants with HIE are subjective and unreliable. To overcome this issue, an early and reliable biomarker of HIE severity must be identified. MicroRNA (miRNA) are a class of small non-coding RNA molecules which have potential as biomarkers of disease state and potential therapeutic targets. These tiny molecules can modulate gene expression by inhibiting translation of messenger RNA (mRNA) and as a result, can regulate protein synthesis. These miRNA are understood to be released into the circulation during cellular stress, where they are highly stable and relatively easy to quantify. Therefore, these miRNAs may be ideal candidates for biomarkers of HIE severity and may aid in directing the clinical management of these infants. By using both transcriptomic and proteomic approaches to analyse the expression of miRNAs and their potential targets in the umbilical cord blood, I have confirmed that infants with perinatal asphyxia and HIE have a significantly different UCB miRNA signature compared to UCB samples from healthy controls. Finally, I have identified and investigated 2 individual miRNAs; both of which show some potential as classifiers of HIE severity and predictors of long term outcome, particularly when coupled with their downstream targets. While this work will need to be validated and expanded in a new and larger cohort of infants, it suggests the potential of miRNA as biomarkers of neonatal pathological conditions such as HIE.

Formal function and phrase structure in contemporary music : Pierre Boulez’s late solo works and Sean Clarke’s "Lucretia Overture" and "4 Impromptus"

Cette thèse présente une théorie de la fonction formelle et de la structure des phrases dans la musique contemporaine, théorie qui peut être utilisée aussi bien comme outil analytique que pour créer de nouvelles œuvres. Deux concepts théoriques actuels aident à clarifier la structure des phrases : les projections temporelles de Christopher Hasty et la théorie des fonctions formelles de William Caplin, qui inclut le concept de l’organisation formelle soudée versus lâche (tight-knit vs. loose). Les projections temporelles sont perceptibles grâce à l’accent mis sur les paramètres secondaires, comme le style du jeu, l’articulation et le timbre. Des sections avec une organisation formelle soudée ont des projections temporelles claires, qui sont créées par la juxtaposition des motifs distincts, généralement sous la forme d'une idée de base en deux parties. Ces projections organisent la musique en phrases de présentation, en phrases de continuité et finalement, à des moments formels charnières, en phrases cadentielles. Les sections pourvues d’une organisation plus lâche tendent à présenter des projections et mouvements harmoniques moins clairs et moins d’uniformité motivique. La structure des phrases de trois pièces tardives pour instrument soliste de Pierre Boulez est analysée : Anthèmes I pour violon (1991-1992) et deux pièces pour piano, Incises (2001) et une page d’éphéméride (2005). Les idées proposées dans le présent document font suite à une analyse de ces œuvres et ont eu une forte influence sur mes propres compositions, en particulier Lucretia Overture pour orchestre et 4 Impromptus pour flûte, saxophone soprano et piano, qui sont également analysés en détail. Plusieurs techniques de composition supplémentaires peuvent être discernés dans ces deux œuvres, y compris l'utilisation de séquence mélodiques pour contrôler le rythme harmonique; des passages composés de plusieurs couches musicales chacun avec un structure de phrase distinct; et le relâchement de l'organisation formelle de matériels récurrents. Enfin, la composition de plusieurs autres travaux antérieurs a donné lieu à des techniques utilisées dans ces deux œuvres et ils sont brièvement abordés dans la section finale.