Bayesian refinement of association signals for 14 loci in 3 common diseases

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies. © 2012 Nature America, Inc. All rights reserved.

Effects of particle/matrix interface and strengthening mechanisms on the mechanical properties of metal matrix composites

A randomly distributed multi-particle model considering the effects of particle/matrix interface and strengthening mechanisms introduced by the particles has been constructed. Particle shape, distribution, volume fraction and the particles/matrix interface due to the factors including element diffusion were considered in the model. The effects of strengthening mechanisms, caused by the introduction of particles on the mechanical properties of the composites, including grain refinement strengthening, dislocation strengthening and Orowan strengthening, are incorporated. In the model, the particles are assumed to have spheroidal shape, with uniform distribution of the centre, long axis length and inclination angle. The axis ratio follows a right half-normal distribution. Using Monte Carlo method, the location and shape parameters of the spheroids are randomly selected. The particle volume fraction is calculated using the area ratio of the spheroids. Then, the effects of particle/matrix interface and strengthening mechanism on the distribution of Mises stress and equivalent strain and the flow behaviour for the composites are discussed.

Life after Stroke: Coping mechanisms among African Caribbean Women

In the UK stroke is the third most common cause of death for women and the incidence in African Caribbean women is higher than the general population. Stroke burden has major consequences for the physical, mental and social health of African Caribbean women. In order to adjust to life after stroke individuals affected employ a range of strategies which may include personal, religious (church) or spiritual support (i.e. prayer), individual motivation, or resignation to life with a disability. This study explored these areas through the coping mechanisms that African Caribbean women utilised post stroke in the context of stroke recovery and lifestyle modification efforts needed to promote healthy living post stroke. A qualitative approach using Interpretative Phenomenological Analysis was adopted. Eight women were recruited into the study. Semi structured in-depth interviews were audio recorded and were transcribed verbatim. Data were analysed using a four-stage framework: familiarisation, sense making, developing themes and data refinement and analysis. Three main themes on coping emerged: the need to follow medical rules to manage stroke, strength and determination, and the use of religion and faith to cope with life after stroke. These findings illustrate both a tension between religious beliefs and the medical approach to stroke and highlight the potential benefits that religion and the church can play in stroke recovery. Implications for practice include acknowledgement and inclusion of religion and church based health promotion in post stroke recovery.

Grain refinement studies on Mg and Mg-Al based alloys

Demand on magnesium and its alloys is increased significantly in the automotive industry because of their great potential in reducing the weight of components, thus resulting in improvement in fuel efficiency of the vehicle. To date, most of Mg products have been fabricated by casting, especially, by die-casting because of its high productivity, suitable strength, acceptable quality & dimensional accuracy and the components produced through sand, gravity and low pressure die casting are small extent. In fact, higher solidification rate is possible only in high pressure die casting, which results in finer grain size. However, achieving high cooling rate in gravity casting using sand and permanent moulds is a difficult task, which ends with a coarser grain nature and exhibit poor mechanical properties, which is an important aspect of the performance in industrial applications. Grain refinement is technologically attractive because it generally does not adversely affect ductility and toughness, contrary to most other strengthening methods. Therefore formation of fine grain structure in these castings is crucial, in order to improve the mechanical properties of these cast components. Therefore, the present investigation is “GRAIN REFINEMENT STUDIES ON Mg AND Mg-Al BASED ALLOYS”. The primary objective of this present investigation is to study the effect of various grain refining inoculants (Al-4B, Al- 5TiB2 master alloys, Al4C3, Charcoal particles) on Pure Mg and Mg-Al alloys such as AZ31, AZ91 and study their grain refining mechanisms. The second objective of this work is to study the effect of superheating process on the grain size of AZ31, AZ91 Mg alloys with and without inoculants addition. In addition, to study the effect of grain refinement on the mechanical properties of Mg and Mg-Al alloys. The thesis is well organized with seven chapters and the details of the studies are given below in detail.

Structural refinement, growth process, photoluminescence and photocatalytic properties of (Ba1-xPr2x/3)WO4 crystals synthesized by the coprecipitation method

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structural refinement and photoluminescence properties of cube-like (Ca 1-xCu x)TiO 3 crystals synthesized by the microwave-hydrothermal method

In this work, (Ca 1-xCu x)TiO 3 crystals with (x = 0, 0.01 and 0.02), labeled as CTO, CCTO1 and CCTO2, were synthesized by the microwave-hydrothermal method at 140°C for 32 min. XRD patterns (Fig. 1), Rietveld refinement and FT-Raman spectroscopy indicated that these crystals present orthorhombic structure Pbnm. Micro-Raman and XANES spectra suggested that the substitution of Ca by Cu in A-site promoted a displacement of the [TiO6]-[TiO6] clusters adjacent from its symmetric center, which leads distortions on the [CaO 12] clusters neighboring and consequently cause the strains into the CaTiO3 lattice. FE-SEM images showed that these crystals have an irregular shape as cube like probably indicating an Ostwald-ripening and self-assemble as dominant mechanisms to crystals growth. The powders presented an intense PL blue-emission.

Structural refinement, growth mechanism, infrared/Raman spectroscopies and photoluminescence properties of PbMoO4 crystals

Lead molybdate (PbMoO4) crystals were synthesized by the co-precipitation method at room temperature and then processed in a conventional hydrothermal (CH) system at low temperature (70 °C for different times). These crystals were structurally characterized by X-ray diffraction (XRD), Rietveld refinement, micro-Raman (MR) and Fourier transformed infrared (FT-IR) spectroscopies. Field emission scanning electron microscopy images were employed to observe the shape and monitor the crystal growth process. The optical properties were investigated by ultraviolet-visible (UV-Vis) absorption and photoluminescence (PL) measurements. XRD patterns and MR spectra indicate that these crystals have a scheelite-type tetragonal structure. Rietveld refinement data possibilities the evaluation of distortions in the tetrahedral [MoO 4] clusters. MR and FT-IR spectra exhibited a high mode ν1(Ag) ascribed to symmetric stretching vibrations as well as a large absorption band with two modes ν3(Eu and Au) related to anti-symmetric stretching vibrations in [MoO 4] clusters. Growth mechanisms were proposed to explain the stages involved for the formation of octahedron-like PbMoO4 crystals. UV-Vis absorption spectra indicate a reduction in optical band gap with an increase in the CH processing time. PL properties of PbMoO4 crystals have been elucidated using a model based on distortions of tetrahedral [MoO4] clusters due to medium-range intrinsic defects and intermediary energy levels (deep and shallow holes) within the band gap. © 2012 Elsevier Ltd. All rights reserved.

Structural refinement, growth process, photoluminescence and photocatalytic properties of (Ba1-xPr2x/3)WO4 crystals synthesized by the coprecipitation method

Barium praseodymium tungstate (Ba1-xPr2x/3)WO4 crystals with (x = 0, 0.01, and 0.02) were prepared by the coprecipitation method. These crystals were structurally characterized by X-ray diffraction (XRD), Rietveld refinements, Fourier-transform Raman (FT-Raman) and Fourier-transform infrared (FT-IR) spectroscopies. The shape and size of these crystals were observed by field emission scanning electron microcopy (FE-SEM). Their optical properties were investigated by ultraviolet visible (UV-vis) absorption and photoluminescence (PL) measurements. Moreover, we have studied the photocatalytic (PC) activity of crystals for degradation of rhodamine B (RhB) dye. XRD patterns, Rietveld refinements data, FT-Raman and FT-IR spectroscopies indicate that all crystals exhibit a tetragonal structure without deleterious phases. FT-Raman spectra exhibited 13 Raman-active modes in a range from 50 to 1000 cm(-1), while FT-IR spectra have 8 infrared active modes in a range from 200 to 1050 cm(-1). FE-SEM images showed different shapes (bonbon-, spindle-, rice-and flake-like) as well as a reduction in the crystal size with an increase in Pr3+ ions. A possible growth process was proposed for these crystals. UV-vis absorption measurements revealed a decrease in optical band gap values with an increase of Pr3+ into the matrix. An intense green PL emission was noted for (Ba1-xPr2x/3)WO4 crystals (x = 0), while crystals with (x = 0.01 and 0.02) produced a reduction in the wide band PL emission and the narrow band PL emission which is related to f-f transitions from Pr3+ ions. High photocatalytic efficiency was verified for the bonbon-like BaWO4 crystals as a catalyst in the degradation of the RhB dye after 25 min under UV-light. Finally, we discuss possible mechanisms for PL and PC properties of these crystals.

Role of BDNF secretion and signaling in the activity-dependent refinement of synaptic connections

Neuronal networks exhibit diverse types of plasticity, including the activity-dependent regulation of synaptic functions and refinement of synaptic connections. In addition, continuous generation of new neurons in the “adult” brain (adult neurogenesis) represents a powerful form of structural plasticity establishing new connections and possibly implementing pre-existing neuronal circuits (Kempermann et al, 2000; Ming and Song, 2005). Neurotrophins, a family of neuronal growth factors, are crucially involved in the modulation of activity-dependent neuronal plasticity. The first evidence for the physiological importance of this role evolved from the observations that the local administration of neurotrophins has dramatic effects on the activity-dependent refinement of synaptic connections in the visual cortex (McAllister et al, 1999; Berardi et al, 2000; Thoenen, 1995). Moreover, the local availability of critical amounts of neurotrophins appears to be relevant for the ability of hippocampal neurons to undergo long-term potentiation (LTP) of the synaptic transmission (Lu, 2004; Aicardi et al, 2004). To achieve a comprehensive understanding of the modulatory role of neurotrophins in integrated neuronal systems, informations on the mechanisms about local neurotrophins synthesis and secretion as well as ditribution of their cognate receptors are of crucial importance. In the first part of this doctoral thesis I have used electrophysiological approaches and real-time imaging tecniques to investigate additional features about the regulation of neurotrophins secretion, namely the capability of the neurotrophin brain-derived neurotrophic factor (BDNF) to undergo synaptic recycling. In cortical and hippocampal slices as well as in dissociated cell cultures, neuronal activity rapidly enhances the neuronal expression and secretion of BDNF which is subsequently taken up by neurons themselves but also by perineuronal astrocytes, through the selective activation of BDNF receptors. Moreover, internalized BDNF becomes part of the releasable source of the neurotrophin, which is promptly recruited for activity-dependent recycling. Thus, we described for the first time that neurons and astrocytes contain an endocytic compartment competent for BDNF recycling, suggesting a specialized form of bidirectional communication between neurons and glia. The mechanism of BDNF recycling is reminiscent of that for neurotransmitters and identifies BDNF as a new modulator implicated in neuro- and glio-transmission. In the second part of this doctoral thesis I addressed the role of BDNF signaling in adult hippocampal neurogenesis. I have generated a transgenic mouse model to specifically investigate the influence of BDNF signaling on the generation, differentiation, survival and connectivity of newborn neurons into the adult hippocampal network. I demonstrated that the survival of newborn neurons critically depends on the activation of the BDNF receptor TrkB. The TrkB-dependent decision regarding life or death in these newborn neurons takes place right at the transition point of their morphological and functional maturation Before newborn neurons start to die, they exhibit a drastic reduction in dendritic complexity and spine density compared to wild-type newborn neurons, indicating that this receptor is required for the connectivity of newborn neurons. Both the failure to become integrated and subsequent dying lead to impaired LTP. Finally, mice lacking a functional TrkB in the restricted population of newborn neurons show behavioral deficits, namely increased anxiety-like behavior. These data suggest that the integration and establishment of proper connections by newly generated neurons into the pre-existing network are relevant features for regulating the emotional state of the animal.

Envy: A Psychometric Refinement of the Construct

The noticeable differences in the theoretical and operative definitions of envy across studies and approaches have produced a fragmentary representation and understanding of the envious emotion. The present dissertation aimed to clarify the inherent nature of the construct of envy through the integration of findings from three independent studies. We focused on malicious envy, and investigated it from both a dispositional and an episodic perspective. Studies 1 and 2 investigated the dimensionality of envy as a stable individual characteristic and an episodic emotional state, respectively. In order to elicit episodic envy, a scenario-based experiment was conducted. Results indicated that, in both its dispositional and episodic facets, envy is a bidimensional construct composed by an inner-directed dimension of inferiority and helplessness, and an outer-directed dimension of feelings of anger and ill will. Moreover, findings from Study 1 allowed to establish boundaries between envy and competing constructs that have often been included in conceptualizations of envy. The psychometrically validated definition of envy provided by Studies 1 and 2 represents a valuable contribution to empirical research. Implications for envy research concern the promotion of a shared operationalization of envy in future studies, which will arguably facilitate the comparison of findings between studies and between approaches. Study 3 examined the mechanisms through which dispositional envy affects individuals’ social adjustment and psychological wellbeing. Findings revealed that the detrimental effects of envy on perceived social support and subjective well-being are mostly mediated by other personal characteristics, such as neuroticism and self-esteem. By reducing global self-esteem, the envious disposition may damage supportive social networks via antisocial direct and indirect behaviors that may arise from envy and that are likely to drive others away. On the other hand, by damaging both emotional stability and self-worth, dispositional envy leads to reduced subjective well-being. Implications for clinical practice are discussed.

Cellular and network mechanisms of rhythm generation in spinal cord circuits

The generation of rhythmic electrical activity is a prominent feature of spinal cord circuits that is used for locomotion and also for circuit refinement during development. The mechanisms involved in rhythm generation in spinal cord networks are not fully understood. It is for example not known whether spinal cord rhythms are driven by pacemaker neurons and if yes, which neurons are involved in this function. We studied the mechanisms involved in rhythm generation in slice cultures from fetal rats that were grown on multielectrode arrays (MEAs). We combined multisite extracellular recordings from the MEA electrodes with intracellular patch clamp recordings from single neurons. We found that spatially restricted oscillations of activity appeared in most of the cultures spontaneously. Such activity was based on intrinsic activity in a percentage of the neurons that could activate the spinal networks through recurrent excitation. The local oscillator networks critically involved NMDA, AMPA and GABA / glycine receptors at subsequent phases of the oscillation cycle. Intrinsic spiking in individual neurons (in the absence of functional synaptic coupling) was based on persistent sodium currents. Intrinsic firing as well as persistent sodium currents were increased by 5-HT through 5-HT2 receptors. Comparing neuronal activity to muscle activity in co-cultures of spinal cord slices with muscle fibers we found that a percentage of the intrinsically spiking neurons were motoneurons. These motoneurons were electrically coupled among each other and they could drive the spinal networks through cholinergic recurrent excitation. These findings open the possibility that during development rhythmic activity in motoneurons is not only involved in circuit refinement downstream at the neuromuscular endplates but also upstream at the level of spinal cord circuits.

Refinement of tourniquet-induced peripheral ischemia/reperfusion injury in rats: comparison of 2 h vs 24 h reperfusion.

Prolonged ischemia of skeletal muscle tissue, followed by reperfusion, leads to ischemia/reperfusion injury (IRI), which is a feared local and systemic inflammatory reaction. With respect to the 3Rs, we wanted to determine which parameters for assessment of IRI require a reperfusion time of 24 h and for which 2 h of reperfusion are sufficient. Rats were subjected to 3 h of hind limb ischemia and 2 h or 24 h of reperfusion. Human plasma derived C1 inhibitor was used as a drug to prevent reperfusion injury. For 2 h of reperfusion the rats stayed under anesthesia throughout (severity grade 1), whereas for 24 h they were awake under analgesia during reperfusion (grade 2). The femoral artery was clamped and a tourniquet was placed, under maintenance of venous return. C1 esterase inhibitor was systemically administered 5 min before the induction of ischemia. No differences in local muscle edema formation and depositions of immunoglobulin G and immunoglobulin M were observed between 2 h and 24 h (P > 0.05), whereas lung edema was only observed after 24 h. Muscle viability was significantly lower after 24 h vs 2 h reperfusion (P < 0.05). Increased plasma creatine kinase (CK)-MM and platelet-derived growth factor (PDGF)-bb could be detected after 2 h, but not after 24 h of reperfusion. By contrast, depositions of C3b/c and fibrin in muscle were only detected after 24 h (P < 0.001). In conclusion, for a first screening of drug candidates to reduce IRI, 2 h reperfusions are sufficient, and these reduce the severity of the animal experiment. Twenty-four-hour reperfusions are only needed for in-depth analysis of the mechanisms of IRI, including lung damage.

Procedures and parameters in the real-time program refinement calculus

The real-time refinement calculus is a formal method for the systematic derivation of real-time programs from real-time specifications in a style similar to the non-real-time refinement calculi of Back and Morgan. In this paper we extend the real-time refinement calculus with procedures and provide refinement rules for refining real-time specifications to procedure calls. A real-time specification can include constraints on, not only what outputs are produced, but also when they are produced. The derived programs can also include time constraints oil when certain points in the program must be reached; these are expressed in the form of deadline commands. Such programs are machine independent. An important consequence of the approach taken is that, not only are the specifications machine independent, but the whole refinement process is machine independent. To implement the machine independent code on a target machine one has a separate task of showing that the compiled machine code will reach all its deadlines before they expire. For real-time programs, externally observable input and output variables are essential. These differ from local variables in that their values are observable over the duration of the execution of the program. Hence procedures require input and output parameter mechanisms that are references to the actual parameters so that changes to external inputs are observable within the procedure and changes to output parameters are externally observable. In addition, we allow value and result parameters. These may be auxiliary parameters, which are used for reasoning about the correctness of real-time programs as well as in the expression of timing deadlines, but do not lead to any code being generated for them by a compiler. (c) 2006 Elsevier B.V. All rights reserved.