Second messenger pathways in the action of cachectic factors

Cachexia in cancer is characterised by progressive depletion of both adipose tissue stores and skeletal muscle mass. Two catabolic factors produced by cachexia-inducing tumours have the potential for inducing these changes in body composition: (i) proteolysis-inducing factor (PIF) which acts on skeletal muscle to induce both protein degradation and inhibit protein synthesis, (ii) lipid-mobilising factor (LMF), which has been shown to directly induce lipolysis in isolated epididymal murine white adipocytes. Administration of lipid-mobilising factor (LMF) to mice produced a specific reduction in carcass lipid with a tendency to increase non-fat carcass mass. Treatment of murine myoblasts, myotubes and tumour cells with tumour-produced LMF, caused concentration dependent stimulation of protein synthesis, within a 24hr period. It produced an increase in intracellular cyclic AMP levels, which was linearly related to the increase in protein synthesis. The observed effect was attenuated by pretreating cells with the adenylate cyclase inhibitor, MDL12330A and was additive with stimulation produced by forskolin. Both propranolol and a specific 3 adrenergic antagonist SR59230A, significantly reduced the stimulation of protein synthesis induced by LMF. LMF also affected protein degradation in vitro, as demonstrated by a reduction in proteasome activity, a key component of the ubiquitin-dependent proteolytic pathway. These effects were opposite to those produced by PIF which caused both a decrease in the rate of protein synthesis and an elevation on protein breakdown when incubated in vitro.Incubation of LMF with a fat cell line produced alterations in the levels of guanine-nucleotide binding proteins (G proteins). This was also evident in adipocyte plasma membranes isolated from mice bearing the tumour model of cachexia, MAC16 adenocarcinoma and from patients with cancer cachexia. Progression through the cachectic state induced an upregulation of stimulatory G proteins paralleled with a downregulation of inhibitory G proteins. These changes would contribute to the increased lipid mobilisation seen in cancer cachexia.

Pathways utilized by heavy metal pollutants in urban stormwater runoff

The research concerned the assessment of the pathways utilized by heavy metal pollutants in urban stormwater runoff. A separately sewered urban residential catchment of approximately 107 hectares in Chelmsley Wood, north-east Birmingham was the subject of the field investigation. The catchment area, almost entirely residential, had no immediate industrial heavy metal input, however, industry was situated to the north of the catchment. The perimeter of the catchment was bounded by the M6 motorway on the northern and eastern sides and was believed to contribute to aerial deposition. Metal inputs to the ground surface were assumed to be confined to normal suburban activities, namely, aerial deposition, vehicular activity and anthropological activities. A programme of field work was undertaken over a 12 month period, from July 1983 to July 1984. Monthly deposition rates were monitored using a network of deposit cannisters and roadside sediment and soil samples were taken. Stormwater samples were obtained for 19 separate events. All samples were analysed for iron, lead, zinc, copper, chromium, nickel and cadmium content. Rainfall was recorded on site with additional meteorological data obtained from local Meteorological Offices. Use was made of a simple conceptual model designed for the catchment to substantiate hypotheses derived from site investigations and literature, to investigate the pathways utilized for the transportation of heavy metals throughout the catchment.

Electrophysiological studies of the visual pathways in Alzheimer's and Parkinson's disease

It is known that parallel pathways exist within the visual system. These have been described as magnocellular and parvocellular as a result of the layered organisation of the lateral geniculate nucleus and extend from the retina to the cortex. Dopamine (DA) and acetylcholine (ACH) are neurotransmitters that are present in the visual pathway. DA is present in the retina and is associated with the interplexiform cells and horizontal cells. ACH is also present in the retina and is associated with displaced amacrine cells; it is also present in the superior colliculus. DA is found to be significantly depleted in the brain of Parkinson's disease (PD) patients and ACH in Alzheimer's disease (AD) patients. For this reason these diseases were used to assess the function of DA and ACH in the electrophysiology of the visual pathway. Experiments were conducted on young normals to design stimuli that would preferentially activate the magnocellular or parvocellular pathway. These stimuli were then used to evoke visual evoked potentials (VEP) in patients with PD and AD, in order to assess the function of DA and ACH in the visual pathway. Electroretinograms (ERGs) were also measured in PD patients to assess the role of DA in the retina. In addition, peripheral ACH function was assessed by measuring VEPs, ERGs and contrast sensitivity (CS) in young normals following the topical instillation of hyoscine hydrobromide (an anticholinergic drug). The results indicate that the magnocellular pathway can be divided into two: a cholinergic tectal-association area pathway carrying luminance information, and a non-cholinergic geniculo-cortical pathway carrying spatial information. It was also found that depletion of DA had very little effect on the VEPs or ERGs, confirming a general regulatory function for this neurotransmitter.

BMI not WHR modulates BOLD fMRI responses in a sub-cortical reward network when participants judge the attractiveness of human female bodies

In perceptual terms, the human body is a complex 3d shape which has to be interpreted by the observer to judge its attractiveness. Both body mass and shape have been suggested as strong predictors of female attractiveness. Normally body mass and shape co-vary, and it is difficult to differentiate their separate effects. A recent study suggested that altering body mass does not modulate activity in the reward mechanisms of the brain, but shape does. However, using computer generated female body-shaped greyscale images, based on a Principal Component Analysis of female bodies, we were able to construct images which covary with real female body mass (indexed with BMI) and not with body shape (indexed with WHR), and vice versa. Twelve observers (6 male and 6 female) rated these images for attractiveness during an fMRI study. The attractiveness ratings were correlated with changes in BMI and not WHR. Our primary fMRI results demonstrated that in addition to activation in higher visual areas (such as the extrastriate body area), changing BMI also modulated activity in the caudate nucleus, and other parts of the brain reward system. This shows that BMI, not WHR, modulates reward mechanisms in the brain and we infer that this may have important implications for judgements of ideal body size in eating disordered individuals.

Cross-orientation masking is speed invariant between ocular pathways but speed dependent within them

In human (D. H. Baker, T. S. Meese, & R. J. Summers, 2007b) and in cat (B. Li, M. R. Peterson, J. K. Thompson, T. Duong, & R. D. Freeman, 2005; F. Sengpiel & V. Vorobyov, 2005) there are at least two routes to cross-orientation suppression (XOS): a broadband, non-adaptable, monocular (within-eye) pathway and a more narrowband, adaptable interocular (between the eyes) pathway. We further characterized these two routes psychophysically by measuring the weight of suppression across spatio-temporal frequency for cross-oriented pairs of superimposed flickering Gabor patches. Masking functions were normalized to unmasked detection thresholds and fitted by a two-stage model of contrast gain control (T. S. Meese, M. A. Georgeson, & D. H. Baker, 2006) that was developed to accommodate XOS. The weight of monocular suppression was a power function of the scalar quantity ‘speed’ (temporal-frequency/spatial-frequency). This weight can be expressed as the ratio of non-oriented magno- and parvo-like mechanisms, permitting a fast-acting, early locus, as befits the urgency for action associated with high retinal speeds. In contrast, dichoptic-masking functions superimposed. Overall, this (i) provides further evidence for dissociation between the two forms of XOS in humans, and (ii) indicates that the monocular and interocular varieties of XOS are space/time scale-dependent and scale-invariant, respectively. This suggests an image-processing role for interocular XOS that is tailored to natural image statistics—very different from that of the scale-dependent (speed-dependent) monocular variety.

Rewarding customer service? Using reward and recognition to deliver your customer service strategy

This report examines the role of reward and recognition in helping organisations deliver excellent customer service. It identifies the impact that reward and recognition practice has upon customer service and highlights which practices are more effective; shows the extent to which employees are satisfied with the rewards and recognition they receive; indicates those approaches to reward and recognition most associated with staff commitment; and looks at how other factors affect employee satisfaction with reward and recognition.

In vivo and ex vivo regulation of visfatin production by leptin in human and murine adipose tissue: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways

Visfatin is an adipogenic adipokine with increased levels in obesity, properties common to leptin. Thus, leptin may modulate visfatin production in adipose tissue (AT). Therefore, we investigated the effects of leptin on visfatin levels in 3T3-L1 adipocytes and human/murine AT, with or without a leptin antagonist. The potential signaling pathways and mechanisms regulating visfatin production in AT was also studied. Real-time RT-PCR and Western blotting were used to assess the relative mRNA and protein expression of visfatin. ELISA was performed to measure visfatin levels in conditioned media of AT explants, and small interfering RNA technology was used to reduce leptin receptor expression. Leptin significantly (P<0.01) increased visfatin levels in human and murine AT with a maximal response at leptin 10(-9) M, returning to baseline at leptin 10(-7) M. Importantly, ip leptin administration to C57BL/6 ob/ob mice further supported leptin-induced visfatin protein production in omental AT (P<0.05). Additionally, soluble leptin receptor levels rose with concentration dependency to a maximal response at leptin 10(-7) M (P<0.01). The use of a leptin antagonist negated the induction of visfatin and soluble leptin receptor by leptin. Furthermore, leptin-induced visfatin production was significantly decreased in the presence of MAPK and phosphatidylinositol 3-kinase inhibitors. Also, when the leptin eceptor gene was knocked down using small interfering RNA, eptin-induced visfatin expression was significantly decreased. Thus, leptin increases visfatin production in AT in vivo and ex vivo via pathways involving MAPK and phosphatidylinositol 3-kinase signaling. The pleiotropic effects of leptin may be partially mediated by visfatin.

The reward pocketbook

This book covers a broad spectrum from job evaluation systems and how they help staff to understand different job benchmarks, to a range of financial incentive schemes and other benefits which are important to employees - helping you to build loyalty, motivation and productivity. The author highlights the pitfalls of some schemes, using real case studies and offers advice and guidance on packages that work.

Frontopolar cortical inefficiency may underpin reward and working memory dysfunction in bipolar disorder

Objectives. Emotional dysregulation in bipolar disorder is thought to arise from dysfunction within prefrontal cortical regions involved in cognitive control coupled with increased or aberrant activation within regions engaged in emotional processing. The aim of this study was to determine the common and distinct patterns of functional brain abnormalities during reward and working memory processing in patients with bipolar disorder. Methods. Participants were 36 euthymic bipolar disorder patients and 37 healthy comparison subjects matched for age, sex and IQ. Functional magnetic resonance imaging (fMRI) was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task. Results. During both tasks, patients with bipolar disorder demonstrated a pattern of inefficient engagement within the ventral frontopolar prefrontal cortex with evidence of segregation along the medial-lateral dimension for reward and working memory processing, respectively. Moreover, patients also showed greater activation in the anterior cingulate cortex during the Iowa Gambling Task and in the insula during the n-back task. Conclusions. Our data implicate ventral frontopolar dysfunction as a core abnormality underpinning bipolar disorder and confirm that overactivation in regions involved in emotional arousal is present even in tasks that do not typically engage emotional systems. © 2012 Informa Healthcare.

Regulation of IL-1β-induced NFκB by hydroxylases links key hypoxic and inflammatory signaling pathways

Hypoxia is a prominent feature of chronically inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor ?B (NF-?B), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1ß, a major proinflammatory cytokine that regulates NF-?B, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1ß-induced NF-?B at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1ß-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. Thus, we hypothesize that hydroxylases regulate IL-1ß signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1ß-dependent inflammatory signaling.

Common variants in left/right asymmetry genes and pathways are associated with relative hand skill

Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10-9), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development. © 2013 Brandler et al.

The signal transduction pathways involved in the respiratory burst of murine peritoneal macrophages

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Pathways to leadership:board independence, diversity, and the emerging pipeline in the US for women directors

In the wake of this decade's corporate scandals, crimes and excesses, improving the effectiveness of corporate governance in the United States has become a priority. An important influence on a board's effectiveness at monitoring is its members’ degree of independence from senior management. While the current definition of independence revolves around the absence of familial and economic connections between a firm and its directors, research suggests that this standard may be inadequate in ensuring independent oversight. Rather, diversity along racial, gender and other dimensions has been proposed as a potentially more effective standard for board independence. This is especially welcome news for women, who currently comprise 51 per cent of the US managerial workforce but only 14.8 per cent of the directors on boards of large, publicly traded US corporations. Some explain the current dearth of women board members by claiming that there are no qualified women available for board service and/or that women are not interested in board service. However, there is more anecdotal rather than empirical evidence on the issue. Surveying women at a women's leadership conference in Boston, this research investigates the extent to which women are currently involved in some type of board service and the extent to which women aspire to future board service. We find that women are currently more active in governance activities than prior research on corporate boards suggests and that they aspire to play a continued and expanded role in governance activities.