Inhibiting epidermal growth factor receptor at a distance.

The epidermal growth factor receptor (EGFR) tyrosine kinase is implicated in a large number of human cancers. Most EGFR inhibitors target the extracellular, growth factor-binding domain or the intracellular, ATP-binding domain. Here we describe molecules that inhibit the kinase activity of EGFR in a new way, by competing with formation of an essential intradimer coiled coil containing the juxtamembrane segment from each member of the receptor partnership. The most potent molecules we describe bind EGFR directly, decrease the proliferation of wild-type and mutant EGFR-dependent cells lines, inhibit phosphorylation of EGFR and downstream targets, and block coiled coil formation as judged by bipartite tetracysteine display. Potency is directly correlated with the ability to block coiled coil formation within full-length EGFR in cells

The role of HIV-1 in the pathogenesis of cerebral cortical changes in HIV-positive patients: a study using immunohistochemistry and the polymerase chain reaction

The human immunodeficiency virus (HIV-1) is believed to cause neurological dysfunctions, including dementia. Subcortical lesions were originally thought to underlie these problems; however, the recent application of immunohistochemical and morphometric methods has revealed that cortical changes, consisting of a glial cell reaction and a loss of nerve cells, are also present in AIDS. It has even been suggested that these cortical changes are a more likely correlate of dementia, especially since the association between subcortical lesions and dementia "is not entirely convincing. As yet, the existence of HIV-1 within these cortical lesions has not been demonstrated; indeed, viral antigen and nucleic acid are found more often in the white matter than in the cortex. This study attempts to correlate the presence of HIV-1 in the cerebral cortex, with changes in astrocyte and microglial cell density and morphology. The frontal cortex of AIDS patients with and without immunohistochemical evidence of HIV-1 cerebral infection and HIV-1-seropositive non-AIDS brains were compared with normal controls. However, immunohistochemical localisation of HIV-1 may not be optimal. A more sensitive detection technique, the polymerase chain reaction (PCR), was therefore also employed, to detect HIV-1 proviral DNA from the cortex of AIDS and HIV-1-seropositive non-AIDS cases. HIV-1 antigens were found in the cortex of a small proportion of AIDS brains, despite being present the white matter of many cases. In fact, when antigen was 3 detected in the cortex and white matter of the same section, antigen was invariably more abundant in the white matter. In contrast, HIV-1 proviral DNA can be detected in both cortex and white matter of the majority of AIDS patients using PCR. The amount of proviral DNA seems to be equal in both regions, while there is a clear difference in antigen detection. These findings suggest that although both regions are infected, replication of HIV is more restricted in the cortex, than in the white matter. HIV-1 antigen was not detected in any of the HIV-1-seropositive non-AIDS brains; however proviral DNA was detected in 2 out of 8 cases, confirming that HIV- 1 can enter the brain at a relatively early stage of disease. An astroglial reaction was observed in the anterior frontal cortex of the majority of AIDS patients, but not in most of the HIV-1-seropositive non-AIDS. A more subtle microglial cell reaction was also present in many AIDS cases whilst the density of microglial cells was significantly higher in the HIV-1-seropositive non-AIDS cases than the AIDS. However, it was not determined whether this was due to the different risk factors or the stage of disease. The presence of HIV-1 proviral DNA in the cortex of AIDS brains was associated with an increased density of GFAP positive astrocytes and the presence of reactive microglial cells. However these changes also existed, although less severely, in cases from which HIV-1 proviral DNA was not detected. These results suggest that HIV-1 contributes to the glial reaction observed in the cerebral cortex, but is not the only factor involved

Jointly Evaluating the Federal Reserve’s Forecasts of GDP Growth and Inflation

In this paper we jointly evaluate the Federal Reserve staff forecasts of U.S. real output growth and the inflation rate assuming the forecasts are to be used as inputs for the Taylor rule. Our simple methodology generates “policy forecast errors” which have a direct interpretation for the impact of forecast errors on the target interest rate given by the Taylor rule. Without interest rate smoothing, we find that, on average, the Taylor rule target interest rate would have been approximately a full percentage point away from the intended target because of errors in forecasting output growth and inflation. Our results are robust to changes in the forecast horizon and to changes in the weights on the variables in the policy rule.Evaluating Forecasts, Macroeconomic Forecasts, Loss Function,Inflation Forecasting, GDP Growth Forecasting, Monetary Policy

Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes.

Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28- T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28- cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation

The influence of cognition on self-management of type 2 diabetes in older people

Diabetes is a growing public health issue, increasing in prevalence, eroding quality of life, and burdening health care systems. The complications of diabetes can be avoided or delayed by maintaining good glycemic control, which is achievable through self-management and, where necessary, medication. Older people with diabetes are at increased risk for cognitive impairment. This review aims to bring together current research that has investigated both cognition and diabetes self-management together. The Cumulative Index to Nursing and Allied Health (Cinahl), Excerpta Medica Database (Embase), Medical Literature Analysis and Retrieval System (Medline), and Psychological Information (PsychInfo) databases were searched. Studies were included if they featured older people with type 2 diabetes and had looked for associations between at least one distinct measure of cognition and at least one distinct measure of diabetes self-management. English language publications from the year 2000 were included. Cognitive measures of executive function, memory, and low scores on tests of global cognitive functioning showed significant correlations with multiple areas of diabetes self-management, including diabetes-specific numeracy ability, diabetes knowledge, insulin adjustment skills, ability to learn to perform insulin injections, worse adherence to medications, decreased frequency of self-care activities, missed appointments, decreased frequency of diabetes monitoring, and increased inaccuracies in reporting blood glucose monitoring. The nature of the subjects studied was quite variable in terms of their disease duration, previous medical histories, associated medical comorbidities, and educational level attained prior to being diagnosed with diabetes. The majority of studies were of an associational nature and not findings confirmed by repeat testing or by the effects of an intervention, neither were the majority of studies designed to give a view or conclusion on the clinical value or implications of the research. This only allows speculation of their importance. Most studies do not separate out the influence of aging itself in altering diabetes self-care behavior. We conclude that older people with type 2 diabetes are at increased risk for cognitive dysfunction. Changes in cognition may negatively affect diabetes self-management behaviors, influencing self-care outcomes. Age and depression may exacerbate any cognitive impairment

Methods to Engage Students in Their Mathematical Learning Experience

In 2005 Park studied the effects of different classroom variables and engagement on students\u27 achievement He found that there was a positive correlation between student engagement and student achievement We conducted our self study research in Geometry and Pre-Calculus classes with the goal of answering the question: what teaching methods can we use to engage students and facilitate their learning of thematical concepts? Our study required planning lessons that elicited student engagement and then evaluating the effectiveness of these lessons. This process included reflecting, learning, and extending our knowledge to make decisions about our future practice. We found the most successful activities were goal oriented: students performed immediately to answer specific questions. Another characteristic of engaging lessons was when students took leading roles in the lesson while we acted as facilitators. As this research focused on students\u27 short-term retention of concepts, an interesting extension could evaluate the effect engaging lessons had on long-term retention of mathematical concepts

Suppressive actions of eicosapentaenoic acid on lipid droplet formation in 3T3-L1 adipocytes

Background : Lipid droplet (LD) formation and size regulation reflects both lipid influx and efflux, and is central in the regulation of adipocyte metabolism, including adipokine secretion. The length and degree of dietary fatty acid (FA) unsaturation is implicated in LD formation and regulation in adipocytes. The aims of this study were to establish the impact of eicosapentaenoic acid (EPA; C20:5n-3) in comparison to SFA (STA; stearic acid, C18:0) and MUFA (OLA; oleic acid, C18:1n-9) on 3T3-L1 adipocyte LD formation, regulation of genes central to LD function and adipokine responsiveness. Cells were supplemented with 100 &mu;M FA during 7-day differentiation.Results : EPA markedly reduced LD size and total lipid accumulation, suppressing PPAR&gamma;, Cidea and D9D/SCD1 genes, distinct from other treatments. These changes were independent of alterations of lipolytic genes, as both EPA and STA similarly elevated LPL and HSL gene expressions. In response to acute lipopolysaccharide exposure, EPA-differentiated adipocytes had distinct improvement in inflammatory response shown by reduction in monocyte chemoattractant protein-1 and interleukin-6 and elevation in adiponectin and leptin gene expressions.Conclusions : This study demonstrates that EPA differentially modulates adipogenesis and lipid accumulation to suppress LD formation and size. This may be due to suppressed gene expression of key proteins closely associated with LD function. Further analysis is required to determine if EPA exerts a similar influence on LD formation and regulation in-vivo.<br /

Timeless considerations : an historical analysis of the development of residency and contract law, gender and parenting

This thesis engages with historical issues of infant custody laws that have a particular focus in contemporary times. Over the last three decades, complex socio-economic changes have reshaped traditional employment patterns and challenged gender understandings of social relationships, parenting practices and the structure of the family. The outcomes have raised concerns about the effects of these changes on children, the stability of the family and questions of wider social cohesion. Social policies and legal reforms have reflected these changes, for example in relation to ideas of formal gender equality, and a rethinking of parental responsibility. This is particularly relevant after parental separation and the law now encourages shared parenting. However, gendered divisions relating to the roles of men and women as parents remain entrenched within many aspects of parenting cultures. This thesis adds to the contemporary debates through an exploration of the historical context of the development of the laws regulating the care of children post-separation. The methodology follows emerging ideas around the uncovering of personal experiences of separated parents and ways that might add depth of knowledge to research findings. The primary focus is on the inter-war period of the nineteen twenties and thirties. The implications of the massive socio-economic upheavals and legislative reforms following the First World War signalled a new age and a key period in women’s history and struggle for formal legal equality. Despite legal reforms and social change, the evidence shows for some parents the reality was different and rooted in gender politics. Via a critical analysis of primary resources, including original and up until now, unseen testamentary evidence, the case studies provide a snapshot of the experiences of mothers and fathers after separation dealing with the contradictions in their gendered roles in the care of children. The thesis sets out to argue that in the legal regulation of the care of children post-separation the issues of parenting are timeless considerations underpinned by gender politics and need to remain within political, legal and public debates.EThOS - Electronic Theses Online ServiceGBUnited Kingdo