rRNA complementarity within mRNAs: A possible basis for mRNA-ribosome interactions and translational control

Our recent demonstration that many eukaryotic mRNAs contain sequences complementary to rRNA led to the hypothesis that these sequences might mediate specific interactions between mRNAs and ribosomes and thereby affect translation. In the present experiments, the ability of complementary sequences to bind to rRNA was investigated by using photochemical cross-linking. RNA probes with perfect complementarity to 18S or 28S rRNA were shown to cross-link specifically to the corresponding rRNA within intact ribosomal subunits. Similar results were obtained by using probes based on natural mRNA sequences with varying degrees of complementarity to the 18S rRNA. RNase H cleavage localized four such probes to complementary regions of the 18S rRNA. The effects of complementarity on translation were assessed by using the mRNA encoding ribosomal protein S15. This mRNA contains a sequence within its coding region that is complementary to the 18S rRNA at 20 of 22 nucleotides. RNA from an S15-luciferase fusion construct was translated in a cell-free lysate and compared with the translation of four related constructs that were mutated to decrease complementarity to the 18S rRNA. These mutations did not alter the amino acid sequence or the codon bias. A correlation between complementarity and translation was observed; constructs with less complementarity increased the amount of translation up to 54%. These findings raised the possibility that direct base-pairing of particular mRNAs to rRNAs within ribosomes may function as a mechanism of translational control.

Parkinson disease: A new link between monoamine oxidase and mitochondrial electron flow

Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO). Here we show that the two are linked. Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport. MAO inhibitors prevent this action. Mitochondrial damage is also reversed during electron flow. A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function. In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport. In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria. These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover. The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.

Why are patients prescribed proton pump inhibitors? Retrospective analysis of link between morbidity and prescribing in the General Practice Research Database

Objectives: To establish the relation between new prescriptions for proton pump inhibitors and recorded upper gastrointestinal morbidity within a large computerised general practitioner database.

GIPC and GAIP Form a Complex with TrkA: A Putative Link between G Protein and Receptor Tyrosine Kinase Pathways

NGF initiates the majority of its neurotrophic effects by promoting the activation of the tyrosine kinase receptor TrkA. Here we describe a novel interaction between TrkA and GIPC, a PDZ domain protein. GIPC binds to the juxtamembrane region of TrkA through its PDZ domain. The PDZ domain of GIPC also interacts with GAIP, an RGS (regulators of G protein signaling) protein. GIPC and GAIP are components of a G protein-coupled signaling complex thought to be involved in vesicular trafficking. In transfected HEK 293T cells GIPC, GAIP, and TrkA form a coprecipitable protein complex. Both TrkA and GAIP bind to the PDZ domain of GIPC, but their binding sites within the PDZ domain are different. The association of endogenous GIPC with the TrkA receptor was confirmed by coimmunoprecipitation in PC12 (615) cells stably expressing TrkA. By immunofluorescence GIPC colocalizes with phosphorylated TrkA receptors in retrograde transport vesicles located in the neurites and cell bodies of differentiated PC12 (615) cells. These results suggest that GIPC, like other PDZ domain proteins, serves to cluster transmembrane receptors with signaling molecules. When GIPC is overexpressed in PC12 (615) cells, NGF-induced phosphorylation of mitogen-activated protein (MAP) kinase (Erk1/2) decreases; however, there is no effect on phosphorylation of Akt, phospholipase C-γ1, or Shc. The association of TrkA receptors with GIPC and GAIP plus the inhibition of MAP kinase by GIPC suggests that GIPC may provide a link between TrkA and G protein signaling pathways.

Cancer-predisposing mutations within the RING domain of BRCA1: Loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity

BRCA1 is a breast and ovarian cancer-specific tumor suppressor that seems to be involved in transcription and DNA repair. Here we report that BRCA1 exhibits a bona fide ubiquitin (Ub) protein ligase (E3) activity, and that cancer-predisposing mutations within the BRCA1 RING domain abolish its Ub ligase activity. Furthermore, these mutants are unable to reverse γ-radiation hypersensitivity of BRCA1-null human breast cancer cells, HCC1937. Additionally, these mutations within the BRCA1 RING domain are not capable of restoring a G2 + M checkpoint in HCC1937 cells. These results establish a link between Ub protein ligase activity and γ-radiation protection function of BRCA1, and provide an explanation for why mutations within the BRCA1 RING domain predispose to cancer. Furthermore, we propose that the analysis of the Ub ligase activity of RING-domain mutations identified in patients may constitute an assay to predict predisposition to cancer.

The Experience of Minority Female Coaches within Intercollegiate Athletics

It has been suggested that the United States has shown an increase of acceptance and positive attitudes toward diverse cultures and populations. However, there continues to be a drought in research that examines the experience of minority women. In addition, few studies have focused on minority female coaches within athletic environments, which have been known to be both heterosexist and homonegative (Griffin, 1992; Griffin, 1998; Krane, 1996; Krane & Barber, 2003; Krane & Barber, 2005; Roper & Halloran, 2007; Schreibstein, 2010). A person who holds a minority identity has been defined by this paper as belonging to an underrepresented group, including: race, ethnicity, gender, disability, age, religion, and/or sexual orientation. This study, in particular, focused on three specific minority groups: race, gender, and sexual orientation. The proposed study assessed the experiences, challenges, and strategies to overcome obstacles of female coaches who hold minority statuses within National Collegiate Athletic Association (NCAA) athletic departments.

Predicting Children’s Early School Outcomes from their Social-Regulatory Profiles: A Person-Centered Approach

Thesis (Ph.D.)--University of Washington, 2016-06

40Ar/39Ar constraints on a temporal link between gold mineralization, magmatism, and continental margin transtension in the Jiaodong Gold Province, eastern China

The Jiaodong gold province is the largest gold repository in China. Both mineralization and granitoid hosts are spatially related to the crustal-scale Tan-Lu strike-slip fault system, which developed along the Mesozoic continental margin in eastern China. A series of Ar-40/Ar-39 laser incremental heating analyses of hydrothermal sericite/muscovite from three major gold deposits (Jiaojia, Xincheng, and Wangershan) and igneous biotite from the granodiorite hosts were performed to establish a possible temporal link between gold mineralization, magmatism, and movement along the Tan-Lu fault zone. Magmatic biotite crystals yield well-defined and concordant plateau ages between 124.5+/-0.4 Ma and 124.0+/-0.4 Ma (2sigma), whereas sericite and muscovite samples (a total of 30 single separates) give reproducible plateau ages ranging from 121.0+/-0.4 Ma to 119.2+/-0.2 Ma (2sigma). An integration of our Ar-40/Ar-39 results with age data from other major gold deposits in Jiaodong demonstrates that widespread gold mineralization occurred contemporaneously during a 2-3-m.yr. period. Most gold deposits show intimate spatial associations with abundant mafic to intermediate dikes. The mafic dikes have K-Ar ages of 123.5-119.6 Ma, in excellent agreement with those of the gold deposits. These newly obtained Ar-40/Ar-39 ages, in combination with other independent geological and geochronological data on granodioritic intrusions (130-126 Ma), volcanic rocks (1243.6-114.7 Ma), and deformed rocks within strike-slip faults (132-120 Ma) in Jiaodong or adjacent areas, also support the idea that gold mineralization postdated the granodioritic magmatism but was contemporaneous with mafic magmatism and volcanism, all controlled by the transtensional motion along the Tan-Lu fault in the Early Cretaceous.

Columnar cell lesions of the breast: The missing link in breast cancer progression? A morphological and molecular analysis

Columnar cell lesions (CCLs) of the breast are a spectrum of lesions that have posed difficulties to pathologists for many years, prompting discussion concerning their biologic and clinical significance. We present a study of CCL in context with hyperplasia of usual type (HUT) and the more advanced lesions ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. A total of 81 lesions from 18 patients were subjected to a comprehensive morphologic review based upon a modified version of Schnitt's classification system for CCL, immunophenotypic analysis (estrogen receptor [ER], progesterone receptor [PgR], Her2/neu, cytokeratin 5/6 [CK5/6], cytokeratin 14 [CK14], E-cadherin, p53) and for the first time, a whole genome molecular analysis by comparative genomic hybridization. Multiple CCLs from 3 patients were studied in particular detail, with topographic information and/or showing a morphologic spectrum of CCL within individual terminal duct lobular units. CCLs were ER an PgR positive, CK5/6 and CK14 negative, exhibit low numbers of genetic alterations and recurrent 16q loss, features that are similar to those of low grade in situ and invasive carcinoma. The molecular genetic profiles closely reflect the degree of proliferation and atypia in CCL, indicating some of these lesions represent both a morphologic and molecular continuum. In addition, overlapping chromosomal alterations between CCL and more advanced lesions within individual terminal duct lobular units suggest a commonality in molecular evolution. These data further support the hypothesis that CCLs are a nonobligate, intermediary step in the development of some forms of low grade in situ and invasive carcinoma. Copyright: © 2005 Lippincott Williams & Wilkins, Inc.

Modelling Apoptotic cell clearance within the atherosclerotic plaque

The aged population have an increased susceptibility to infection, therefore function of the innate immune system may be impaired as we age. Macrophages, and their precursors monocytes, play an important role in host defence in the form of phagocytosis, and also link the innate and adaptive immune system via antigen presentation. Classically-activated 'M1' macrophages are pro-inflammatory, which can be induced by encountering pathogenic material or pro-inflammatory mediators. Alternatively activated 'M2' macrophages have a largely reparative role, including clearance of apoptotic bodies and debris from tissues. Despite some innate immune receptors being implicated in the clearance of apoptotic cells, the process has been observed to have a dominant anti-inflammatory phenotype with cytokines such as IL-10 and TGF-ß being implicated. The atherosclerotic plaque contains recruited monocytes and macrophages, and is a highly inflammatory environment despite high levels of apoptosis. At these sites, monocytes differentiate into macrophages and gorge on lipoproteins, resulting in formation of 'foam cells' which then undergo apoptosis, recruiting further monocytes. This project seeks to understand why, given high levels of apoptosis, the plaque is a pro-inflammatory environment. This phenomenon may be the result of the aged environment or an inability of foam cells to elicit an anti-inflammatory effect in response to dying cells. Here we demonstrate that lipoprotein treatment of macrophages in culture results in reduced capacity to clear apoptotic cells. The effect of lipoprotein treatment on apoptotic cell-mediated immune modulation of macrophage function is currently under study.

The evolution of "classical mythology" within marketing measure development

Purpose - This paper provides a deeper examination of the fundamentals of commonly-used techniques - such as coefficient alpha and factor analysis - in order to more strongly link the techniques used by marketing and social researchers to their underlying psychometric and statistical rationale. Design/methodology approach - A wide-ranging review and synthesis of psychometric and other measurement literature both within and outside the marketing field is used to illuminate and reconsider a number of misconceptions which seem to have evolved in marketing research. Findings - The research finds that marketing scholars have generally concentrated on reporting what are essentially arbitrary figures such as coefficient alpha, without fully understanding what these figures imply. It is argued that, if the link between theory and technique is not clearly understood, use of psychometric measure development tools actually runs the risk of detracting from the validity of the measures rather than enhancing it. Research limitations/implications - The focus on one stage of a particular form of measure development could be seen as rather specialised. The paper also runs the risk of increasing the amount of dogma surrounding measurement, which runs contrary to the spirit of this paper. Practical implications - This paper shows that researchers may need to spend more time interpreting measurement results. Rather than simply referring to precedence, one needs to understand the link between measurement theory and actual technique. Originality/value - This paper presents psychometric measurement and item analysis theory in easily understandable format, and offers an important set of conceptual tools for researchers in many fields. © Emerald Group Publishing Limited.

Export memory: a preliminary investigation of its quality, its use, and its link to export performance

Exporting is one of the main ways in which organizations internationalize. With the more turbulent, heterogeneous, sophisticated and less familiar export environment, the organizational learning ability of the exporting organization may become its only source of sustainable competitive advantage. However, achieving a competitive level of learning is not easy. Companies must be able to find ways to improve their learning capability by enhancing the different aspects of the learning process. One of these is export memory. Building from an export information processing framework this research work particularly focuses on the quality of export memory, its determinants, its subsequent use in decision-making, and its ultimate relationship with export performance. Within export memory use, four export memory use dimensions have been discovered: instrumental, conceptual, legitimizing and manipulating. Results from the qualitative study based on the data from a mail survey with 354 responses reveal that the development of export memory quality is positively related with quality of export information acquisition, the quality of export information interpretation, export coordination, and integration of the information into the organizational system. Several company and environmental factors have also been examined in terms of their relationship with export memory use. The two factors found to be significantly related to the extent of export memory use are acquisition of export information quality and export memory quality. The results reveal that export memory quality is positively related to the extent of export memory use which in turn was found to be positively related to export performance. Furthermore, results of the study show that there is only one aspect of export memory use that significantly affects export performance – the extent of export memory use. This finding could mean that there is no particular type of export memory use favored since the choice of the type of use is situation specific. Additional results reveal that environmental turbulence and export memory overload have moderating effects on the relationship between export memory use and export performance.

A prediction of outcomes: a psychological investigation into cognitive and affective development within the framework of adult literacy provision

This investigation seeks to explore the hypothesis, derived from observation and practice, that there is a strong relationship between the development of literacy skills and the growth of confidence in adult literacy students. Implicit in the developmental approach is the notion of progression towards some cognitive goal. Such a goal necessitates the establishment of a base line of existing attainment, together with subsequent assessment so that progress and development can be measured. The study includes an evaluation of existing formal and informal methods of initial and subsequent assessment and diagnosis available at the time for Adult Literacy Scheme Co-ordinators. Underlying the funding by Cheshire County Council for the project is the assumption that the results will be available for all practitioners and that the tools of measurement may be used by other Adult Literacy Co-ordinators in the County. It is intended, therefore, that this research should result in practical outcomes in which methods of assessment will involve active participation by students as well as by tutors, becoming part of the learning process. It is hypothesised that this kind of co-operation could lead ultimately to self-directed learning and student-independence. For the purposes of this research, a balance is attempted in the use of assessment tools, between standardised tests and informal methods. The study provides facts about students! reading habits; as well as their reading levels, their spelling levels, their handwriting, their writing skills and their writing habits. The study seeks to show the students' feelings towards education, their educational attainments and the type of school which they attended. The study also attempts to come to some measurement of those aspects of student personality which relate to confidence, by means of tests and questionnaires. The study concludes with an examination of the link between cognitive and affective progress.

Pharmacy and public health: examining the link between strategy and practice

Despite having been described by the then (2003) Chief Pharmaceutical Officer for England as ·probably the biggest untapped resource for health improvement", the development of the public health function of community pharmacists has been limited. However, devolution of healthcare budgets has led 10 differential rates of development of the public health function in each administration of the UK (England, Scotland, Wales and Northern Ireland). This is measured and reflected upon in this thesis. Two large-scale surveys were conducted, one of key strategic personnel (Directors of Public Health and Chief Pharmacists) in Primary Care Organisations (PCOs) and one of practicing community pharmacists. This research highlights the fact that community pharmacists have developed an individualistic, service-based approach to their engagement with public health that is contrary to the more collective approach adopted by the wider public health movement. The study measures the scope and level of health-improving services through community pharmacy across the UK and shows that the nature of the pharmacy contractor (independent, multiple etc.) may impact on the range and nature of services provided. Survey data also suggest that attitudes towards pharmacy involvement in the public health agenda vary markedly between Directors of Public Health, PCO Chief Pharmacists, and community pharmacists. Furthermore, within the community pharmacist population, attitudes are affected by a wide range of factors including the nature of employment (owner, employee, self-employed) and the type of employing pharmacy (independent, multiple etc.). Implications for policy and areas for further research aimed at maximising the public health function of community pharmacists are suggested.

Institutional work at field-configuring events:shaping industry change within sustainable transitions

Adopting an institutional approach from organization studies, this paper explores the role of key actors on “purposeful governance for sustainability” (Smith, Voss et al. 2010: 444) through the case of smart metering in the UK. Institutions are enduring patterns in social life, reflected in identities, routines, rules, shared meanings and social relations, which enable, and constrain, the beliefs and behaviours of individual and collective actors within a field (Thornton and Ocasio 2008). Large-scale external initiatives designed to drive regime-level change prompt ‘institutional entrepreneurs’ to perform ‘institutional work’ – “purposive action aimed at creating, maintaining and disrupting institutions” (Lawrence and Suddaby, 2006). Organization scholars are giving increasing attention to ‘field-configuring events’ (FCEs) which provide social spaces for diverse organizational actors to come together to collectively shape socio-technical pathways (Lampel and Meyer 2008). Our starting point for this exploratory study is that FCEs can offer important insights to the dynamics, politics and governance of sustainability transitions. Methodologically, FCEs allow us to observe and “link field evolution at the macro-level with individual action at the micro-level” (Lampel and Meyer, 2008: 1025). We examine the work of actors during a series of smart metering industry forums over a three-year period (industry presentations [n= 77] and panel discussions [n= 16]). The findings reveal new insights about how institutional change unfolds, alongside technological transitions, in ways that are partial and aligned with the interests of powerful incumbents whose voices are frequently heard at FCEs. The paper offers three contributions. First, the study responds to calls for more research examining FCEs and the role they play in transforming institutional fields. Second, the emergent findings extend research on institutional work by advancing our understanding of a specific site of institutional work, namely a face-to-face inter-organizational arena. Finally, in line with the research agenda for innovation studies and sustainability transitions elaborated by Smith et al (2010), the paper illustrates how actors in a social system respond to, translate, and enact interventions designed to promote industrial transformation, ultimately shaping the sustainability transition pathway.