913 resultados para Partner


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Osteopontin is a secreted, integrin-binding and phosphorylated acidic glycoprotein, which has an important role in tumour progression. We have shown that Wnt, Ets, AP-1, c-jun and beta-catenin/Lef-1/Tcf-1 stimulates OPN transcription in rat mammary carcinoma cells by binding to a specific promoter sequence. However, co-repressors of OPN have not been identified. In this study, we have used the bacterial two-hybrid system to isolate cDNA-encoding proteins that bind to OPN and modulate its role in malignant transformation. Using this approach we isolated interferon-induced transmembrane protein 3 gene (IFITM3) as a potential protein partner. We show that IFITM3 and OPN interact in vitro and in vivo and that IFITM3 reduces osteopontin (OPN) mRNA expression, possibly by affecting OPN mRNA stability. Stable transfection of IFITM3 inhibits OPN, which mediates anchorage-independent growth, cell adhesion and cell invasion. Northern blot analysis revealed an inverse mRNA expression pattern of IFITM3 and OPN in human mammary cell lines. Inhibition of IFITM3 by antisense RNA promoted OPN protein expression, enhanced cell invasion by parental benign non-invasive Rama 37 cells, indicating that the two proteins interact functionally as well. We also identified an IFITM3 DNA-binding domain, which interacts with OPN, deletion of which abolished its inhibitive effect on OPN. This work has shown for the first time that IFITM3 physically interacts with OPN and reduces OPN mRNA expression, which mediates cell adhesion, cell invasion, colony formation in soft agar and metastasis in a rat model system. Oncogene (2010) 29, 752-762; doi: 10.1038/onc.2009.379; published online 9 November 2009

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There is an increasing demand to develop biosensor monitoring devices capable of biomarker profiling for predicting animal adulteration and detecting multiple chemical contaminants or toxins in food produce. Surface plasmon resonance (SPR) biosensors are label free detection systems that monitor the binding of specific biomolecular recognition elements with binding partners. Essential to this technology are the production of biochips where a selected binding partner, antibody, biomarker protein or low molecular weight contaminant, is immobilised. A micro-fluidic immobilisation device allowing the covalent attachment of up to 16 binding partners in a linear array on a single surface has been developed for compatibility with a prototype multiplex SPR analyser.

The immobilisation unit and multiplex SPR analyser were respectively evaluated in their ability to be fit-for-purpose for binding partner attachment and detection of high and low molecular weight molecules. The multiplexing capability of the dual technology was assessed using phycotoxin concentration analysis as a model system. The parent compounds of four toxin groups were immobilised within a single chip format and calibration curves were achieved. The chip design and SPR technology allowed the compartmentalisation of the binding interactions for each toxin group offering the added benefit of being able to distinguish between toxin families and perform concentration analysis. This model is particularly contemporary with the current drive to replace biological methods for phycotoxin screening.

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Aims To examine the associations between psychological adjustment to Type 2 diabetes and the reported quality and type of relationships with partners. Methods All participants (n = 88) completed a number of questionnaires, including twomeasures of relationship quality: the Dyadic Adjustment Scale and the PersonalAssessment of Intimacy inRelationships Scale, theDiabetesQuality of Life Scale and the ATT-19 (which assesses personal integration of diabetes). Additionally, HbA1c levels were obtained from medical notes. Results Measures of relationship quality significantly contributed to the explanation of two outcomes: personal integration of diabetes and satisfaction with the burden of self-management behaviours. More specifically, the findings demonstrate that a specific aspect of relationship quality—intimacy in recreational activities—is positively associated with the outcomesmentioned above. Conclusions People with Type 2 diabetes who are not taking insulin, who share engagement in physical activities with their partner are more likely to be psychologically well-adjusted to their diagnosis of diabetes.

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Background: The serine/threonine protein kinase B (PKB/Akt) is involved in insulin signaling, cellular survival, and transformation. Carboxyl-terminal modulator protein (CTMP) has been identified as a novel PKB binding partner in a yeast two-hybrid screen, and appears to be a negative PKB regulator with tumor suppressor-like properties. In the present study we investigate novel mechanisms by which CTMP plays a role in apoptosis process.

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Carboxyl-terminal modulator protein (CTMP) is a tumor suppressor-like binding partner of Protein kinase B (PKB/Akt) that negative regulates this kinase. In the course of our recent work, we identified that CTMP is consistently associated with leucine zipper/EF-hand-containing transmembrane-1 (LETM1). Here, we report that adenovirus-LETM1 increased the sensitivity of HeLa cells to apoptosis, induced by either staurosporine or actinomycin D. As shown previously, LETM1 localized to the inner mitochondrial membrane. Electron-microscopy analysis of adenovirus-LETM1 transduced cells revealed that mitochondrial cristae were swollen in these cells, a phenotype similar to that observed in optic atrophy type-1 (OPA1)-ablated cells. OPA1 cleavage was increased in LETM1-overexpressing cells, and this phenotype was reversed by overexpression of OPA1 variant-7, a cleavage resistant form of OPA1. Taken together, these data suggest that LETM1 is a novel binding partner for CTMP that may play an important role in mitochondrial fragmentation via OPA1-cleavage. (C) 2009 Elsevier Inc. All rights reserved

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Objective: to assess the separate contributions of marital status, living arrangements and the presence of children to subsequent admission to a care home.

Design and methods: a longitudinal study derived from the health card registration system and linked to the 2001 Census, comprising 28% of the Northern Ireland population was analysed using Cox regression to assess the likelihood of admission for 51,619 older people in the 6 years following the census. Cohort members’ age, sex, marital and health status and relationship to other household members were analysed.

Results: there were 2,138 care home admissions; a rate of 7.4 admissions per thousand person years. Those living alone had the highest likelihood of admission [hazard ratio (HR) compared with living with partner 1.66 (95% CI 1.48, 1.87)] but there was little difference between the never-married and the previously married. Living with children offered similar protection as living with a partner (HR 0.97; 95% CI 0.81, 1.16). The presence of children reduced admissions especially for married couples (HR 0.67 95% CI 0.54, 0.83; models adjusting for age, gender and health). Women were more likely to be admitted, though there were no gender differences for people living alone or those co-habiting with siblings.

Implications: presence of potential caregivers within the home, rather than those living elsewhere, is a major factor determining admission to care home. Further research should concentrate on the health and needs of these co-residents.

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Background BRCA1 and cyclin D1 are both essential for normal breast development and mutation or aberration of their expression is associated with breast cancer [1,2]. Cyclin D1 is best known as a G1 cyclin where it regulates the G1 to S phase transition by acting as a rate-limiting subunit of CDK4/6 kinase activity. More recently, however, Stacey has demonstrated that cyclin D1 levels in G2/M determine whether a cell continues to proliferate or exits the cell cycle [3]. The majority of BRCA1 in the cell is bound to BARD1 through their N-terminal RING domains. Heterodimerization is essential for the stability and correct localization of the complex and confers ubiquitin ligase activity to BRCA1. The importance of the ligase activity of BRCA1 to breast cancer development is inferred from the fact that N-terminal diseaseassociated mutations are proposed to reduce ligase activity [4]. Methods Protein–protein interactions were demonstrated using yeast-two-hybrid and coimmunoprecipitation. Protein levels were altered through overexpression, siRNA and antisense technology. The effect of proteasome inhibitors and cycloheximide treatment was also examined. Results We initially identified cyclin D1 as a binding partner of BARD1 in a yeast-two-hybrid screen and defined the minimal binding region as the N-terminus of BARD1. This interaction was confirmed in vivo by coimmunoprecipitation. The N-terminus of BARD1 also binds BRCA1 and imparts ubiquitin ligase activity to the complex. Covalent modification of proteins with ubiquitin is a common regulatory mechanism in eukaryotic cells. Traditionally polyubiquitin chains linked through lysine 48 target proteins for degradation by the 26 S proteasome. We have demonstrated that cyclin D1 protein levels are inversely related to BRCA1 and BARD1 levels in several model systems. Furthermore, regulation of cyclin D1 levels occurs through a post-transcriptional mechanism and requires the ligase activity of BRCA1. Interestingly, this phenomenon is cell-cycle regulated, occurring in G2/M. Conclusion We propose that cyclin D1 is a potential substrate for BRCA1 ubiquitination and that this targets cyclin D1 for proteasomal-mediated degradation. Future work will focus on ascertaining the functional consequence of cyclin D1 regulation by the BRCA1–BARD1 complex; in particular, the impact of BRCA1, mediated through regulation of cyclin D1, on the proliferation versus differentiation decision.

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We carried out a yeast two-hybrid screen using a BRCA1 bait composed of amino acids 1 to 1142 and identified BRD7 as a novel binding partner of BRCA1. This interaction was confirmed by coimmunoprecipitation of endogenous BRCA1 and BRD7 in T47D and HEK-293 cells. BRD7 is a bromodomain containing protein, which is a subunit of PBAF-specific Swi/Snf chromatin remodeling complexes. To determine the functional consequences of the BRCA1-BRD7 interaction, we investigated the role of BRD7 in BRCA1-dependent transcription using microarray-based expression profiling. We found that a variety of targets were coordinately regulated by BRCA1 and BRD7, such as estrogen receptor alpha (ERalpha). Depletion of BRD7 or BRCA1 in either T47D or MCF7 cells resulted in loss of expression of ERalpha at both the mRNA and protein level, and this loss of ERalpha was reflected in resistance to the antiestrogen drug fulvestrant. We show that BRD7 is present, along with BRCA1 and Oct-1, on the ESR1 promoter (the gene which encodes ERalpha). Depletion of BRD7 prevented the recruitment of BRCA1 and Oct-1 to the ESR1 promoter; however, it had no effect on the recruitment of the other Swi/Snf subunits BRG1, BAF155, and BAF57 or on RNA polymerase II recruitment. These results support a model whereby the regulation of ERalpha transcription by BRD7 is mediated by its recruitment of BRCA1 and Oct-1 to the ESR1 promoter.

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The paper focuses on the ways in which medical discourses of HIV transmission risk, personal bodily meanings and reproductive decision-making are re-negotiated within the context of sero-different relationships, in which one partner is known to be HIV-positive. Eighteen in-depth interviews were conducted with 10 individuals in Northern Ireland during 2008–2009. Drawing on an embodied sociological approach, the findings show that physical pleasure, love, commitment, a desire to conceive without medical interventions and a dislike of condoms within regular ongoing relationships, shaped individuals' sense of biological risk. In addition, the subjective logic that a partner had not previously become infected through unprotected sex prior to knowledge of HIV status and the added security of an undetectable viral load significantly impacted upon women's and, especially, men's decisions to have unprotected sex in order to conceive. The findings speak to the importance of reframing public health campaigns and clinical counselling discourses on HIV risk transmission to acknowledge how couples negotiate this risk, alongside pleasure and commitment within ongoing relationships.

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Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkyl-acetylenes (with Ph3SnH and Et3B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate the great utility of this process in a complex natural product total synthesis setting for the very first time. We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Overman's pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of preparative HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original synthesis of 9.

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Females are often thought to use several cues and more than one modality in selection of a mate, possibly because they offer complementary information on a mate's suitability. In the red mason bee, Osmia rufa, we investigated the criteria a female uses to choose a mating partner. We hypothesized that the female uses male thorax vibrations and size as signs of male viability and male odor for kin discrimination and assessment of genetic relatedness. We therefore compared males that had been accepted by a female for copulation with those rejected, in terms of their size, their immediate precopulatory vibrations (using laser vibrometry), the genetic relatedness of unmated and mated pairs (using microsatellite markers) and emitted volatiles (using chemical analyses). Females showed a preference for intermediate-sized males that were slightly larger than the modal male size. Furthermore, male precopulatory vibration burst duration was significantly longer in males accepted for copulation compared with rejected males. Vibrations may indicate vigor and assure that males selected by females are metabolically active and healthy. Females preferentially copulated with males that were genetically more closely related, possibly to avoid outbreeding depression. Volatiles of the cuticular surface differed significantly between accepted and rejected males in the relative amounts of certain hydrocarbons, although the relationship between male odor and female preference was complex. Females may therefore also use differences in odor bouquet to select among males. Our investigations show that O. rufa females appear to use multiple cues in selecting a male. Future investigations are needed to demonstrate whether odor plays a role in kin recognition and how the multiple cues are integrated in mate choice by females.

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The IQGAP [IQ-motif-containing GAP (GTPase-activating protein)] family members are eukaryotic proteins that act at the interface between cellular signalling and the cytoskeleton. As such they collect numerous inputs from a variety of signalling pathways. A key binding partner is the calcium-sensing protein CaM (calmodulin). This protein binds mainly through a series of IQ-motifs which are located towards the middle of the primary sequence of the IQGAPs. In some IQGAPs, these motifs also provide binding sites for CaM-like proteins such as myosin essential light chain and S100B. Using synthetic peptides and native gel electrophoresis, the binding properties of the IQ-motifs from human IQGAP2 and IQGAP3 have been mapped. The second and third IQ-motifs in IQGAP2 and all four of the IQ-motifs of IQGAP3 interacted with CaM in the presence of calcium ions. However, there were differences in the type of interaction: while some IQ-motifs were able to form complexes with CaM which were stable under the conditions of the experiment, others formed more transient interactions. The first IQ-motifs from IQGAP2 and IQGAP3 formed transient interactions with CaM in the absence of calcium and the first motif from IQGAP3 formed a transient interaction with the myosin essential light chain MIc1sa. None of these IQ-motifs interacted with S100B. Molecular modelling suggested that all of the IQ-motifs, except the first one from IQGAP2 formed alpha-helices in solution. These results extend our knowledge of the selectivity of IQ-motifs for CaM and related proteins.

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This article examines the work and roles of HR managers in the Irish recession. It tests the validity of three competing views about the future of HR: that the profession needs to become a business partner; that it is knee-deep in a legitimacy crisis; and that it is fragmenting by being unable to cope with the complexity of modern organizational life. Three key findings emerge from the research. First, HR managers have gained greater influence in business decision-making, but much of this influence arises from short-run retrenchment measures. Second, many HR managers remain committed to long established professional values and ideas of good practice. Third, modern HR managers are developing a professional identity that allows them to perform multiple, competing roles. These findings challenge existing arguments about the effects of the current recession. They also speak to ongoing debates about changing HR roles by showing how HR managers remain adept at making pragmatic adaptations to secure their role in organizational life. © The Author(s) 2012.

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Peroxiredoxins are ubiquitous proteins that catalyze the reduction of hydroperoxides, thus conferring resistance to oxidative stress. Using high-resolution mass spectrometry, we recently reclassified one such peroxiredoxin, bacterioferritin comigratory protein (BCP) of Escherichia coli, as an atypical 2-Cys peroxiredoxin that functions through the formation of an intramolecular disulfide bond between the active and resolving cysteine. An engineered E. coli BCP, which lacked the resolving cysteine, retained enzyme activity through a novel catalytic pathway. Unlike the active cysteine, the resolving cysteine of BCP peroxiredoxins is not conserved across all members of the family. To clarify the catalytic mechanism of native BCP enzymes that lack the resolving cysteine, we have investigated the BCP homologue of Burkholderia cenocepacia. We demonstrate that the B. cenocepacia BCP (BcBCP) homologue functions through a 1-Cys catalytic pathway. During catalysis, BcBCP can utilize thioredoxin as a reductant for the sulfenic acid intermediate. However, significantly higher peroxidase activity is observed utilizing glutathione as a resolving cysteine and glutaredoxin as a redox partner. Introduction of a resolving cysteine into BcBCP changes the activity from a 1-Cys pathway to an atypical 2-Cys pathway, analogous to the E. coli enzyme. In contrast to the native B. cenocepacia enzyme, thioredoxin is the preferred redox partner for this atypical 2-Cys variant. BCP-deficient B. cenocepacia exhibit a growth-phase-dependent hypersensitivity to oxidative killing. On the basis of sequence alignments, we believe that BcBCP described herein is representative of the major class of bacterial BCP peroxiredoxins. To our knowledge, this is the first detailed characterization of their catalytic activity. These studies support the subdivision of the BCP family of peroxiredoxins into two classes based on their catalytic activity.

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A vibrant inner city parish needed space for meetings, language classes, children’s play and other support accommodation as well as a clearer link between the interior of the listed church and the space outside.

The project builds itself about the entrance to the church. The form is manipulated such that the intervention recedes from those entering the church, drawing them into the plan before becoming readable as an addition. The resultant poché between this entrance sequence and the fabric of the church is hollowed out to provide the required accommodation. These rooms are insulated and lined in cork to allow for their use separate to the main body of the church. With budget at a premium the construction methodology was developed from an analysis of traditional Irish boat building techniques, which allowed the use of the solid timber to act as the primary structure with no additional material support.

Constructed in solid walnut the intervention reads with the existing brick interior and yet is clearly identifiable as a contemporary addition.

Aims / Objectives Questions

1 To accommodate new space inside an existing protected structure.
2 To form a new threshold between interior and exterior.
3 To develop an affordable means of construction that would be durable and rapid to erect.
4 To make a contemporary addition in sympathy with the qualities of the existing protect structure, in line with best conservation practice and research.
5 Traditional forms of construction as a model for contemporary technologies.


Principal Investigator: Clancy Moore Architects –Colm Moore

Co-investigator(s): Andrew Clancy, Mathew O’Malley

Funding partner/ Client: Select Vestry of St George and St Thomas

Finance. €35’000

Date (start – finished) Start June 2008 – Completed December 2008