Discovery of novel Agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening

The G-protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on two-dimensional (2D) similarity, three-dimensional (3D) pharmacophore searches, and docking studies by using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions and provided important information on the role of specific amino acids in binding and activation of FFAR1.

Isolation and culture of mouse intestinal cells.

Complex cell signal transduction mechanisms regulate intestinal epithelial shape, polarity, motility, organelles, cell membrane components as well as physical and mechanical properties to influence alimentary digestion, absorption, secretion, detoxification and fluid balance. Interactions between the epithelial cells and adjacent mesenchyme are central to intestinal homeostasis although the key regulatory molecules of specific differentiation steps remain unclear. Isolation and primary culture of heterotypic murine intestinal cells provides a model system for elucidation of essential molecular cross-talk between epithelium and mesenchyme that may provide several biological and practical advantages over transformed cell lines. An in vitro primary culture system for neonatal rat or mouse intestinal cells has been established that forms monolayers, expresses intestine-specific epithelial features including intestinal brush borders and appropriate hydrolase enzymes. Our studies confirm the promise of this method which may advance our understanding of heterotypic cellular interactions implicated in intestinal function and may provide important insights into the pathobiology of disease.

Mutation altering the miR-184 seed region causes keratoconus with cataract

MicroRNAs (miRNAs) bind to complementary sequences within the 3? untranslated region (UTR) of mRNAs from hundreds of target genes, leading either to mRNA degradation or suppression of translation. We found that a mutation in the seed region of miR-184 (MIR184) is responsible for familial severe keratoconus combined with early-onset anterior polar cataract, by deep sequencing of a linkage region known to contain the mutation. The mutant form fails to compete with miR-205 (MIR205) for overlapping target sites on the 3? UTRs of INPPL1 and ITGB4. Although these target genes and miR-205 are expressed widely, the phenotype is restricted to the cornea and lens because of the very high expression of miR-184 in these tissues. Our finding highlights the tissue-specificity of a gene network regulated by a miRNA. Awareness of the important function of miRNAs may aid identification of susceptibility genes and new therapeutic targets for treatment of both rare and common diseases.

The effect of increasing dietary fibre and the provision of straw racks on the welfare of sows housed in small static groups

This study assessed the effects of increasing dietary fibre levels in concentrate rations and providing access to straw in racks on the welfare of pregnant sows housed in small static groups. In a 2 x 2 factorial design experiment, 128 Large White x Landrace pregnant sows were offered one of two diets: (i) High fibre diet with 9% crude fibre, or (ii) Control diet with 4.5% CF, and one of two levels of access to a foraging substrate: (i) access to straw in racks or (ii) no straw. The study was replicated eight times using groups of four sows, and treatment periods lasted four weeks. Sows were housed in pens with voluntary cubicles and a slatted exercise area and were offered a wet diet twice a day. Back-fat levels were measured before sows were mixed into groups at 28 days post partum, and four weeks later. Aggressive interactions were recorded on the day of mixing, and injury scores were recorded one week post mixing. Scan sampling was used to collect data on general activity, posture and location of the sows, and on sham-chewing and bar-biting behaviours across the treatment period. In addition, detailed focal observations were carried out on all sows across the treatment period. Straw usage was also recorded. There were no treatment effects on changes in back-fat levels over the treatment period. Treatments had no effect on post-mixing aggression or on injury scores. However, focal observations showed that sows with access to straw were involved in fewer bouts of head-thrusting over the treatment period. Control diet sows spent more time inactive than sows on the high fibre diet, however high fibre diet sows spent more time lying with eyes closed than sows on the control diet. Sows on the high fibre diet with access to straw showed less sham-chewing and bar-biting behaviour than sows in other treatments. These results show that although a diet containing 9% crude fibre promoted resting behaviour, it was necessary to combine it with access to straw to reduce stereotypic behaviour of sows in small static groups.

Design of a thick-walled screen for flow equalization in microstructured reactors

A systematic computational fluid dynamics (CFD) approach has been applied to design the geometry of the channels of a three-dimensional (thick-walled) screen comprising upstream and downstream sets of elongated channels positioned at an angle of 90 degrees with respect to each other. Such a geometry of the thick-wall screen can effectively drop the ratio of the maximum flow velocity to mean flow velocity below 1.005 in a downstream microstructured reactor at low Reynolds numbers. In this approach the problem of flow equalization reduces to that of flow equalization in the first and second downstream channels of the thick-walled screen. In turn, this requires flow equalization in the corresponding cross-sections of the upstream channels. The validity of the proposed design method was assessed through a case study. The effect of different design parameters on the flow non-uniformity in the downstream channels has been established. The design equation is proposed to calculate the optimum values of the screen parameters. The CFD results on flow distribution were experimentally validated by Laser Doppler Anemometry measurements in the range of Reynolds numbers from 6 to 113. The measured flow non-uniformity in the separate reactor channels was below 2%.

Evolution of Organisational Structure and Capabilities in Internationalising Banks: The CEE Operations of UniCredit's Vienna Office

Cross-border integration is the central management issue for banks that expand internationally, and this is especially true in Central and Eastern Europe, where the pace of internationalisation through mergers and acquisitions has been rapid. A critical challenge in cross-border integration is aligning a multinational company's formal organizational structure with the distribution of capabilities across its subsidiary units, and this issue is explored by tracking the co-evolution of organizational structure and capabilities during the internationalisation of a large banking network into this region. Our focus is the Vienna head office of Bank Austria Creditanstalt, which was acquired first by HypoVereinsbank (Germany) and then UniCredit (Italy). Despite its formal role being downgraded during these changes, the unit continued to develop its distinctive capabilities. The key insight our article offers is that managing cross-border integration is not simply about recognizing the value of the distinctive capabilities of individual units and designing formal structures that successfully align with them. It is also about understanding the need for dynamic interaction between formal corporate structure and individual units' desires to retain power and influence, which have significant implications for the development of their organizational capabilities.

Dangerously empty? Hegemony and the construction of the Irish entrepreneur

In this article we build on Jones and Spicer's (2009) conceptualization of the entrepreneur as an empty signifier. We explore the function of the signifier 'entrepreneurship' within a social context marked by crisis: Ireland 2007-2010. In doing so, we show how its articulation by government acted to legitimize the continuation of market logics and, relatedly, the existing political status quo. Theoretically, we demonstrate the usefulness of Laclau and Mouffe's conception of hegemony, which shares a Lacanian legacy with Jones and Spicer. This helps us to understand the contradictory nature of the signifier of the entrepreneur in Irish political and social discourse, along with its relationship to the reproduction of political hegemony.

Purification of measles virus with preservation of infectivity and antigenicity

Measles virus Edmonston strain was purified by ultrafiltration followed by two successive sedimentations through sucrose. Purified virus retained infectivity and, when used as an immunogen, elicited high titred antibody to measles antigens by conventional serology. The measles preparations were examined by SDS-PAGE followed by staining. In addition, following PAGE, the purity of these preparations was assessed immunochemically using antisera directed to measles and host cell antigens. The results of these studies demonstrate the utility of the purification method for the preparation of milligram quantities of relatively pure measles virus.

The solution structure of 1:2 phenol/N-methylpyridinium bis{(trifluoromethyl)sulfonyl}imide liquid mixtures

Neutron diffraction has been used to investigate the liquid structure of a 1:2 solution of phenol in the ionic liquid N-methylpyridinium bis{(trifluoromethyl)sulfonyl}imide at 60 ◦C, using the empirical potential structure refinement (EPSR) process to model the data obtained from the SANDALS diffractometer at ISIS. Addition of phenol results in suppression of the melting point of the pyridinium salt and formation of a room temperature solution with aromatic phenol–cation and phenol-OH to anion hydrogen-bonding interactions.

Article 23: Equality between women and men

This analysis of Article 23 CFREU (Charter of Fundamental Rights for the European Union) argues that this provision can promote a more progressive understanding of gender equality then promoted by the European Court of Justice, in that it requires actual change in gender relations. It also finds shortcomings in that the EU conceptualises gender equality by relating women to men, thus falling short of providing a basis for women's rights.

Does vicarious traumatisation affect oncology nurses?:A literature review

It is widely documented that nurses experience work-related stress [Quine, L., 1998. Effects of stress in an NHS trust: a study. Nursing Standard 13 (3), 36-41; Charnley, E., 1999. Occupational stress in the newly qualified staff nurse. Nursing Standard 13 (29), 32-37; McGrath, A., Reid, N., Boore, J., 2003. Occupational stress in nursing. International Journal of Nursing Studies 40, 555-565; McVicar, A., 2003. Workplace stress in nursing: a literature review. Journal of Advanced Nursing 44 (6), 633-642; Bruneau, B., Ellison, G., 2004. Palliative care stress in a UK community hospital: evaluation of a stress-reduction programme. International Journal of Palliative Nursing 10 (6), 296-304; Jenkins, R., Elliott, P., 2004. Stressors, burnout and social support: nurses in acute mental health settings. Journal of Advanced Nursing 48 (6), 622-631], with cancer nursing being identified as a particularly stressful occupation [Hinds, P.S., Sanders, C.B., Srivastava, D.K., Hickey, S., Jayawardene, D., Milligan, M., Olsen, M.S., Puckett, P., Quargnenti, A., Randall, E.A., Tyc, V., 1998. Testing the stress-response sequence model in paediatric oncology nursing. Journal of Advanced Nursing 28 (5), 1146-1157; Barnard, D., Street, A., Love, A.W., 2006. Relationships between stressors, work supports and burnout among cancer nurses. Cancer Nursing 29 (4), 338-345]. Terminologies used to capture this stress are burnout [Pines, A.M., and Aronson, E., 1988. Career Burnout: Causes and Cures. Free Press, New York], compassion stress [Figley, C.R., 1995. Compassion Fatigue. Brunner/Mazel, New York], emotional contagion [Miller, K.I., Stiff, J.B., Ellis, B.H., 1988. Communication and empathy as precursors to burnout among human service workers. Communication Monographs 55 (9), 336-341] or simply the cost of caring (Figley, 1995). However, in the mental health field such as psychology and counselling, there is terminology used to captivate this impact, vicarious traumatisation. Vicarious traumatisation is a process through which the therapist's inner experience is negatively transformed through empathic engagement with client's traumatic material [Pearlman, L.A., Saakvitne, K.W., 1995a. Treating therapists with vicarious traumatization and secondary traumatic stress disorders. In: Figley, C.R. (Ed.), Compassion Fatigue: Coping with Secondary Traumatic Stress Disorder in Those Who Treat the Traumatized. Brunner/Mazel, New York, pp. 150-177]. Trauma not only affects individuals who are primarily present, but also those with whom they discuss their experience. If an individual has been traumatised as a result of a cancer diagnosis and shares this impact with oncology nurses, there could be a risk of vicarious traumatisation in this population. However, although Thompson [2003. Vicarious traumatisation: do we adequately support traumatised staff? The Journal of Cognitive Rehabilitation 24-25] suggests that vicarious traumatisation is a broad term used for workers from any profession, it has not yet been empirically determined if oncology nurses experience vicarious traumatisation. This purpose of this paper is to introduce the concept of vicarious traumatisation and argue that it should be explored in oncology nursing. The review will highlight that empirical research in vicarious traumatisation is largely limited to the mental health professions, with a strong recommendation for the need to empirically determine whether this concept exists in oncology nursing.

Epidermal growth factor receptor (EGFR), HER2 and insulin-like growth factor-1 receptor (IGF-1R) status in ovarian adult granulosa cell tumours

AIMS: Adult granulosa cell tumours (AGCTs) are uncommon ovarian sex cord-stromal tumours which recur following surgical removal in up to 50% of patients. Treatment options for recurrent and advanced stage AGCTs are limited, with poor response to chemotherapy and radiotherapy. We aimed to assess epidermal growth factor receptor (EGFR), HER2 and insulin-like growth factor-1 receptor (IGF-1R) status in AGCTs with a view to investigating whether or not these receptors might be potential therapeutic targets in these neoplasms.

METHODS AND RESULTS: Immunohistochemical staining for EGFR, HER2 and IGF-1R was undertaken in 31 AGCTs. Tumour DNA was also analysed for mutations in the tyrosine kinase domain of EGFR (exons 18-21) by Cobas mutation RT-PCR. Twenty-three of 31 (74%) AGCTs showed some degree of EGFR expression, generally with cytoplasmic or mixed membranous and cytoplasmic staining of variable intensity. Eleven of 27 (41%) cases exhibited strong membranous and cytoplasmic expression of IGF-1R. HER2 expression was not seen. No mutations were found in exons 18-21 of the EGFR gene in hot-spots of therapeutic relevance.

CONCLUSIONS: This study raises the possibility that anti-EGFR and/or anti-IGF-1R therapies may be of potential benefit in ovarian AGCTs, and this requires further study. Lack of known mutations within the tyrosine kinase domain of EGFR suggests that EGFR-related tyrosine kinase inhibitors may not be useful therapeutically.