The Bitter Taste Receptor TAS2R14 as a Drug Target

G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. Besides human senses like vision and olfaction, taste perception is mostly mediated by GPCRs. Hence, the bitter taste receptor family TAS2R comprises 25 distinct receptors and plays a key role in food acceptance and drug compliance. The TAS2R14 subtype is the most broadly tuned bitter taste receptor, recognizing a range of chemically highly diverse agonists. Besides other tissues, it is expressed in human airway smooth muscle and may represent a novel drug target for airway diseases. Several natural products as well as marketed drugs including flufenamic acid have been identified to activate TAS2R14, but higher potency ligands are needed to investigate the ligand-controlled physiological function and to facilitate the targeted modulate for potential future clinical applications. A combination of structure-based molecular modeling with chemical synthesis and in vitro profiling recently resulted in new flufenamic acid agonists with improved TAS2R14 potency and provided a validated and refined structural model of ligand–TAS2R14 interactions, which can be applied for future drug design projects

Development and operalisation of a support programme for nursing service managers: Part 2

This paper describes research conducted to develop and implement a support programme for nursing service managers suffering from fatigue. The support programme was developed on the basis of results obtained from a survey that ascertained nursing service managers' views about the problems they were experiencing in their everyday lives. A multiple case-study design was utilised to describe the operationalisation of the support programme. The sample consisted of forty-eight English speaking and fifty-two Afrikaans speaking nursing service managers from the old Transvaal region (Gauteng, North West and Eastern Transvaal The support programme was implemented during two one-day workshops, one with the Afrikaans speaking group and one with the English speaking group of nursing service managers. Data were gathered about operationalisation of the support programme through multiple methods: observation, audiotape recordings, written documents and field notes. The data were analysed by utilising the methods of descriptive analysis

The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs

Topoisomerase 1 (Top1) enzymes regulate DNA superhelicity by forming covalent cleavage complexes that undergo controlled rotation. Substitution of nucleoside analogs at the +1 position of the DNA duplex relative to the Top1 cleavage site inhibits DNA religation. The reduced efficiency for Top1-mediated religation contributes to the anticancer activity of widely used anticancer drugs including fluoropyrimidines and gemcitabine. In the present study, we report that mismatched base pairs at the +1 position destabilize the duplex DNA components for a model Top1 cleavage complex formation even though one duplex component does not directly include a mismatched base pair. Molecular dynamics simulations reveal G-dU and G-FdU mismatched base pairs, but not a G-T mismatched base pair, increase flexibility at the Top1 cleavage site, and affect coupling between the regions required for the religation reaction to occur. These results demonstrate that substitution of dT analogs into the +1 position of the non-scissile strand alters the stability and flexibility of DNA contributing to the reduced efficiency for Top1-mediated DNA religation. These effects are inherent in the DNA duplex and do not require formation of the Top1:DNA complex. These results provide a biophysical rationale for the inhibition of Top1-mediated DNA religation by nucleotide analog substitution

Community-based curriculum in psychiatric nursing science

As community-based health care delivery is now a prominent feature of the health care system in South Africa, nursing curricula are being challenged to prepare student nurses for community based nursing roles and responsibilities. The purpose of this study was to describe guidelines for a community-based curriculum in psychiatric nursing science for a nursing college in KwaZulu-Natal. A qualitative, quantitative, exploratory, descriptive and contextual design was employed. To reach the purpose of the study, a situational analysis was done in three phases to identify the principles for a community-based curriculum for psychiatric nursing science. Phase I: A document analysis of relevant government policies and legislation. Phase II: Statistics from psychiatric hospitals and community psychiatric clinics. Phase III: Focus group interviews with nurse educators and literature control and conceptual framework The principles obtained from the three phases were used to formulate the guidelines for a community-based curriculum in psychiatric nursing science (Phase IV). Eight guidelines with practical implications are described for the implementation of a Community-based curriculum in Psychiatric Nursing Science

The UEFA EURO 2012 anti-doping programme - scientific review

The final tournament of the UEFA European Football Championship is one of the top sporting events in the world, and a high-profile event of this kind requires a well-planned and well-executed anti-doping programme to ensure the integrity of results in the competition. UEFA EURO 2012 presented a unique logistical challenge, with the tournament spread across two countries, both covering a large geographical area. This paper discusses the planning and delivery of both the pre tournament out-of-competition (OOC) testing programme and the in-competition (IC) programme, as well as reviewing the activities of doping control officers (DCOs), the whereabouts programme and assessing the sample collection and transport process. The analytical approach applied is also discussed, along with an overview of the distribution of T/E ratios and blood parameters

Seasonality in Major Depressive Disorder: Effect of Sex and Age

Background: Aside from the concept of seasonal affective disorder, the evidence for a seasonal pattern (SP) of major depressive disorder (MDD) is controversial. Furthermore, the effect of sex and age is still unclear. Methods: This is a nationwide, registry-based study assessing all inpatient admissions in mental health hospitals due to MDD episodes according to ICD-10 (moderate (F32/33.1), severe (F32/33.2) and severe with psychotic features (F32/33.3)) in Austria across 14 years. Calculations were based on deviations from expected monthly admissions. Results: The sample comprised 231,824 hospitalisations (36.8% men) for MDD. A significant SP (p=0.001) in moderate and severe depressive episodes in both women and men with decreased admission rates in the summer months and December was detected. In psychotic depression a significant SP was only evidenced in women (p = 0.002, men: p = 0.291). Patients older than 55 years had a reduced SP compared to those being younger. Limitations: Only anonymised admission data of inpatient treatments were available. Hospitalization rates cannot fully be equated to the occurrence of MDD. Conclusions: The current study indicates a seasonal variation in MDD symptoms that may go beyond seasonal affective disorder. Knowledge about the predictability of depressive symptoms in patients should encourage preventive strategies

Axionic dark energy and a composite QCD axion

We discuss the idea that the model-independent (MI) axion of string theory is the source of quintessential dark energy. The scenario is completed with a composite QCD axion from hidden sector squark condensation that could serve as dark matter candidate. The mechanism relies on the fact that the hidden sector anomaly contribution to the composite axion is much smaller than the QCD anomaly term. This intuitively surprising scenario is based on the fact that below the hidden sector scale $\Lambda_h$ there are many light hidden sector quarks. Simply, by counting engineering dimensions the hidden sector instanton potential can be made negligible compared to the QCD anomaly term.Comment: 9 pages, 7 figure

Intersecting D-Branes on Shift Z2 x Z2 Orientifolds

We investigate Z2 x Z2 orientifolds with group actions involving shifts. A complete classification of possible geometries is presented where also previous work by other authors is included in a unified framework from an intersecting D-brane perspective. In particular, we show that the additional shifts not only determine the topology of the orbifold but also independently the presence of orientifold planes. In the second part, we work out in detail a basis of homological three cycles on shift Z2 x Z2 orientifolds and construct all possible fractional D-branes including rigid ones. A Pati-Salam type model with no open-string moduli in the visible sector is presented.Comment: 36 pages, 4 figures, refs. adde