Mechanism of action of coumarin and silver(I)- coumarin complexes against the pathogenic yeast Candida albicans

The anti-fungal activity and mode of action of a range of silver(I)- coumarin complexes was examined. The most potent silver(I)- coumarin complexes, namely 7-hydroxycoumarin-3-carboxylatosilver(I), 6-hydroxycoumarin-3-carboxylatosilver(I) and 4-oxy-3-nitrocoumarinbis(1,10-phenanthroline)silver(I), had MIC80 values of between 69.1 and 4.6 M against the pathogenic yeast Candida albicans. These compounds also reduced respiration, lowered the ergosterol content of cells and increased the trans-membrane leakage of amino acids. A number of the complexes disrupted cytochrome synthesis in the cell and induced the appearance of morphological features consistent with cell death by apoptosis. These compounds appear to act by disrupting the synthesis of cytochromes which directly aVects the cell's ability to respire. A reduction in respiration leads to a depletion in ergosterol biosynthesis and a consequent disruption of the integrity of the cell membrane. Disruption of cytochrome biosynthesis may induce the onset of apoptosis which has been shown previously to be triggered by alteration in the location of cytochrome c. Silver(I)- coumarin complexes demonstrate good anti-fungal activity and manifest a mode of action distinct to that of the conventional azole and polyene drugs thus raising the possibility of their use when resistance to conventional drug has emerged or in combination with such drugs

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site

Super star clusters in Haro 11: Properties of a very young starburst and evidence for a near-infrared flux excess

We have used multi-band imaging to investigate the nature of the extreme starburst environment in Haro 11 galaxy. The central starburst region has been observed in 8 HST wavebands and at 2.16 micron at the ESO-VLT. We constructed integrated spectral energy distributions (SEDs) for about 200 star clusters and compared them with single stellar population models in order to derive ages, masses and extinctions of thestar clusters. The present starburst has lasted for 40 Myr, and shows a peak of cluster formation only 3.5 Myr old. With such an extremely young cluster population, Haro 11 represents a unique opportunity to investigate the youngest phase of the cluster formation process and evolution in starburst systems. Extinction tends to diminish as function of the cluster age, but the spread is large and for clusters in partial embedded phases ( 10^4 Msun), very young (1-3 Myr) clusters is missing, either because they are embedded inthe parental molecular cloud and heavily extinguished, or because of blending. Almost half of the cluster sample is affected by flux excesses at wavelengths 8000 \AA which cannot be explained by simple stellar evolutionary models. Fitting SED models over all wavebands leads to systematic overestimates of cluster ages and incorrect masses for the stellar population supplying the light in these clusters. We show that the red excess affects also the HST F814W filter, which is typically used to constrain cluster physical properties. The clusters which show the red excess are younger than 40 Myr; we propose possible physical explanations for the phenomenon. Finally, we estimate that Haro 11 hasproduced bound clusters at a rate almost a factor of 10 higher than the massive and regular spirals, like the Milky Way. (Abriged)Comment: Accepted for publication in MNRAS. 23 pages, 23 figure

Realistic Anatomical Prostate Models for Surgical Skills Workshops Using Ballistic Gelatin for Nerve-Sparing Radical Prostatectomy and Fruit for Simple Prostatectomy

PURPOSE: Understanding of prostate anatomy has evolved as techniques have been refined and improved for radical prostatectomy (RP), particularly regarding the importance of the neurovascular bundles for erectile function. The objectives of this study were to develop inexpensive and simple but anatomically accurate prostate models not involving human or animal elements to teach the terminology and practical aspects of nerve-sparing RP and simple prostatectomy (SP). MATERIALS AND METHODS: The RP model used a Foley catheter with ballistics gelatin in the balloon and mesh fabric (neurovascular bundles) and balloons (prostatic fascial layers) on either side for the practice of inter- and intrafascial techniques. The SP model required only a ripe clementine, for which the skin represented compressed normal prostate, the pulp represented benign tissue, and the pith mimicked fibrous adhesions. A modification with a balloon through the fruit center acted as a "urethra." RESULTS: Both models were easily created and successfully represented the principles of anatomical nerve-sparing RP and SP. Both models were tested in workshops by urologists and residents of differing levels with positive feedback. CONCLUSIONS: Low-fidelity models for prostate anatomy demonstration and surgical practice are feasible. They are inexpensive and simple to construct. Importantly, these models can be used for education on the practical aspects of nerve-sparing RP and SP. The models will require further validation as educational and competency tools, but as we move to an era in which human donors and animal experiments become less ethical and more difficult to complete, so too will low-fidelity models become more attractive

Planetary Nebulae as standard candles XI. Application to Spiral Galaxies

We report the results of an [O III] lambda 5007 survey for planetary nebulae (PN) in three spiral galaxies: M101 (NGC 5457), M51 (NGC 5194/5195) and M96 (NGC 3368). By comparing on-band/off-band [O III] lambda 5007 images with images taken in H-alpha and broadband R, we identify 65, 64 and 74 PN candidates in each galaxy, respectively. From these data, an adopted M31 distance of 770 kpc, and the empirical planetary nebula luminosity function (PNLF), we derive distances to M101, M51, and M96 of 7.7 +/- 0.5, 8.4 +/- 0.6, and 9.6 +/- 0.6 Mpc. These observations demonstrate that the PNLF technique can be successfully applied to late-type galaxies, and provide an important overlap between the Population I and Population II distance scales. We also discuss some special problems associated with using the PNLF in spiral galaxies, including the effects of dust and the possible presence of [O III] bright supernova remnants.Comment: 38 pages, TeX, with tables included but not figures. Uses epsf.tex and kpnobasic.tex. To be published in the Astophysical Journal. Full paper is available at http://www.astro.psu.edu/users/johnf/Text/research.htm

Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo

Background: Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored. Results: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis. Conclusions: These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity

Efficacy of metformin in pregnant obese women:a randomised controlled trial

Introduction Increasing evidence suggests obesity has its origins prior to birth. There is clear correlation between maternal obesity, high birthweight and offspring risk of obesity in later life. It is also clear that women who are obese during pregnancy are at greater risk of adverse outcomes, including gestational diabetes and stillbirth. The mechanism(s) by which obesity causes these problems is unknown, although hyperglycaemia and insulin resistance are strongly implicated. We present a protocol for a study to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high birthweight babies and other pregnancy complications. Methods and analysis The Efficacy of Metformin in Pregnant Obese Women, a Randomised controlled (EMPOWaR) trial is a double-masked randomised placebo-controlled trial to determine whether metformin given to obese (body mass index >30 kg/m2) pregnant women from 16 weeks’ gestation until delivery reduces the incidence of high birthweight babies. A secondary aim is to test the mechanism(s) of any effect. Obese women with a singleton pregnancy and normal glucose tolerance will be recruited prior to 16 weeks’ gestation and prescribed study medication, metformin or placebo, to be taken until delivery. Further study visits will occur at 28 and 36 weeks’ gestation for glucose tolerance testing and to record anthropometric measurements. Birth weight and other measurements will be recorded at time of delivery. Anthropometry of mother and baby will be performed at 3 months postdelivery. As of January 2014, 449 women had been randomised across the UK. Ethics and dissemination The study will be conducted in accordance with the principles of Good Clinical Practice. A favourable ethical opinion was obtained from Scotland A Research Ethics Committee, reference number 10/MRE00/12. Results will be disseminated at conferences and published in peer-reviewed journals

Meeting the health and social needs of pregnant asylum seekers; midwifery students’ perspectives. Part 2; Dominant discourses and approaches to care

YesPregnant women seeking asylum in the United Kingdom appear particularly vulnerable, having complex health and social care needs and could benefit from a woman centred approach to midwifery care. This article is the second of three parts and reports on the findings from one objective of a wider doctorate study. It focuses on exploring midwifery students' perceptions of how to approach the care of pregnant women seeking asylum. Although the design of the study is explored in article one, in this context, the data was subject to critical discourse analysis to meet this objective. Key words and phrases were highlighted which appeared to reveal power and ideology implicit in the language used when discussing midwifery care of the pregnant woman seeking asylum. Dominant discourses were identified which appeared to influence the way in which care was approached and the possible sources of these discourses critically analysed. The findings suggest an underpinning ideology around following policies and guidelines to meet the physical needs of the woman at the expense of her other holistic needs. Despite learning to adopt a woman centred approach in theory, once in practice some students appear to be socialised into (re)producing these dominant medical and managerial discourses with “midwifery discourse” being marginalised. In addition, some students appeared to have difficulty understanding how to adopt a woman centred approach and the importance of considering the woman's context and its impact on care. These findings have implications for midwifery educators and this article identifies that the recent Nursing and Midwifery Council requirement for students to undertake a caseloading activity could provide the opportunity for them to adopt a consistent woman centred approach in practice, rejecting dominant medical and managerial discourses. However, these discourses appear to influence midwives caring for women more widely and will be difficult to challenge

Young massive stars in the ISOGAL survey II. The catalogue of bright YSO candidates

The 7 and 15 um observations of selected fields in the Galactic Plane obtained with ISOCAM during the ISOGAL program offer an unique possibility to search for previously unknown YSOs, undetected by IRAS because of lower sensitivity or confusion problems. In a previous paper (Felli et al. 2000) we established criteria of general validity to select YSOs from the much larger population of Post Main Sequence (Post-MS) stars present in the ISOGAL fields by comparing radio and IR observations of five fields located at l +45 deg. The selection was based primarily on the position of the point sources in the [15] - [7]--[15] diagram, which involves only ISOGAL data and allows to find possible YSOs using the survey data alone. In the present work we revise the adopted criteria by comparing radio-identified UC HII regions and ISOGAL observations over a much larger region. The main indications of the previous analysis are confirmed, but the criteria for selecting YSO candidates had to be revised to select only bright objects, in order to limit the contamination of the sample by Post-MS stars. The revised criteria ([15]=1.8) are then used to extract YSO candidates from the ISOGAL Point Source Catalogue in preparation. We select a total of 715 YSO candidates, corresponding to ~2% of the sources with good detections at 7 and 15 um. The results are presented in a table form that provides an unique input list of small diameter, <=6", Galactic YSO candidates. The global properties of the sample of YSO candidates are briefly discussed.Comment: 21 pages, A&A in press, table 3 and full resolution pictures available at: http://www.arcetri.astro.it/~lt/preprints/preprints.htm