Linking pseudouridine synthases to growth, developmentand cell competition

Eukaryotic pseudouridine synthases direct RNA pseudouridylation and bind H⁄ACA small nucleolar RNA (snoRNAs), which, in turn, may act as precursors of microRNA-like molecules. In humans, loss of pseudouridine synthase activity causes dyskeratosis congenita (DC), a complex systemic disorder characterized by cancer susceptibility, failures in ribosome biogenesis and telomere stability, and defects in stem cell formation. Considering the significant interest in deciphering the various molecular consequences of pseudouridine synthase failure, we performed a loss of function analysis of minifly (mfl), the pseudouridine synthase gene of Drosophila, in the wing disc, an advantageous model system for studies of cell growth and differentiation. In this organ, depletion of the mfl-encoded pseudouridine synthase causes a severe reduction in size by decreasing both the number and the size of wing cells. Reduction of cell number was mainly attributable to cell death rather than reduced proliferation, establishing that apoptosis plays a key role in the development of the loss of function mutant phenotype. Depletion of Mfl also causes a proliferative disadvantage in mosaic tissues that leads to the elimination of mutant cells by cell competition. Intriguingly, mfl silencing also triggered unexpected effects on wing patterning and cell differentiation, including deviations from normal lineage boundaries, mingling of cells of different compartments, and defects in the formation of the wing margin that closely mimic the phenotype of reduced Notch activity. These results suggest that a component of the pseudouridine synthase loss of function phenotype is caused by defects in Notch signalling

Use of antifungal Saponin SC-2 of Solanum chrysotrichum for the treatment of vulvovaginal candidiasis: in vitro studies and clinical experiences

Saponin SC-2 from Solanum chrysotrichum showed antifungal activity, demonstrated in vitro, which inhibited the growth of dermatophytes, and in vivo, to be effective in the treatment against tinea pedis and pityriasis capitis. Fungistatic and fungicidal activity of saponin SC-2 on Candida albicans and other Candida species, fluconazole and ketoconazole resistaent strains was demostrated. SC-2-associated ultrastructural alterations in several Candida species were observed. An exploratoryclinical, randomized, double-blind, and controlled ketoconazole study of ketoconazole was conducted with the aim of assessing the effectiveness and tolerability of an herbal medicinal product containing SC-2, on women with Vulvovaginal candidiasis (VVC). The results exhibited a percentage of therapeutic clinical effectiveness similar to that of ketoconazole (X2, p .0.30), but obtained a smaller percentage of mycological effectiveness, and 100% tolerability. In conclusion, saponin SC-2 possesses fungicidale and fungistatic activity on Candida albicans and other multi resistant Candida species, causes morphological changes and fungal death, and it is an alternative therapy for the treatment of VVC.Key words: Solanum chrysotrichum, saponins, antifungal activity, vulvovaginal candidiasis, alternative therapy

Social Cohesion, Structural Holes, and a Tale of Two Measures

EMBARGOED - author can archive pre-print or post-print on any open access repository after 12 months from publication. Publication date is May 2013 so embargoed until May 2014.This is an author’s accepted manuscript (deposited at arXiv arXiv:1211.0719v2 [physics.soc-ph] ), which was subsequently published in Journal of Statistical Physics May 2013, Volume 151, Issue 3-4, pp 745-764. The final publication is available at link.springer.com http://link.springer.com/article/10.1007/s10955-013-0722-

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

Objective: To determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM). Research Design and Methods: This was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM ($\geq$2 abnormal values on a 100-g glucose tolerance test at ~28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM. Results: Women who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013-18,939] vs. 30,670 [18,370-55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6-35.3]) and multivariate (14.0 [4.1-47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ~28-week nonfasting glucose levels (r = -0.30, P < 0.001). Conclusions: First-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy

Scenario-Based Design Theorizing:The Case of a Digital Idea Screening Cockpit

As ever more companies encourage employees to innovate, a surplus of ideas has become reality in many organizations – often exceeding the available resources to execute them. Building on insights from a literature review and a 3-year collaboration with a banking software provider, the paper suggests a Digital Idea Screening Cockpit (DISC) to address this challenge. Following a design science research approach, it suggests a prescriptive design theory that provides practitioner-oriented guidance for implementing a DISC. The study shows that, in order to facilitate the assessment, selection, and tracking of ideas for different stakeholders, such a system needs to play a dual role: It needs to structure decision criteria and at the same be flexible to allow for creative expression. Moreover, the paper makes a case for scenario-based design theorizing by developing design knowledge via scenarios

Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m−2 on days 1 and 15, PTX 60 mg m−2 on days 1, 8 and 15 and continuous infusion of 5-FU at 200 mg m−2 every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable

Agrin Binds BMP2, BMP4 and TGFβ1

The C-terminal 95 kDa fragment of some isoforms of vertebrate agrins is sufficient to induce clustering of acetylcholine receptors but despite two decades of intense agrin research very little is known about the function of the other isoforms and the function of the larger, N-terminal part of agrins that is common to all isoforms. Since the N-terminal part of agrins contains several follistatin-domains, a domain type that is frequently implicated in binding TGFβs, we have explored the interaction of the N-terminal part of rat agrin (Agrin-Nterm) with members of the TGFβ family using surface plasmon resonance spectroscopy and reporter assays. Here we show that agrin binds BMP2, BMP4 and TGFβ1 with relatively high affinity, the KD values of the interactions calculated from SPR experiments fall in the 10−8 M–10−7 M range. In reporter assays Agrin-Nterm inhibited the activities of BMP2 and BMP4, half maximal inhibition being achieved at ∼5×10−7 M. Paradoxically, in the case of TGFβ1 Agrin N-term caused a slight increase in activity in reporter assays. Our finding that agrin binds members of the TGFβ family may have important implications for the role of these growth factors in the regulation of synaptogenesis as well as for the role of agrin isoforms that are unable to induce clustering of acetylcholine receptors. We suggest that binding of these TGFβ family members to agrin may have a dual function: agrin may serve as a reservoir for these growth factors and may also inhibit their growth promoting activity. Based on analysis of the evolutionary history of agrin we suggest that agrin's growth factor binding function is more ancient than its involvement in acetylcholine receptor clustering