Calcium signalling links MYC to NUAK1

NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1. Here we show that, in tumour cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway involving calcium-dependent activation of PKCα. Calcium/PKCα-dependent activation of NUAK1 supports engagement of the AMPK-TORC1 metabolic checkpoint, thereby protecting tumour cells from MYC-driven cell death, and indeed, MYC selects for this pathway in part via transcriptional regulation of PKCα and ITPR. Our data point to a novel role for calcium in supporting tumour cell viability and clarify the synthetic lethal interaction between NUAK1 and MYC

The history of introduction of the African baobab (Adansonia digitata, Malvaceae: Bombacoideae) in the Indian subcontinent

To investigate the pathways of introduction of the African baobab, Adansonia digitata, to the Indian subcontinent, we examined 10 microsatellite loci in individuals from Africa, India, the Mascarenes and Malaysia, and matched this with historical evidence of human interactions between source and destination regions. Genetic analysis showed broad congruence of African clusters with biogeographic regions except along the Zambezi (Mozambique) and Kilwa (Tanzania), where populations included a mixture of individuals assigned to at least two different clusters. Individuals from West Africa, the Mascarenes, southeast India and Malaysia shared a cluster. Baobabs from western and central India clustered separately from Africa. Genetic diversity was lower in populations from the Indian subcontinent than in African populations, but the former contained private alleles. Phylogenetic analysis showed Indian populations were closest to those from the Mombasa-Dar es Salaam coast. The genetic results provide evidence of multiple introductions of African baobabs to the Indian subcontinent over a longer time period than previously assumed. Individuals belonging to different genetic clusters in Zambezi and Kilwa may reflect the history of trafficking captives from inland areas to supply the slave trade between the fifteenth and nineteenth centuries. Baobabs in the Mascarenes, southeast India and Malaysia indicate introduction from West Africa through eighteenth and nineteenth century European colonial networks

The Automated Delimitation of Maritime Boundaries - An Australian Perspective

Determining the accurate location of maritime boundaries and computing the outer limits of the extended continental shelf can be a mathematically demanding and computationally intensive task. This paper considers the relevant issues, particularly from an Australian perspective. An efficient and automated solution to maritime boundary and extended continental shelf delimitation has been designed and implemented in the form of a software package known as MarZone. This paper introduces the MarZone software. In the design of MarZone, emphasis was placed on a geodetically rigorous methodology while at the same time maintaining strict agreement with the relevant provisions of the United Nations Convention on the Law of the Sea. The reasons for such an emphasis are explained in the paper

Development of a grass measurement optimisation tool to efficiently measure herbage mass on grazed pastures

peer-reviewedAccurate and efficient estimation of herbage mass is essential for optimising grass utilisation and increasing profit for pasture farming. There is no definitive sampling protocol for grass measurement on Irish pastures. This paper presents the Grass Measurement Optimisation Tool (GMOT), designed to generate measurement protocols that optimise for time and accuracy. The GMOT was designed in the form of a decision support tool that generates interactive paddock maps that guide the farmer on how to optimally measure their pastures in a random stratified manner based on GPS co-ordinates, resulting in accurate non-biased estimations of mean herbage mass. Rising plate meter (RPM) measurements and reference herbage cuts were performed on trial plots and grazed paddocks over three years. Measurement routes were optimised using a genetic algorithm based on a traveling salesman problem. Actual survey error was estimated in terms of relative prediction error using Monte Carlo simulations that combined measurement and calibration error distributions for the RPM. Cost benefit analysis was conducted to evaluate the feasibility of using the GMOT on Irish grasslands. Actual error for the RPM decreased from 37% to 26% as measurement rates increased from 1 to 8 ha−1 and reductions in error were negligible (<1%) as measurements increased from 8 to 32 ha−1. Calibration error was the largest source of error (25.9%) compared to measurement error (8%). Optimal measurement value was achieved by performing 8 measures ha−1 and further increasing the measurement rate resulted in diminishing returns. The GMOT is compatible with a range of pasture measurement technologies

An important role for Myb-MuvB and its target gene KIF23 in a mouse model of lung adenocarcinoma

The conserved Myb-MuvB (MMB) multiprotein complex has an important role in transcriptional activation of mitotic genes. MMB target genes are overexpressed in several different cancer types and their elevated expression is associated with an advanced tumor state and a poor prognosis. This suggests that MMB could contribute to tumorigenesis by mediating overexpression of mitotic genes. However, although MMB has been extensively characterized biochemically, the requirement for MMB in tumorigenesis in vivo has not been investigated. Here we demonstrate that MMB is required for tumor formation in a mouse model of lung cancer driven by oncogenic K-RAS. We also identify a requirement for the mitotic kinesin KIF23, a key target gene of MMB, in tumorigenesis. RNA interference-mediated depletion of KIF23 inhibited lung tumor formation in vivo and induced apoptosis in lung cancer cell lines. Our results suggest that inhibition of KIF23 could be a strategy for treatment of lung cancer

In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells

Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS61K in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation

Adult beginner distance language learner perceptions and use of assignment feedback

This qualitative study examines perceptions and use of assignment feedback among adult beginner modern foreign language learners on higher education distance learning courses. A survey of responses to feedback on assignments by 43 Open University students on beginner language courses in Spanish, French, and German indicated that respondents can be classified into three groups: those who use feedback strategically by integrating it into the learning process and comparing it with, for example, informal feedback from interaction with native speakers, those who take note of feedback, but seem not to use it strategically, and those who appear to take little account of either marks or feedback. The first group proved to be the most confident and most likely to maintain their motivation in the longer term. The conclusion discusses some of the pedagogical and policy implications of the findings

Washington Park Main Street Plan

There is an immense variety of privately owned businesses. They will be stakeholders because their businesses are located there, but they will also be assets in themselves in drawing people to the area. There is basically everything anyone could possible want or need in this area. There are two gas stations, a Family Dollar, a liquor store, a few sit down restaurants, numerous places where one can get a quick bite to eat, a frame shop, a clothing store, a pawn shop, a store with fresh produce (which is hard to find in urban areas), a store that sells sports uniforms, a frame shop, a lawyerʼs office, an animal hospital, two Laundromats, a record shop, a health food store, two cell phone stores, an automotive shop, and a karate school with an afterschool program. With such variety, it will draw people to the area and then give them other reasons to keep coming back

Women’s views on the impact of operative delivery in the second stage of labour: Qualitative interview study

Objective: To obtain the views of women on the impact of operative delivery in the second stage of labour. Design: Qualitative interview study. Setting: Two urban teaching hospitals in the United Kingdom. Participants: Purposive sample of 27 women who had undergone operative delivery in the second stage of labour between January 2000 and January 2002. Key themes: Preparation for birth, understandings of the indications for operative delivery, and explanation or debriefing after birth. Results: The women felt unprepared for operative delivery and thought that their birth plan or antenatal classes had not catered adequately for this event. They emphasised the importance of maintaining an open mind about the management of labour. They had difficulty understanding the need for operative delivery despite a review by medical and midwifery staff before discharge. Operative delivery had a noticeable impact on women's views about future pregnancy and delivery. Conclusions: Women consider postnatal debriefing and medical review important deficiencies in current care. Those who experienced operative delivery in the second stage of labour would welcome the opportunity to have a later review of their intrapartum care, physical recovery, and management of future pregnancies

Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25–50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent