Exploring the significance of land-cover change in South Africa

Changing land cover is a phenomenon that is growing in magnitude and significance, both globally1 and in South Africa2 . Changes in land cover include the conversion of natural vegetation to agricultural crops and forest plantations, changes to natural vegetation through bush encroachment and overgrazing, soil erosion, invasion by alien plant species, and accelerating urbanisation. Land-cover changes increasingly relate to climate and atmospheric changes in ways that are currently poorly understood but potentially significant, especially in terms of compromising or enhancing the delivery of vital ecosystem services from rangelands, agricultural croplands, water catchments and conservation areas. Land-cover change is being studied in different ways, and at different scales, by ecologists, plant physiologists, applied biologists and social scientists. A core group of scientists has recently formed the Land Cover Change Consortium (LCCC), which aims to begin integrating the results of the varied approaches to studying land-cover change, and to guide future research directions, with a view to building a better science base for informing policy and management decision-making in conservation, agriculture and environmental management. The group has developed a simple conceptual outline that links field experiments, observation and monitoring, modelling and prediction of land-cover change (Figure 1), and is currently developing a funding base to support collaboration in addressing fundamental questions about how ecosystems might change in the coming decades, in training new graduates, and in communicating effectively with policymakers. The LCCC hopes to provide a theoretical and practical multidisciplinary platform for scientific collaboration on global change issues that also includes different stakeholder groups and contributes to policy and decision-making. Multidisciplinary collaboration is notoriously challenging, but holds great promise for novel insights

Cognitive Performances Are Selectively Enhanced during Chronic Caloric Restriction or Resveratrol Supplementation in a Primate

Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus)

Heregulin β1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells

Introduction Resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies is an emerging clinical problem. The efficacy of anti-EGFR therapies can be influenced by the presence of heregulins (HRGs), which can bind erbB3/4 receptors and can activate alternative signalling pathways. In the present study we have examined whether HRG signalling can circumvent EGFR blockade in an EGFR-positive tamoxifen-resistant MCF-7 (Tam-R) breast cancer cell line. Methods Tam-R cells, incubated with the selective EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839), were exposed to HRGβ1 and the effects on erbB receptor dimerization profiles and on activation of associated downstream signalling components were assessed by immunoprecipitation, western blotting and immunocytochemistry. The effects of HRGβ1 on gefitinib-treated Tam-R cell growth and invasion were also examined, and HRGβ1 expression levels were assessed in breast cancer tissue by immunohistochemistry to address the potential clinical relevance of such a resistance mechanism. Results In Tam-R cells, HRGβ1 promoted erbB3/erbB2 and erbB3/EGFR heterodimerization, promoted ERK1/2 and AKT pathway activation and increased cell proliferation and invasion. Gefitinib prevented HRGβ1-driven erbB3/EGFR heterodimerization, ERK1/2 activation and Tam-R cell proliferation, but HRGβ1-driven erbB3/erbB2 heterodimerization, AKT activation and Tam-R cell invasion were maintained. A combination of gefitinib and the phosphatidylinositol 3-kinase inhibitor LY294002 effectively blocked HRGβ1-mediated intracellular signalling activity, growth and invasion in Tam-R cells. Similarly, targeting erbB2 with trastuzumab in combination with gefitinib in Tam-R cells reduced HRGβ1-induced erbB2 and ERK1/2 activity; however, HRGβ1-driven AKT activity and cell growth were maintained while cell invasion was significantly enhanced with this combination. In clinical tissue all samples demonstrated cytoplasmic tumour epithelial HRGβ1 protein staining, with expression correlating with EGFR positivity and activation of both AKT and ERK1/2. Conclusion HRGβ1 can overcome the inhibitory effects of gefitinib on cell growth and invasion in Tam-R cells through promotion of erbB3/erbB2 heterodimerization and activation of the phosphatidylinositol 3-kinase/AKT signalling pathway. This may have implications for the effectiveness of anti-EGFR therapies in breast cancer as HRGβ1 is enriched in many EGFR-positive breast tumours

Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Background: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders, by whole-exome sequencing in families with one or more members affected by multi-locus imprinting disturbance. Methods: Whole-exome sequencing was performed in 38 pedigrees where probands had multi-locus imprinting disturbance, in five of whom, maternal variants in NLRP5 have previously been found. Results: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal-effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. Conclusion: The identification of 20 putative maternal-effect variants in 38 families affected by multi-locus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.<br/

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

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Observations arising from the use of pure antioestrogens on oestrogen-responsive (MCF-7) and oestrogen growth-independent (K3) human breast cancer cells

INTRODUCTION During the last 7 years the Breast Cancer Group within the Tenovus Cancer Research Centre has maintained an involvement in the use of pure antioestrogens in two important areas of breast cancer research. First, their development as clinical agents, where we hoped to induce total oestrogen deprivation and thereby improve the effectiveness of first-line endocrine therapy (Nicholson et al. 1992, Nicholson 1993, Nicholson et al. 1993a, DeFriend et al. 1994, Nicholson et al. 1994c). Second, as pharmacological probes to investigate the cellular and molecular actions of oestrogens and tamoxifen (Nicholson et al. 1988, Weatherill et al. 1988, Wilson et al. 1990). Implicit in each of these areas of research are questions associated with the impact which pure antioestrogens might have on the therapy of endocrine-resistant states and whether resistance develops as a consequence of incomplete oestrogen withdrawal, with tumour cells more efficiently utilising either a reduced oestrogenic poo