Root suckering in Dichrostachys cinerea and a comparison of subspecies africana and nyassana

Clonal growth has been studied little in Africa, and models of savanna tree-grass interactions have not included vegetatively reproducing trees or shrubs. Root suckering has been observed in both subspecies of Dichrostachys cinerea that occur in Southern Africa. This study, performed in Hluhluwe-iMfolozi Game Reserve, KwaZulu Natal South Africa, examines variability in subspecies distribution and the extent of root suckering under different fire regimes, and levels of herbivory. Variations in subspecies distribution are clear. Subspecies africana, with greater structural defenses, survives in areas of high herbivory but is rarely seen under high fire disturbance. The opposite is true for subspecies nyassana, which is poorly defended against herbivory. There was no difference in vegetative propogation by root suckering in areas of different fire regime, rainfall, soil type or degree of herbivory. The implication is that the management of the species will be a formidable task. A combination of burning during summer, when below ground reserves are depleted, and heavy browsing may aid in the control of this species

Limitations of savanna trees in the highveld grasslands of South Africa

Includes bibliographical references (leaves 85-91).Many grassland areas throughout the world may support a woody biomass if fire is suppressed. It is puzzling that fire-tolerant savanna trees do not grow in these grasslands. The Highveld grasslands of South Africa are one such grassland. Hypotheses including fire, human intervention, grass competition and various attributes of soil have been proposed to explain the tree-less nature of the Highveld grasslands, but they have mostly been discounted. In this study it was hypothesised that cool temperatures or low nutrient availability would result in slow growth of saplings in grassland areas that would subsequently not be able to escape frequent fires. Alternatively, frost may exclude trees from grasslands. A seedling transplant experiment of savanna tree species of the Acacia genus, into grassland and savanna areas arranged across an altitudinal gradient, was used to compare growth in these varying climates over one growing season, and the influence of frost on seedlings in the following winter. Soils were collected from grassland and savanna regions to establish if nutrients varied between these areas, and seedling growth was measured in a pot experiment including these different soils. To minimise the effect of other variables, seedlings were watered and grass was excluded. Higher altitude grassland areas were cooler, and the grassland soils that were collected were nutrient-poor, relative to the savanna equivalents, with the exception of one nutrient-poor low altitude soil. Growth was well correlated to both temperature and nutrient availability, and in general there was slower growth in grassland climates and grassland soils compared to in savannas. These seedling growth rates were extrapolated to the growth rates of saplings in natural environments and the time it would take saplings to reach a height above flame height was calculated. This showed that although there were significant differences between growth rates in grassland and savanna soils, the magnitude of these differences was not large enough to prevent saplings from growing into adults in grassland soils. Differences in growth due to temperature variations, however, were large enough to suggest that saplings in grassland climates would grow too slowly to ever reach escape height between frequent fires. Frost caused damage to seedlings and decreased seedling survival at the highest elevation sites, but trees were absent well below the altitudinal limit of frost damage. There has been much discussion about the tree-less nature of the Highveld grasslands, but very little experimental work to back it. Neither temperature nor fire alone can explain the lack of trees. This study provides empirical evidence that slow growth due to low temperatures in combination with frequent fire could exclude savanna trees from the grasslands. The effect of grass competition still needs investigation. The incorporation of fire is useful as it is a fundamental part of C4 ecosystems; this, on top of a base of variable growth due to changes in resource availability. The barely recognised savanna tree-line deserves attention, as savannas continue to invade grasslands in a warming world

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/

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year