Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia

Interleukin 7 (IL-7) and its receptor, formed by IL-7Rα (encoded by IL7R) and γc, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region and promote de novo formation of intermolecular disulfide bonds between mutant IL-7Rα subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, γc or JAK3. IL7R mutations induce a gene expression profile partially resembling that provoked by IL-7 and are enriched in the T-ALL subgroup comprising TLX3 rearranged and HOXA deregulated cases. Notably, IL7R mutations promote cell transformation and tumor formation. Overall, our findings indicate that IL7R mutational activation is involved in human T-cell leukemogenesis, paving the way for therapeutic targeting of IL-7R-mediated signaling in T-ALL.     

Your Vision or My Model? Lessons from Participatory Land Use Scenario Development on a European Scale

Participatory processes in scenario development have received increasing attention throughout the last years. Combining qualitative stakeholder and quantitative expert information (i.e. modelling) offers unique opportunities to mix good data, scientific rigour, imagination and expertise from different perspectives. However, this task is all but easy as it requires a careful balancing of approaches and an acceptance of different levels of knowledge and trust in different methods across disciplinary boundaries. In spite of a growing body of literature we are still in the early stages of learning how to deal effectively with participatory scenario development. In the PRELUDE project of the European Environment Agency a relatively far-reaching participatory approach to scenario development was applied: a group of stakeholders from across Europe was given full responsibility to develop long-term alternative land use scenarios in cooperation with experts and modellers. The scenarios have been used in a formal outreach process with key clients and stakeholders at the European and Member State level afterwards. The aim of this paper is to document the methods used, analyse their strengths and weaknesses and draw some general conclusions regarding participatory processes in scenario development. This paper argues that in future scenario development more attention needs to be paid to strengthen the integration of qualitative and quantitative analysis. A set of compelling and coherent storylines can effectively trigger strategic conversations among policy-makers and key stakeholders about potential future developments and related response strategies. A weak integration with quantitative results can undermine this outcome, which is one of the ultimate objectives of any scenario exercise.

Predictability of Equity Models

In this study, we verify the existence of predictability in the Brazilian equity market. Unlike other studies in the same sense, which evaluate original series for each stock, we evaluate synthetic series created on the basis of linear models of stocks. Following the approach of Burgess (Computational Finance, 1999; 99, 297–312), we use the ‘stepwise regression’ model for the formation of models of each stock. We then use the variance ratio profile together with a Monte Carlo simulation for the selection of models with potential predictability using data from 1 April 1999 to 30 December 2003. Unlike the approach of Burgess, we carry out White's Reality Check (Econometrica, 2000; 68, 1097–1126) in order to verify the existence of positive returns for the period outside the sample from 2 January 2004 to 28 August 2007. We use the strategies proposed by Sullivan, Timmermann and White (Journal of Finance, 1999; 54, 1647–1691) and Hsu and Kuan (Journal of Financial Econometrics, 2005; 3, 606–628) amounting to 26,410 simulated strategies. Finally, using the bootstrap methodology, with 1000 simulations, we find strong evidence of predictability in the models, including transaction costs. Copyright © 2015 John Wiley & Sons, Ltd.     

A new species of Austrorhynchus (Platyhelminthes: Kalyptorhynchia) from King George Island (Maritime Antarctic)

A new species of the turbellarian genus Austrorhynchus (Kalyptorhynchia: Polycystididae) was found in King George Island (South Shetland Islands, Maritime Antarctic). The new species has eyes and white to greyish parenchyma. The type II prostate stylet has a funnel and a slightly bent tube with an inner stylet extending throughout its length; a strongly bent hook of about the same size as the tube is present. The type III prostate stylet has a foot and a style connected by a bridge, defining a broad window; the style expands to a comb-bearing plate with large teeth; the foot continues into a narrow flagellum with a distal expansion and a row of fine teeth. The species is oviparous. It can be distinguished from the other known Austrorhynchus species by the shape and size of the type II and type III prostate stylets. Out of the five known species of Austrorhynchus presenting a window in the type III stylet, the four more similar ones are found in the northern arm of the Scotia Arc and the Weddell Sea area. This is the first report of Kalyptorhynchia from the Antarctic portion of the Scotia Sea, and it confirms previous observations that the true number of Austrorhynchus species in the area must be higher than what is currently known.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:098ADF23-763B-41F6-A2F5-54F6AA8620E8     

First record of a non-pollinating fig wasp (Hymenoptera: Sycophaginae) from Dominican amber,with estimation of the size of its host figs

Fig trees and their pollinating fig wasps arose about 75 million years ago in the Cretaceous period. Several other groups of chalcid wasps also utilize figs for larval development, including sycophagines, the putative sister group to pollinating fig wasps. Whereas stone and amber fossil pollinators are known, no fossils representing non-pollinating fig wasp groups have been confirmed previously. Here, we describe the first Sycophaginae from the c.15–20 Ma Dominican amber, Idarnes thanatos sp. nov. Farache, Rasplus, Pereira and Compton, and discuss its relationships within the Idarnes carme species group. Additionally, we use linear regression to compare body size, ovipositor sheaths length, and host fig size data from extant Idarnes species to estimate the size of its host figs. Idarnes thanatos was most likely associated with small to medium sized figs (diameter ≤1.0 cm), that were likely to have been dispersed by birds and primates. The discovery of this close relative of extant non-pollinating fig wasps suggests that early Miocene and modern fig wasp communities may share similar ecological and functional features.     

Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.     

Population ecology and reproduction of the Mexican mud turtle ( Kinosternon integrum ) in Tonatico Estado De México

Ecological data directly from the field are important in understanding the life history strategies of kinosternid species in the tropics. Herein we summarize the basic population ecology and life history of Kinosternon integrum in the municipality of Tonatico (southeastern Estado de México, México). From October 2003 to November 2004, we marked a total of 204 turtles and recaptured 118 of them. Mean population size using the Jolly-Seber model was 197 (95% CI 128–416) individuals, with a sex ratio of 1:1.7, biased to females. Males were larger than females in carapace length and plastron length. The reproductive season starts in late June and finishes in late October. The smallest female with oviductal eggs was 122 mm in carapace length. Mean clutch size was 4 eggs ( s = 1.77, range 1–8) and was significantly and positively related to body size. Mean egg length was 30.43 mm ( s = 2.24, range 23.92–35.96), mean width was 16.35 mm ( s = 1.01, range 12.99–18.30), and mean weight was 5.14 g ( s = 0.60, range 3.41–6.57). Mean egg length was significantly and inversely related to clutch size. Relative clutch mass (reproductive effort) was 0.043 ( s = 0.017, range 0.017–0.071), which is the smallest value reported for the genus Kinosternon. Additionally, there was no evidence of a pelvic restriction on egg size in this population. This is the first study that documents basic population ecology and reproductive characteristics for a single population of the most widespread freshwater turtle in Mexico.     

Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism

Morphogens act in developing tissues to control the spatial arrangement of cellular differentiation. The activity of a morphogen has generally been viewed as a concentration-dependent response to a diffusible signal, but the duration of morphogen signalling can also affect cellular responses. One such example is the morphogen sonic hedgehog (SHH). In the vertebrate central nervous system and limbs, the pattern of cellular differentiation is controlled by both the amount and the time of SHH exposure. How these two parameters are interpreted at a cellular level has been unclear. Here we provide evidence that changing the concentration or duration of SHH has an equivalent effect on intracellular signalling. Chick neural cells convert different concentrations of SHH into time-limited periods of signal transduction, such that signal duration is proportional to SHH concentration. This depends on the gradual desensitization of cells to ongoing SHH exposure, mediated by the SHH-dependent upregulation of patched 1 (PTC1), a ligand-binding inhibitor of SHH signalling. Thus, in addition to its role in shaping the SHH gradient, PTC1 participates cell autonomously in gradient sensing. Together, the data reveal a novel strategy for morphogen interpretation, in which the temporal adaptation of cells to a morphogen integrates the concentration and duration of a signal to control differential gene expression.