p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway

The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.     

Revisiting the saproxylic beetle ‘Propomacrus cypriacus Alexis & Makris, 2002’ (Coleoptera: Euchiridae) using molecular,morphological and ecological data

Propomacrus cypriacus a saproxylic beetle endemic to Cyprus, was described as a species distinct from P. bimucronatus on the basis of a few morphological characters and has been evaluated as Critically Endangered by IUCN, as it depends on veteran trees and has a restricted distribution. Herein we explored the distribution, ecology, morphology and genetic variation of the populations from Cyprus, and we attempted a phylogenetic analysis including related species based on two mitochondrial and one nuclear DNA markers. We also used published mtDNA divergence rates to date cladogenetic events. Despite extensive sampling, we found only a small number of individuals, adding a few additional localities to the known distribution of the species, and we identified two more host species to those previously reported. Morphological examination showed that only the form of male protibiae differs consistently in Cyprus populations compared to those of P. bimucronatus from Turkey and the Lebanon. Nevertheless, genetic analyses do not support a distinct species status for populations from Cyprus, which should instead be considered as a subspecies of P. bimucronatus. Morphological and ecological data further support this conclusion. Cyprus populations have diverged from nearby continental ones in mid to late Pleistocene.     

Modelling and Trading the English and German Stock Markets with Novelty Optimization Techniques

The motivation for this paper was the introduction of novel short‐term models to trade the FTSE 100 and DAX 30 exchange‐traded funds (ETF) indices. There are major contributions in this paper which include the introduction of an input selection criterion when utilizing an expansive universe of inputs, a hybrid combination of partial swarm optimizer (PSO) with radial basis function (RBF) neural networks, the application of a PSO algorithm to a traditional autoregressive moving model (ARMA), the application of a PSO algorithm to a higher‐order neural network and, finally, the introduction of a multi‐objective algorithm to optimize statistical and trading performance when trading an index. All the machine learning‐based methodologies and the conventional models are adapted and optimized to model the index. A PSO algorithm is used to optimize the weights in a traditional RBF neural network, in a higher‐order neural network (HONN) and the AR and MA terms of an ARMA model. In terms of checking the statistical and empirical accuracy of the novel models, we benchmark them with a traditional HONN, with an ARMA, with a moving average convergence/divergence model (MACD) and with a naïve strategy. More specifically, the trading and statistical performance of all models is investigated in a forecast simulation of the FTSE 100 and DAX 30 ETF time series over the period January 2004 to December 2015 using the last 3 years for out‐of‐sample testing. Finally, the empirical and statistical results indicate that the PSO‐RBF model outperforms all other examined models in terms of trading accuracy and profitability, even with mixed inputs and with only autoregressive inputs. Copyright © 2016 John Wiley & Sons, Ltd.     

A choice-semantical approach to theoretical truth

A central topic in the logic of science concerns the proper semantic analysis of theoretical sentences, that is sentences containing theoretical terms. In this paper, we present a novel choice-semantical account of theoretical truth based on the epsilon-term definition of theoretical terms. Specifically, we develop two ways of specifying the truth conditions of theoretical statements in a choice functional semantics, each giving rise to a corresponding logic of such statements. In order to investigate the inferential strength of these logical systems, we provide a translation of each truth definition into a modal definition of theoretical truth. Based on this, we show that the stronger notion of choice-semantical truth captures more adequately our informal semantic understanding of scientific statements.     

Radioactive 26Al from massive stars in the Galaxy

Gamma-rays from radioactive 26Al (half-life approximately 7.2 x 10(5) years) provide a 'snapshot' view of continuing nucleosynthesis in the Galaxy. The Galaxy is relatively transparent to such gamma-rays, and emission has been found concentrated along its plane. This led to the conclusion that massive stars throughout the Galaxy dominate the production of 26Al. On the other hand, meteoritic data show evidence for locally produced 26Al, perhaps from spallation reactions in the protosolar disk. Furthermore, prominent gamma-ray emission from the Cygnus region suggests that a substantial fraction of Galactic 26Al could originate in localized star-forming regions. Here we report high spectral resolution measurements of 26Al emission at 1808.65 keV, which demonstrate that the 26Al source regions corotate with the Galaxy, supporting its Galaxy-wide origin. We determine a present-day equilibrium mass of 2.8 (+/- 0.8) solar masses of 26Al. We use this to determine that the frequency of core collapse (that is, type Ib/c and type II) supernovae is 1.9 (+/- 1.1) events per century.     

Essential role for collectrin in renal amino acid transport

Angiotensin -converting enzyme 2 (ACE2) is a regulator of the renin angiotensin system involved in acute lung failure, cardiovascular functions and severe acute respiratory syndrome (SARS) infections in mammals. A gene encoding a homologue to ACE2, termed collectrin (Tmem27), has been identified in immediate proximity to the ace2 locus. The in vivo function of collectrin was unclear. Here we report that targeted disruption of collectrin in mice results in a severe defect in renal amino acid uptake owing to downregulation of apical amino acid transporters in the kidney. Collectrin associates with multiple apical transporters and defines a novel group of renal amino acid transporters. Expression of collectrin in Xenopus oocytes and Madin-Darby canine kidney (MDCK) cells enhances amino acid transport by the transporter B(0)AT1. These data identify collectrin as a key regulator of renal amino acid uptake.     

Contrasting patterns of early twenty-first-century glacier mass change in the Himalayas

Glaciers are among the best indicators of terrestrial climate variability, contribute importantly to water resources in many mountainous regions and are a major contributor to global sea level rise. In the Hindu Kush-Karakoram-Himalaya region (HKKH), a paucity of appropriate glacier data has prevented a comprehensive assessment of current regional mass balance. There is, however, indirect evidence of a complex pattern of glacial responses in reaction to heterogeneous climate change signals. Here we use satellite laser altimetry and a global elevation model to show widespread glacier wastage in the eastern, central and south-western parts of the HKKH during 2003-08. Maximal regional thinning rates were 0.66?±?0.09 metres per year in the Jammu-Kashmir region. Conversely, in the Karakoram, glaciers thinned only slightly by a few centimetres per year. Contrary to expectations, regionally averaged thinning rates under debris-mantled ice were similar to those of clean ice despite insulation by debris covers. The 2003-08 specific mass balance for our entire HKKH study region was -0.21?±?0.05?m?yr(-1) water equivalent, significantly less negative than the estimated global average for glaciers and ice caps. This difference is mainly an effect of the balanced glacier mass budget in the Karakoram. The HKKH sea level contribution amounts to one per cent of the present-day sea level rise. Our 2003-08 mass budget of -12.8?±?3.5 gigatonnes (Gt) per year is more negative than recent satellite-gravimetry-based estimates of -5?±?3?Gt?yr(-1) over 2003-10 (ref. 12). For the mountain catchments of the Indus and Ganges basins, the glacier imbalance contributed about 3.5% and about 2.0%, respectively, to the annual average river discharge, and up to 10% for the Upper Indus basin.     

Viral immune modulators perturb the human molecular network by common and unique strategies

Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein?U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies.