A 3′UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like Kinase 1

BACKGROUND: The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. METHODS: The coding region, the 5′ and 3′UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3′UTR polymorphism. RESULTS: Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3′untranslated region (3′UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). CONCLUSION: The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors

Climate policy implications of nonlinear decline of Arctic land permafrost and other cryosphere elements

Arctic feedbacks accelerate climate change through carbon releases from thawing permafrost and higher solar absorption from reductions in the surface albedo, following loss of sea ice and land snow. Here, we include dynamic emulators of complex physical models in the integrated assessment model PAGE-ICE to explore nonlinear transitions in the Arctic feedbacks and their subsequent impacts on the global climate and economy under the Paris Agreement scenarios. The permafrost feedback is increasingly positive in warmer climates, while the albedo feedback weakens as the ice and snow melt. Combined, these two factors lead to significant increases in the mean discounted economic effect of climate change: +4.0% ($24.8 trillion) under the 1.5 °C scenario, +5.5$33.8 trillion) under the 2 °C scenario, and +4.8% ($66.9 trillion) under mitigation levels consistent with the current national pledges. Considering the nonlinear Arctic feedbacks makes the 1.5 °C target marginally more economically attractive than the 2 °C target, although both are statistically equivalent.This work is part of the ICE-ARC project funded by the European Union’s 7th Framework Programme, (grant 603887, contribution 006). D.Y. received additional funding from ERIM, Erasmus University Rotterdam, and Paul Ekins at the ISR, University College London. K.S. was funded by NSF (grant 1503559) and NASA (grants NNX14A154G, NNX17AC59A). E.J. was funded by the NGEE Arctic project supported by the BER Office of Science at the U.S. DOE. Y.E. was funded by the NSF (grant 1900795). E.B. was supported by the UK Met Office Hadley Centre Climate Programme funded by BEIS and DEFRA

The 1430s: a cold period of extraordinary internal climate variability during the early Spörer Minimum with social and economic impacts in north-western and central Europe

Changes in climate affected human societies throughout the last millennium. While European cold periods in the 17th and 18th century have been assessed in detail, earlier cold periods received much less attention due to sparse information available. New evidence from proxy archives, historical documentary sources and climate model simulations permit us to provide an interdisciplinary, systematic assessment of an exceptionally cold period in the 15th century. Our assessment includes the role of internal, unforced climate variability and external forcing in shaping extreme climatic conditions and the impacts on and responses of the medieval society in north-western and central Europe. Climate reconstructions from a multitude of natural and anthropogenic archives indicate that the 1430s were the coldest decade in north-western and central Europe in the 15th century. This decade is characterised by cold winters and average to warm summers resulting in a strong seasonal cycle in temperature. Results from comprehensive climate models indicate consistently that these conditions occurred by chance due to the partly chaotic internal variability within the climate system. External forcing like volcanic eruptions tends to reduce simulated temperature seasonality and cannot explain the reconstructions. The strong seasonal cycle in temperature reduced food production and led to increasing food prices, a subsistence crisis and a famine in parts of Europe. Societies were not prepared to cope with failing markets and interrupted trade routes. In response to the crisis, authorities implemented numerous measures of supply policy and adaptation such as the installation of grain storage capacities to be prepared for future food production shortfalls

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

AIMS: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). beta-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. METHODS AND RESULTS: We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (DeltaKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. beta-Adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05). CONCLUSION: Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.status: publishe

Can convective precipitation variability be deduced from the variability in CAPE and CIN? An analysis of global CAPE and CIN variability in present and future climates

The variability of convective precipitation is relevant for its prediction on short and long time scales. On short time scales severe weather events are vital for weather forecasting, on long time scales convection anomalies affect wetness and droughts. Since convective precipitation requires parameterisation in numerical models, CAPE (convective available potential energy) and CIN (convective inhibition) are applied to estimate trends and long-term memory. Their variability is determined in present-day climate (ECMWF reanalysis: 6 hourly during 1979-2001 in T106 trun- cation; ECHAM5/MPI-OM, 20C simulation: 6 hourly during 1902-2001 in T63 truncation) and a possible warmer future scenario (ECHAM5/MPI-OM, A1B scenario: 6 hourly during 2002-2101 in T63 truncation). Future changes in CAPE and CIN reveal similar changes for small, mean and large values. A global pattern is found of increasing values in CAPE and CIN over most regions of the conti- nents and northern hemispheric ocean basins, while decreasing values are found over the Southern Ocean. This pattern changes towards mostly positive trends if CAPE is analysed for large CIN occurring simultaneously. In contrast, the original pattern remains similar if CAPE is investigated for small CIN. Temperature and humidity, which form the basis of CAPE and CIN, show almost entirely higher values in the future. Decreasing values in CAPE and CIN correlate with large scale patterns like the North Atlantic Oscillation (NAO), El Ni ̃ no/Southern Oscillation (ENSO) and the Southern Annular Mode (SAM). Furthermore, a southward shift of the descending branch of the southern hemisphere Hadley Cell in a warmer climate decreases CAPE further. The correlations of CAPE with the above named teleconnections influence the distribution of global memory on long time scales. The influence of ENSO on the memory in CAPE and CIN intensifies in a warmer climate with regards to spread and frequency. Furthermore, the impact of the NAO on CAPE also spreads in terms of location, while the frequency remains similar in a warmer climate. In contrast, the regions where SAM influences CAPE decrease due to declining values of the SAM index. Additional analyses with an ECHAM5 simulation and climatological sea surface temperature reveal that the variability of the ocean has a stronger influence on CAPE than on CIN

Random data for testing purposes

These data are purely random and have been created to test scripts with