Impact of steric constraints on the product distribution of phosphate-branched oligonucleotide models of the large ribozymes

To assess the extent to which steric constraints may influence the product distribution of the reactions of the large ribozymes, phosphate-branched oligonucleotides of varying length and sequence have been synthesized and their alkaline hydrolysis studied over a wide temperature range. At low temperatures, the branching trinucleoside-3 ',3 ',5 '-monophosphate moiety is hydrolyzed almost exclusively by P-O3 ' fission. At higher temperatures, P-O5 ' fission competes, accounting at most for 22% of the overall reaction. The results suggest that steric constraints imposed by the secondary structure of the reaction site may significantly contribute to the observed regioselectivity of the transesterification reactions catalyzed by the large ribozymes

Aberrant expression of ALK and EZH2 in Merkel cell carcinoma

BACKGROUND: Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC. METHODS: RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent Suite Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue. RESULTS: ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under-expressed compared to the MCV-positive tumors. CONCLUSIONS: High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC.Peer reviewe

Simulated seasonal impact on middle atmospheric ozone from high-energy electron precipitation related to pulsating aurorae

Recent simulation studies have provided evidence that a pulsating aurora (PsA) associated with high-energy electron precipitation is having a clear local impact on ozone chemistry in the polar middle mesosphere. However, it is not clear if the PsA is frequent enough to cause longer-term effects of measurable magnitude. There is also an open question of the relative contribution of PsA-related energetic electron precipitation (PsA EEP) to the total atmospheric forcing by solar energetic particle precipitation (EPP). Here we investigate the PsA-EEP impact on stratospheric and mesospheric odd hydrogen, odd nitrogen, and ozone concentrations. We make use of the Whole Atmosphere Community Climate Model and recent understanding on PsA frequency, latitudinal and magnetic local time extent, and energy-flux spectra. Analysing an 18-month time period covering all seasons, we particularly look at PsA-EEP impacts at two polar observation stations located at opposite hemispheres: Tromsø in the Northern Hemisphere (NH) and Halley Research Station in the Southern Hemisphere (SH). We find that PsA EEP can have a measurable impact on ozone concentration above 30 km altitude, with ozone depletion by up to 8 % seen in winter periods due to PsA-EEP-driven NOx enhancement. We also find that direct mesospheric NOx production by high-energy electrons (E> 100 keV) accounts for about half of the PsA-EEP-driven upper stratospheric ozone depletion. A larger PsA-EEP impact is seen in the SH where the background dynamical variability is weaker than in the NH. Clearly indicated from our results, consideration of polar vortex dynamics is required to understand PsA-EEP impacts seen at ground observation stations, especially in the NH. We conclude that PsA-EEP has the potential to make an important contribution to the total EPP forcing; thus, it should be considered in atmospheric and climate simulations.publishedVersio

Broadband Meter-Wavelength Observations of Ionospheric Scintillation

Intensity scintillations of cosmic radio sources are used to study astrophysical plasmas like the ionosphere, the solar wind, and the interstellar medium. Normally these observations are relatively narrow band. With Low Frequency Array (LOFAR) technology at the Kilpisj\"arvi Atmospheric Imaging Receiver Array (KAIRA) station in northern Finland we have observed scintillations over a 3 octave bandwidth. ``Parabolic arcs'', which were discovered in interstellar scintillations of pulsars, can provide precise estimates of the distance and velocity of the scattering plasma. Here we report the first observations of such arcs in the ionosphere and the first broad-band observations of arcs anywhere, raising hopes that study of the phenomenon may similarly improve the analysis of ionospheric scintillations. These observations were made of the strong natural radio source Cygnus-A and covered the entire 30-250\,MHz band of KAIRA. Well-defined parabolic arcs were seen early in the observations, before transit, and disappeared after transit although scintillations continued to be obvious during the entire observation. We show that this can be attributed to the structure of Cygnus-A. Initial results from modeling these scintillation arcs are consistent with simultaneous ionospheric soundings taken with other instruments, and indicate that scattering is most likely to be associated more with the topside ionosphere than the F-region peak altitude. Further modeling and possible extension to interferometric observations, using international LOFAR stations, are discussed.Comment: 11 pages, 17 figure

Procedural recommendations of cardiac PET/CT imaging: standardization in inflammatory-, infective-, infiltrative-, and innervation (4Is)-related cardiovascular diseases: a joint collaboration of the EACVI and the EANM

With this document, we provide a standard for PET/(diagnostic) CT imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is). This standard should be applied in clinical practice and integrated in clinical (multicenter) trials for optimal procedural standardization. A major focus is put on procedures using [18F]FDG, but 4Is PET radiopharmaceuticals beyond [18F]FDG are also described in this document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicenter trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Finally, PET/MR applications in 4Is cardiovascular diseases are also briefly described. Diagnosis and management of 4Is-related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/MR, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications

Contribution of proton and electron precipitation to the observed electron concentration in October–November 2003 and September 2005

Understanding the altitude distribution of particle precipitation forcing is vital for the assessment of its atmospheric and climate impacts. However, the proportion of electron and proton forcing around the mesopause region during solar proton events is not always clear due to uncertainties in satellite-based flux observations. Here we use electron concentration observations of the European Incoherent Scatter Scientific Association (EISCAT) incoherent scatter radars located at Tromsø (69.58° N, 19.23° E) to investigate the contribution of proton and electron precipitation to the changes taking place during two solar proton events. The EISCAT measurements are compared to the results from the Sodankylä Ion and Neutral Chemistry Model (SIC). The proton ionization rates are calculated by two different methods – a simple energy deposition calculation and the Atmospheric Ionization Model Osnabrück (AIMOS v1.2), the latter providing also the electron ionization rates. Our results show that in general the combination of AIMOS and SIC is able to reproduce the observed electron concentration within ± 50% when both electron and proton forcing is included. Electron contribution is dominant above 90 km, and can contribute significantly also in the upper mesosphere especially during low or moderate proton forcing. In the case of strong proton forcing, the AIMOS electron ionization rates seem to suffer from proton contamination of satellite-based flux data. This leads to overestimation of modelled electron concentrations by up to 90% between 75–90 km and up to 100–150% at 70–75 km. Above 90 km, the model bias varies significantly between the events. Although we cannot completely rule out EISCAT data issues, the difference is most likely a result of the spatio-temporal fine structure of electron precipitation during individual events that cannot be fully captured by sparse in situ flux (point) measurements, nor by the statistical AIMOS model which is based upon these observations

Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development

Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF- mutant lineage becomes a cancerized lineage. The TgCreERT2; BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution