DDX54 regulates transcriptome dynamics during DNA damage response

The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of posttranscriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins including many nucleolar proteins showed increased binding to poly(A) RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs which harbor introns with weak acceptor splice sites, as well as by protein-protein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Since DDX54 promotes survival after exposure to IR its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR

Radiotherapy in langerhans cell histiocytosis - a rare indication in a rare disease

Introduction: Langerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as “Histiocytosis X”, “Type II Histiocytosis” or “Langerhans Cell Granulomatosis”. Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described. Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis. Methods and material: Eight closely cooperating centres collected patients’ data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined. Results: A total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9–134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen. Radiation treatment was carried out with a median total dose of 15 Gy (range 3–50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy). Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed. Conclusion: In the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.<br

Radiofrequency electromagnetic fields cause non-temperature-induced physical and biological effects in cancer cells

Non-temperature-induced effects of radiofrequency electromagnetic fields (RF) have been controversial for decades. Here, we established measurement techniques to prove their existence by investigating energy deposition in tumor cells under RF exposure and upon adding amplitude modulation (AM) (AMRF). Using a preclinical device LabEHY-200 with a novel in vitro applicator, we analyzed the power deposition and system parameters for five human colorectal cancer cell lines and measured the apoptosis rates in vitro and tumor growth inhibition in vivo in comparison to water bath heating. We showed enhanced anticancer effects of RF and AMRF in vitro and in vivo and verified the non-temperature-induced origin of the effects. Furthermore, apoptotic enhancement by AM was correlated with cell membrane stiffness. Our findings not only provide a strategy to significantly enhance non-temperature-induced anticancer cell effects in vitro and in vivo but also provide a perspective for a potentially more effective tumor therapy

Electronic Properties of Vinylene-Linked Heterocyclic Conducting Polymers: Predictive Design and Rational Guidance from DFT Calculations

The band structure and electronic properties in a series of vinylene-linked heterocyclic conducting polymers are investigated using density functional theory (DFT). In order to accurately calculate electronic band gaps, we utilize hybrid functionals with fully periodic boundary conditions to understand the effect of chemical functionalization on the electronic structure of these materials. The use of predictive first-principles calculations coupled with simple chemical arguments highlights the critical role that aromaticity plays in obtaining a low band gap polymer. Contrary to some approaches which erroneously attempt to lower the band gap by increasing the aromaticity of the polymer backbone, we show that being aromatic (or quinoidal) in itself does not insure a low band gap. Rather, an iterative approach which destabilizes the ground state of the parent polymer towards the aromatic \leftrightarrow quinoidal level-crossing on the potential energy surface is a more effective way of lowering the band gap in these conjugated systems. Our results highlight the use of predictive calculations guided by rational chemical intuition for designing low band gap polymers in photovoltaic materials.Comment: Accepted by the Journal of Physical Chemistry

Long-term results of radiotherapy for periarthritis of the shoulder: a retrospective evaluation

<p>Abstract</p> <p>Background</p> <p>To evaluate retrospectively the results of radiotherapy for periarthritis of the shoulder</p> <p>Methods</p> <p>In 1983–2004, 141 patients were treated, all had attended at least one follow-up examination. 19% had had pain for several weeks, 66% for months and 14% for years. Shoulder motility was impaired in 137/140 patients. Nearly all patients had taken oral analgesics, 81% had undergone physiotherapy, five patients had been operated on, and six had been irradiated. Radiotherapy was applied using regular anterior-posterior opposing portals and Co-60 gamma rays or 4 MV photons. 89% of the patients received a total dose of 6 Gy (dose/fraction of 1 Gy twice weekly, the others had total doses ranging from 4 to 8 Gy. The patients and the referring doctors were given written questionnaires in order to obtain long-term results. The mean duration of follow-up was 6.9 years [0–20 years].</p> <p>Results</p> <p>During the first follow-up examination at the end of radiotherapy 56% of the patients reported pain relief and improvement of motility. After in median 4.5 months the values were 69 and 89%, after 3.9 years 73% and 73%, respectively. There were virtually no side effects. In the questionnaires, 69% of the patients reported pain relief directly after radiotherapy, 31% up to 12 weeks after radiotherapy. 56% of the patients stated that pain relief had lasted for "years", in further 12% at least for "months".</p> <p>Conclusion</p> <p>Low-dose radiotherapy for periarthropathy of the shoulder was highly effective and yielded long-lasting improvement of pain and motility without side effects.</p

Dynamic changes in genomic and social structures in third millennium BCE central Europe

Europe’s prehistory oversaw dynamic and complex interactions of diverse societies, hitherto unexplored at detailed regional scales. Studying 271 human genomes dated ~4900 to 1600 BCE from the European heartland, Bohemia, we reveal unprecedented genetic changes and social processes. Major migrations preceded the arrival of “steppe” ancestry, and at ~2800 BCE, three genetically and culturally differentiated groups coexisted. Corded Ware appeared by 2900 BCE, were initially genetically diverse, did not derive all steppe ancestry from known Yamnaya, and assimilated females of diverse backgrounds. Both Corded Ware and Bell Beaker groups underwent dynamic changes, involving sharp reductions and complete replacements of Y-chromosomal diversity at ~2600 and ~2400 BCE, respectively, the latter accompanied by increased Neolithic-like ancestry. The Bronze Age saw new social organization emerge amid a ≥40% population turnover.Peer reviewe

Copper (I) selenocyanate (CuSeCN) as a novel hole-transport layer for transistors, organic solar cells, and light-emitting diodes

The synthesis and characterization of copper (I) selenocyanate (CuSeCN) and its application as a solution-processable hole-transport layer (HTL) material in transistors, organic light-emitting diodes, and solar cells are reported. Density-functional theory calculations combined with X-ray photoelectron spectroscopy are used to elucidate the electronic band structure, density of states, and microstructure of CuSeCN. Solution-processed layers are found to be nanocrystalline and optically transparent ( > 94%), due to the large bandgap of ≥3.1 eV, with a valence band maximum located at -5.1 eV. Hole-transport analysis performed using field-effect measurements confirms the p-type character of CuSeCN yielding a hole mobility of 0.002 cm 2 V -1 s -1 . When CuSeCN is incorporated as the HTL material in organic light-emitting diodes and organic solar cells, the resulting devices exhibit comparable or improved performance to control devices based on commercially available poly(3,4-ethylenedioxythiophene):polystyrene sulfonate as the HTL. This is the first report on the semiconducting character of CuSeCN and it highlights the tremendous potential for further developments in the area of metal pseudohalides

Multiple Redox Modes in the Reversible Lithiation of High-Capacity, Peierls-Distorted Vanadium Sulfide.

This is the author accepted manuscript. The final version is available from ACS via http://dx.doi.org/10.1021/jacs.5b03395Vanadium sulfide VS4 in the patronite mineral structure is a linear chain compound comprising vanadium atoms coordinated by disulfide anions [S2](2-). (51)V NMR shows that the material, despite having V formally in the d(1) configuration, is diamagnetic, suggesting potential dimerization through metal-metal bonding associated with a Peierls distortion of the linear chains. This is supported by density functional calculations, and is also consistent with the observed alternation in V-V distances of 2.8 and 3.2 Å along the chains. Partial lithiation results in reduction of the disulfide ions to sulfide S(2-), via an internal redox process whereby an electron from V(4+) is transferred to [S2](2-) resulting in oxidation of V(4+) to V(5+) and reduction of the [S2](2-) to S(2-) to form Li3VS4 containing tetrahedral [VS4](3-) anions. On further lithiation this is followed by reduction of the V(5+) in Li3VS4 to form Li3+xVS4 (x = 0.5-1), a mixed valent V(4+)/V(5+) compound. Eventually reduction to Li2S plus elemental V occurs. Despite the complex redox processes involving both the cation and the anion occurring in this material, the system is found to be partially reversible between 0 and 3 V. The unusual redox processes in this system are elucidated using a suite of short-range characterization tools including (51)V nuclear magnetic resonance spectroscopy (NMR), S K-edge X-ray absorption near edge spectroscopy (XANES), and pair distribution function (PDF) analysis of X-ray data.SB acknowledges Schlumberger Stichting Fund and European Research Council (EU ERC) for funding. JC thanks BK21 plus project of Korea. We thank Phoebe Allan and Andrew J. Morris, University of Cambridge, for useful discussions. We also thank Trudy Bolin and Tianpin Wu of Beamline 9-BM, Argonne National Laboratory for help with XANES measurements. The DFT calculations were performed at the UCSB Center for Scientific Computing at UC Santa Barbara, supported by the California Nanosystems Institute (NSF CNS-0960316), Hewlett-Packard, and the Materials Research Laboratory (DMR-1121053). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357