Altering Chemosensitivity by Modulating Translation Elongation

BACKGROUND: The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Emu-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents. METHODOLOGY/PRINCIPAL FINDINGS: Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Emu-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor. CONCLUSION/SIGNIFICANCE: Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations

Functionally Redundant RXLR Effectors from <em>Phytophthora infestans</em> Act at Different Steps to Suppress Early flg22-Triggered Immunity

Genome sequences of several economically important phytopathogenic oomycetes have revealed the presence of large families of so-called RXLR effectors. Functional screens have identified RXLR effector repertoires that either compromise or induce plant defense responses. However, limited information is available about the molecular mechanisms underlying the modes of action of these effectors in planta. The perception of highly conserved pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), such as flg22, triggers converging signaling pathways recruiting MAP kinase cascades and inducing transcriptional re-programming, yielding a generic anti-microbial response. We used a highly synchronizable, pathogen-free protoplast-based assay to identify a set of RXLR effectors from Phytophthora infestans (PiRXLRs), the causal agent of potato and tomato light blight that manipulate early stages of flg22-triggered signaling. Of thirty-three tested PiRXLR effector candidates, eight, called Suppressor of early Flg22-induced Immune response (SFI), significantly suppressed flg22-dependent activation of a reporter gene under control of a typical MAMP-inducible promoter (pFRK1-Luc) in tomato protoplasts. We extended our analysis to Arabidopsis thaliana, a non-host plant species of P. infestans. From the aforementioned eight SFI effectors, three appeared to share similar functions in both Arabidopsis and tomato by suppressing transcriptional activation of flg22-induced marker genes downstream of post-translational MAP kinase activation. A further three effectors interfere with MAMP signaling at, or upstream of, the MAP kinase cascade in tomato, but not in Arabidopsis. Transient expression of the SFI effectors in Nicotiana benthamiana enhances susceptibility to P. infestans and, for the most potent effector, SFI1, nuclear localization is required for both suppression of MAMP signaling and virulence function. The present study provides a framework to decipher the molecular mechanisms underlying the manipulation of host MAMP-triggered immunity (MTI) by P. infestans and to understand the basis of host versus non-host resistance in plants towards P. infestans

死体肺移植におけるrecombinant tissue-field name="type" plasminogen activator(rt-PA)の効果について

[[sponsorship]]物理研究所[[note]]已出版;[SCI];有審查制度;具代表性[[note]]http://gateway.isiknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Drexel&SrcApp=hagerty_opac&KeyRecord=1434-6044&DestApp=JCR&RQ=IF_CAT_BOXPLO

Search for the Standard Model Higgs boson produced in association with top quarks and decaying into in collisions at with the ATLAS detector

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecomm ons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Funded by SCOAP3.We acknowledge the support of ANPCyT, Argentina; YerPhI, Armenia; ARC, Australia; BMWFW and FWF, Austria; ANAS, Azerbaijan; SSTC, Belarus; CNPq and FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; CONICYT, Chile; CAS, MOST and NSFC, China; COLCIENCIAS, Colombia; MSMT CR, MPO CR and VSC CR, Czech Republic; DNRF, DNSRC and Lundbeck Foundation, Denmark; EPLANET, ERC and NSRF, European Union; IN2P3-CNRS, CEA-DSM/IRFU, France; GNSF, Georgia; BMBF, DFG, HGF, MPG and AvH Foundation, Germany; GSRT and NSRF, Greece; RGC, Hong Kong SAR, China; ISF, MINERVA, GIF, I-CORE and Benoziyo Center, Israel; INFN, Italy; MEXT and JSPS, Japan; CNRST, Morocco; FOM and NWO, Netherlands; BRF and RCN, Norway; MNiSW and NCN, Poland; GRICES and FCT, Portugal; MNE/IFA, Romania; MES of Russia and ROSATOM, Russian Federation; JINR; MSTD, Serbia; MSSR, Slovakia; ARRS and MIZŠ, Slovenia; DST/NRF, South Africa; MINECO, Spain; SRC and Wallenberg Foundation, Sweden; SER, SNSF and Cantons of Bern and Geneva, Switzerland; NSC, Taiwan; TAEK, Turkey; STFC, the Royal Society and Leverhulme Trust, United Kingdom; DOE and NSF, United States of Americ

Age constraints on faulting and fault reactivation: a multi-chronological approach.

Movement within the Earth’s upper crust is commonly accommodated by faults or shear zones, ranging in scale from micro-displacements to regional tectonic lineaments. Since faults are active on different time scales and can be repeatedly reactivated, their displacement chronology is difficult to reconstruct. This study represents a multi-geochronological approach to unravel the evolution of an intracontinental fault zone locality along the Danube Fault, central Europe. At the investigated fault locality, ancient motion has produced a cataclastic deformation zone in which the cataclastic material was subjected to hydrothermal alteration and K-feldspar was almost completely replaced by illite and other phyllosilicates. Five different geochronological techniques (zircon Pb-evaporation, K–Ar and Rb–Sr illite, apatite fission track and fluorite (U-Th)/He) have been applied to explore the temporal fault activity. The upper time limit for initiation of faulting is constrained by the crystallization age of the primary rock type (known as “Kristallgranit”) at 325 ± 7 Ma, whereas the K–Ar and Rb–Sr ages of two illite fractions <2 μm (266–255 Ma) are interpreted to date fluid infiltration events during the final stage of the cataclastic deformation period. During this time, the “Kristallgranit” was already at or near the Earth’s surface as indicated by the sedimentary record and thermal modelling results of apatite fission track data. (U–Th)/He thermochronology of two single fluorite grains from a fluorite–quartz vein within the fault zone yield Cretaceous ages that clearly postdate their Late-Variscan mineralization age. We propose that later reactivation of the fault caused loss of helium in the fluorites. This assertion is supported by geological evidence, i.e. offsets of Jurassic and Cretaceous sediments along the fault and apatite fission track thermal modelling results are consistent with the prevalence of elevated temperatures (50–80°C) in the fault zone during the Cretaceous

The south-western Black Forest and the Upper Rhine Graben Main Border Fault : thermal history and hydrothermal fluid flow

The thermal history of the south-westernmost Black Forest (Germany) and the adjacent Upper Rhine Graben were constrained by a combination of apatite and zircon fission-track (FT) and microstructural analyses. After intrusion of Palaeozoic granitic plutons in the Black Forest, the thermal regime of the studied area re-equilibrated during the Late Permian and the Mesozoic, interrupted by enhanced hydrothermal activity during the Jurassic. At the eastern flank of the Upper Rhine Graben along the Main Border Fault the analysed samples show microstructural characteristics related to repeated tectonic and hydrothermal activities. The integration of microstructural observations of the cataclastic fault gouge with the FT data identifies the existence of repeated tectonic-related fluid flow events characterised by different thermal conditions. The older took place during the Variscan and/or Mesozoic time at temperatures lower than 280A degrees C, whereas the younger was probably contemporary with the Cenozoic rifting of the Upper Rhine Graben at temperatures not higher than 150A degrees C