RNA-dependent association with myosin IIA promotes F-actin-guided trafficking of the ELAV-like protein HuR to polysomes

The role of the mRNA-binding protein human antigen R (HuR) in stabilization and translation of AU-rich elements (ARE) containing mRNAs is well established. However, the trafficking of HuR and bound mRNA cargo, which comprises a fundamental requirement for the aforementioned HuR functions is only poorly understood. By administering different cytoskeletal inhibitors, we found that the protein kinase Cδ (PKCδ)-triggered accumulation of cytoplasmic HuR by Angiotensin II (AngII) is an actin-myosin driven process functionally relevant for stabilization of ARE-bearing mRNAs. Furthermore, we show that the AngII-induced recruitment of HuR and its bound mRNA from ribonucleoprotein particles to free and cytoskeleton bound polysomes strongly depended on an intact actomyosin cytoskeleton. In addition, HuR allocation to free and cytoskeletal bound polysomes is highly sensitive toward RNase and PPtase and structurally depends on serine 318 (S318) located within the C-terminal RNA recognition motif (RRM3). Conversely, the trafficking of the phosphomimetic HuRS318D, mimicking HuR phosphorylation at S318 by the PKCδ remained PPtase resistant. Co-immunoprecipitation experiments with truncated HuR proteins revealed that the stimulus-induced association of HuR with myosin IIA is strictly RNA dependent and mediated via the RRM3. Our data implicate a microfilament dependent transport of HuR, which is relevant for stimulus-induced targeting of ARE-bearing mRNAs from translational inactive ribonucleoprotein particles to polysomes

Electronic properties of Mn-Phthalocyanine - C60_{60} bulk heterojunctions: combining photoemission and electron energy-loss spectroscopy

The electronic properties of co-evaporated mixtures (blends) of manganese phthalocyanine and the fullerene C$_{60}$ (MnPc:C$_{60}$) have been studied as a function of the concentration of the two constituents using two supplementary electron spectroscopic methods, photoemission spectroscopy (PES) as well as electron energy-loss spectroscopy (EELS) in transmission. Our PES measurements provide a detailed picture of the electronic structure measured with different excitation energies as well as different mixing ratios between MnPc and C$_{60}$. Besides a relative energy shift, the occupied electronic states of the two materials remain essentially unchanged. The observed energy level alignment is different compared to that of the related CuPc:C$_{60}$ bulk heterojunction. Moreover, the results from our EELS investigations show that despite of the rather small interface interaction the MnPc related electronic excitation spectrum changes significantly by admixing C$_{60}$ to MnPc thin films

Systems biology-based investigation of cooperating microRNAs as monotherapy or adjuvant therapy in cancer

MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer

zkRelay: Facilitating Sidechains using zkSNARK-based Chain-Relays

We facilitate trusted cross-blockchain state proofs by implementing a chain-relay that validates block headers from proof-of-work blockchains. While current approaches require proof sizes linear to the amount of blocks the state was built on, trusted intermediaries, or economic assumptions, we propose the utilization of off-chain computations through zkSNARKs to provide a cryptographically secure and highly scalable sidechain mechanism. Multiple block headers are included in batches and verified off-chain, while preserving light client support. Only the validity of the off-chain computation is verified on-chain, creating a sidechain mechanism that requires constant verification costs and releases the target ledger from processing and storing every single block header of the source blockchain. We provide a prototypical implementation that facilitates the verification of 504 Bitcoin headers in a single proof on Ethereum using the ZoKrates framework. Hereby, the verification costs are reduced by a factor of 187 compared to current approaches such as BTC Relay

Shear Strength Behavior of Different Geosynthetic Reinforced Soil Structure from Direct Shear Test

This paper presents the results of direct shear test on soil samples reinforced with geosynthetics, conducted with the aim of characterize the shear strength of reinforced soil composite. Two types of granular soil (well graded sand and silty sand) and four types of geosynthetic (woven and nonwoven geotextile—uniaxial and biaxial geogrid) were selected. Laboratory testing program were performed in two shear boxes, circular box with 63 mm in diameter and square box with 100 mm in length; the samples were made with loose and dense sand; the reinforcement layer was placed perpendicular to the failure surface; tests are conducted with three vertical confining pressures: 15.7, 31.4 and 62.8 kPa. The effect of different factors that influence the results of the shear tests is analyzed, such as: the particle size of soils, density of soils, shear box size and type of geosynthetics. The test results reveal that the maximum value of shear strength improvement was achieved for dense silty sand samples reinforced with biaxial geogrid. In general, the improvement was more favorable for samples reinforced with geogrid compared to samples reinforced with geotextile.Fil: Useche Infante, Danny Jose. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Departamento de Ingeniería Civil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Aiassa Martinez, Gonzalo Martin. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Departamento de Ingeniería Civil; ArgentinaFil: Arrua, Pedro Ariel. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Departamento de Ingeniería Civil; ArgentinaFil: Eberhardt, Marcelo Gabriel. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Departamento de Ingeniería Civil; Argentin

Superfluid Helium Tanker (SFHT) study

Replenishment of superfluid helium (SFHe) offers the potential of extending the on-orbit life of observatories, satellite instruments, sensors and laboratories which operate in the 2 K temperature regime. A reference set of resupply customers was identified as representing realistic helium servicing requirements and interfaces for the first 10 years of superfluid helium tanker (SFHT) operations. These included the Space Infrared Telescope Facility (SIRTF), the Advanced X-ray Astrophysics Facility (AXAF), the Particle Astrophysics Magnet Facility (Astromag), and the Microgravity and Materials Processing Sciences Facility (MMPS)/Critical Point Phenomena Facility (CPPF). A mixed-fleet approach to SFHT utilization was considered. The tanker permits servicing from the Shuttle cargo bay, in situ when attached to the OMV and carried to the user spacecraft, and as a depot at the Space Station. A SFHT Dewar ground servicing concept was developed which uses a dedicated ground cooling heat exchanger to convert all the liquid, after initial fill as normal fluid, to superfluid for launch. This concept permits the tanker to be filled to a near full condition, and then cooled without any loss of fluid. The final load condition can be saturated superfluid with any desired ullage volume, or the tank can be totally filed and pressurized. The SFHT Dewar and helium plumbing system design has sufficient component redundancy to meet fail-operational, fail-safe requirements, and is designed structurally to meet a 50 mission life usage requirement. Technology development recommendations were made for the selected SFHT concept, and a Program Plan and cost estimate prepared for a phase C/D program spanning 72 months from initiation through first launch in 1997

Failure of potassium siphoning by Muller cells: a new hypothesis of perfluorocarbon liquid-induced retinopathy,”

PURPOSE. To determine the effect of perfluorocarbon liquid (PFCL)-induced abolition of potassium siphoning by the vitreal end feet of Müller cells. METHODS. Porcine eyecups were filled with stained balanced salt solution and PFCLs (perfluorodecalin, perfluorooctane, perfluoroperhydrophenanthrene or the semifluorocarbon perfluorohexylhexane). With optical coherence tomography, the distance between PFCL and retina was determined, and the size of the aqueous space covering the retinal surface was estimated. The data were used to calculate the retinal potassium siphoning into small aqueous volumes. RESULTS. The distance between PFCL and retinal surface was found to be less than 5 to 10 m with any PFCL tested. The resultant volume of the aqueous space was too small to act as a sufficient sink for K ϩ ion siphoning. CONCLUSIONS. A certain threshold volume of vitreal fluid seems to be necessary for efficient buffering of intraretinal increases of K ϩ and perhaps other (e.g., H ϩ ) ions through the Müller cells. When the aqueous fluid is replaced by a PFCL (or by silicone oil) for longer periods, the outer retina becomes subject to long-lasting K ϩ accumulation, and consequent neurodegeneration and reactive gliosis occurs. The authors propose to search for new vitreous-substituting fluids with the capability to dissolve ions. (Invest Ophthalmol Vis Sci. 2000;41:256 -261

Higgs production cross-section in a Standard Model with four generations at the LHC

We present theoretical predictions for the Higgs boson production cross-section via gluon fusion at the LHC in a Standard Model with four generations. We include QCD corrections through NLO retaining the full dependence on the quark masses, and the NNLO corrections in the heavy quark effective theory approximation. We also include electroweak corrections through three loops. Electroweak and bottom-quark contributions are suppressed in comparison to the Standard Model with three generations.Comment: 6 pages, 2 Tables, to appear in the proceedings of the XLVIth Rencontres de Moriond session devoted to Electroweak Interactions and Unified Theorie

GALEX FUV Observations of Comet C/2004 Q2 (Machholz): The Ionization Lifetime of Carbon

We present a measurement of the lifetime of ground state atomic carbon, C(^3P), against ionization processes in interplanetary space and compare it to the lifetime expected from the dominant physical processes likely to occur in this medium. Our measurement is based on analysis of a far ultraviolet (FUV) image of comet C/2004 Q2 (Machholz) recorded by the Galaxy Evolution Explorer (GALEX) on 2005 March 1. The bright CI 1561 A and 1657 A multiplets dominate the GALEX FUV band. We used the image to create high S/N radial profiles that extended beyond one million km from the comet nucleus. Our measurements yielded a total carbon lifetime of 7.1 -- 9.6 x 10^5 s (scaled to 1 AU). Which compares favorably to calculations assuming solar photoionization, solar wind proton change exchange and solar wind electron impact ionization are the dominant processes occurring in this medium and that comet Machholz was embedded in the slow solar wind. The shape of the CI profiles inside 3x10^5 km suggests that either the CO lifetime is shorter than previously thought and/or a shorter-lived carbon-bearing parent molecule, such as CH_4 is providing the majority of the carbon in this region of the coma of comet Machholz.Comment: 26 pages, 6 figures, accepted for publication in the Astrophysical Journa