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Translation is a tightly regulated process and is predominantly controlled at the level of its initiation. Translation initiation mostly occurs in a cap-dependent manner. Under stress conditions when cap-dependent translation is hampered, internal ribosome entry sites (IRESes) allow for cap-independent translation of certain mRNAs. IRES-dependent translation is commonly regulated by RNA-interacting proteins, known as IRES trans -acting factors (ITAFs). In the present study, we found the 5′ untranslated region (UTR) of the thioredoxin-interacting protein (TXNIP) mRNA to be bound by the ITAF hnRNPA1. Upon verification of an IRES element within the 5′UTR of TXNIP, we determined additional interacting proteins, which predominantly appeared to interact with the IRES-regulatory second half of the 5′UTR. Amongst these PTB emerged as an inhibitory ITAF, whereas FBP3 and GEMIN5 appeared to contain TXNIP IRES-enhancing properties. In summary, we identified and characterized a novel IRES within the 5′UTR of TXNIP, which is regulated by the ITAFs PTB, FBP3, and GEMIN5.

Background and purpose To investigate (1) whether a plan library established at one institution can be applied for another institution's knowledge-based planning (KBP); (2) the performance of cross-institutional KBP compared to Auto-Planning Engine (APE). Material and methods Radboud University Medical Center (RUMC) provided 35 oropharyngeal cancer patients (68Gy to PTV 68 and 50.3Gy to PTV 50.3 ) with clinically-delivered and comparative APE plans. The Johns Hopkins University (JHU) contributed a three-dose-level plan library consisting of 179 clinically-delivered plans. MedStar Georgetown University Hospital (MGUH) contributed a KBP approach employing overlap-volume histogram (OVH-KBP), where the JHU library was used for guiding RUMC patients' KBP. Since clinical protocols adopted at RUMC and JHU are different and both approaches require protocol-specific planning parameters as initial input, 10 randomly selected patients from RUMC were set aside for deriving them. The finalized parameters were applied to the remaining 25 patients for OVH-KBP and APE plan generation. A Wilcoxon rank-sum test was used for statistical comparison. Results PTV 68 and PTV 50.3 's V 95 in OVH-KBP and APE were similar ( p >0.36). Cord's D 0.1 cc in OVH-KBP was reduced by 5.1Gy ( p =0.0001); doses to other organs were similar ( p >0.2). Conclusion APE and OVH-KBP's plan quality is comparable. Institutional-protocol differences can be addressed to allow cross-institutional library sharing.

Translation is an energy-intensive process and tightly regulated. Generally, translation is initiated in a cap-dependent manner. Under stress conditions, typically found within the tumor microenvironment in association with e.g. nutrient deprivation or hypoxia, cap-dependent translation decreases, and alternative modes of translation initiation become more important. Specifically, internal ribosome entry sites (IRES) facilitate translation of specific mRNAs under otherwise translation-inhibitory conditions. This mechanism is controlled by IRES trans-acting factors (ITAF), i.e. by RNA-binding proteins, which interact with and determine the activity of selected IRESs. We aimed at characterizing the translational regulation of the IL-33 decoy receptor sST2, which was enhanced by fibroblast growth factor 2 (FGF2). We identified and verified an IRES within the 5'UTR of sST2. Furthermore, we found that MEK/ERK signaling contributes to FGF2-induced, sST2-IRES activation and translation. Determination of the sST2-5'UTR structure by in-line probing followed by deletion analyses identified 23 nucleotides within the sST2-5'UTR to be required for optimal IRES activity. Finally, we show that the RNA-binding protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds to the sST2-5'UTR, acts as an ITAF, and thus controls the activity of the sST2-IRES and consequently sST2 translation. Specifically, FGF2 enhances nuclear-cytoplasmic translocation of hnRNP A1, which requires intact MEK/ERK activity. In summary, we provide evidence that the sST2-5'UTR contains an IRES element, which is activated by a MEK/ERK-dependent increase in cytoplasmic localization of hnRNP A1 in response to FGF2, enhancing the translation of sST2.

Background & Aim Traumatic events leading to focal lesions in articular cartilage are an important cause of joint functionality deterioration, leading to physical inactivity and osteoarthritis. Although restorative and regenerative strategies utilizing different scaffolds seeded with chondrocytes or progenitor cells have been tested with partial success. Their indication is limited for small lesions and their mechanical insufficiency of the fibrocartilage can result in their degeneration overtime, requiring patients to be re-operated within two years. Treatment modalities that favor the application of rapidly-crosslinking biopolymeric solutions to reconstruct cartilage lesions via an arthroscopic approach are highly desirable to reduce risk, surgery time and post-operative recovery times. The desired features of the alternative materials for lesion restoration should match the mechanical properties of cartilage, mimic its mechanical behavior and exhibit satisfactory chondro-inductive capacity. Methods, Results & Conclusion In this work, a new methacrylamide-functionalized gelatin extracted from a cold-adapted species was evaluated as the principal biopolymer for a photo-curable and injectable formulation for cartilage restoration. Unlike using mammalian gelatin, the cold-adapted nature allowed the formulation of highly concentrated biopolymeric solutions (>35 % W/V), while maintaining arthroscopic extrudability and avoiding sol-gel transition at room temperature. The dense and interconnected network of biopolymers after photo-crosslinking showed similar stiffness to human cartilage (∼ 1 MPa), whereas the chondrocyte-laden biopolymeric network was capable to induce formation of cartilage tissue in vitro, presenting similar values to human cartilage in glycosaminoglycan (GAG) (∼ 2 µg/mg), mRNA collagen(Col)2A/Col1A mRNA ratio (∼7) and similar distribution of GAG and Col staining across the scaffold. Finally, precise arthroscopic restoration of a cartilage lesion has been proven in a 3D simulation model. The developed Injectable functionalized-gelatin formulation respond to all the suitability criteria for using the regeneration of functional hyaline cartilage of patients through minimally invasive procedures.

Deregulation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-70kDa ribosomal protein S6 kinase 1 (p70(S6K)) pathway is commonly observed in many tumors. This pathway controls proliferation, survival, and translation, and its overactivation is associated with poor prognosis for tumor-associated survival. Current efforts focus on the development of novel inhibitors of this pathway. In a cell-based high-throughput screening assay of 15,272 pure natural compounds, we identified pomiferin triacetate as a potent stabilizer of the tumor suppressor programmed cell death 4 (Pdcd4). Mechanistically, pomiferin triacetate appeared as a general inhibitor of the PI3K-Akt-mTOR-p70(S6K) cascade. Interference with this pathway occurred downstream of Akt but upstream of p70(S6K). Specifically, mTOR kinase emerged as the molecular target of pomiferin triacetate, with similar activities against mTOR complexes 1 and 2. In an in vitro mTOR kinase assay pomiferin triacetate dose-dependently inhibited mTOR with an IC50 of 6.2 μM. Molecular docking studies supported the interaction of the inhibitor with the catalytic site of mTOR. Importantly, pomiferin triacetate appeared to be highly selective for mTOR compared to a panel of 17 lipid and 50 protein kinases tested. As a consequence of the mTOR inhibition, pomiferin triacetate efficiently attenuated translation. In summary, pomiferin triacetate emerged as a novel and highly specific mTOR inhibitor with strong translation inhibitory effects. Thus, it might be an interesting lead structure for the development of mTOR- and translation-targeted anti-tumor therapies.

Background Carpal tunnel syndrome is a commonly encountered entrapment disorder resulting from mechanical insult to the median nerve. Magnetic resonance imaging (MRI)-based investigations have documented typical locations of the median nerve within the carpal tunnel; however, it is unclear whether those locations are consistent within an individual on different days. Methods To determine the day-to-day variability of nerve location, 3.0 T MRI scans were acquired from six normal volunteers over multiple sessions on three different days. Half of the scans were acquired with the wrist in neutral flexion and the fingers extended, and the other half were acquired with the wrist in 35° of flexion and the fingers flexed. Prior to half of the scans (in both poses), subjects performed a preconditioning routine consisting of specified hand activities and several repetitions of wrist flexion/extension. The shape, orientation, location, and location radius of variability of the median nerve and three selected flexor tendons were determined for each subject and compared between days. Findings Two of the six subjects had substantial variability in nerve location when the wrist was in neutral, and four of the subjects had high variability in nerve position when the wrist was flexed. Nerve variability was typically larger than tendon variability. The preconditioning routine did not decrease nerve or tendon location variability in either the neutral or the flexed wrist positions. Interpretation The high mobility and potential for large variability in median nerve location within the carpal tunnel needs to be borne in mind when interpreting MR images of nerve location.

There are many large-scale problems that require new approaches to computing, such as earth observation, environmental management, biomedicine, industrial and scientific modeling. The CrossGrid project addresses realistic problems in medicine, environmental protection, flood prediction, and physics analysis and is oriented towards specific end-users: Medical doctors, who could obtain new tools to help them to obtain correct diagnoses and to guide them during operations; industries, that could be advised on the best timing for some critical operations involving risk of pollution; flood crisis teams, that could predict the risk of a flood on the basis of historical records and actual hydrological and meteorological data; physicists, who could optimize the analysis of massive volumes of data distributed across countries and continents. Corresponding applications will be based on Grid technology and could be complex and difficult to use: the CrossGrid project aims at developing several tools that will make the Grid more friendly for average users. Portals for specific applications will be designed, that should allow for easy connection to the Grid, create a customized work environment, and provide users with all necessary information to get their job done.

Here, we will demonstrate a new approach to merge high performance III/V-material properties with optical display technology. In a first step a low temperature grown and processed InP-FET structure not surpassing a temperature of 300°C is transferred to GaAs with the potential of future transfer to Si and other substrate materials. Future large area display panels require electronic overlay circuitry for optical arrays with high performance. FETs with high current densities grown on various substrate materials optimized to drive simultaneously a large number of light sources will be required. Furthermore each process step, including materials growth, has to be performed at extremely low temperatures to prevent degradation of the low-cost substrates, mainly glass and polymer.

A trend to greater precision can be observed in production processes and technical testing procedures. Precision means that the process runs within narrow limits and that these limits are maintained with high probability. Even dyeing or printing processes in the laboratory or production plant are subject to greater or lesser fluctuations when the same processes are repeated. Quality Management according to the ISO 9000-9004 standard requires that, among other things, specifications, reproducibility levels and measurement uncertainties be defined or determined. Fundamental concepts of statistics are treated such as mean value, standard deviation, variation coefficient, confidence interval and measurement uncertainty and statistical process control (SPC). An attempt is made to reply to the question “How precisely can the colour strength of a dyestuff be determined?”. Narrower specifications can only be realistically fulfilled when the measurement uncertainty factor can be correspondingly reduced, which can often only be achieved by additional, cost-intensive measures. Value is attached to the simplest possible presentation. ©

The consolidation of metalized ceramic fibers by hot isostatic pressing (HIP) offers an attractive route for the manufacture of continuous fiber reinforced titanium matrix composites (TMCs). The performance of this class of composites is controlled by the fiber/matrix properties and by the composite's relative density, the grain size of the matrix alloy and the interfacial reaction layer thickness at the fiber–matrix interface after processing. Recently developed process models that predict the evolution of these microstructural attributes during consolidation processing are summarized and combined with consolidation equipment dynamics to simulate the microstructural evolution of PVD Ti–6Al–4V coated Sigma 1240 (SiC) monofilaments during HIP. For this system, diffusion accommodated grain sliding is the dominant densification mechanism for process cycles that preserve the refined grain size of the PVD metal coating.

The vacuum hot pressing (VHP) of silicon carbide monofilaments coated with nanocrystalline Ti–6Al–4V has been studied. During consolidation, very high densification rates were observed, even at temperatures and pressures well below those normally used for processing conventional Ti–6Al–4V. From the cross-sections of partially consolidated specimens, the evolution of coated fiber–fiber contacts and pore shapes were determined. The pores were found to be cusp-shaped throughout the consolidation process. Columns of coated fibers were observed to form along the loading direction and resulted in regions of locally high fiber volume fraction. Simulations of the VHP experiments were performed using a model which incorporated time and temperature dependent microstructure relationships. In the model, the initial densification was based upon a recent micromechanical contact analysis for a metal coated fiber. Final stage densification was analyzed by modifying the Qian et al. strain rate potential for a power law creeping body containing isolated cusp-shaped pores. Overall, the simulations compared well with the experimental density data, although the load supported by the regions of locally high fiber volume fraction resulted in the model slightly overestimating the observed densification time response.

The π 0 momentum dependence of the decay η → π + π − π 0 has been measured with the Crystal Barrel detector. The analysis is based on 3230 events. The results of this independent measurement are compared to new chiral perturbation theory calculations and previous measurements.

The annihilation channel p p →K + K − π 0 in liquid hydrogen at rest has been studied with the Crystal Barrel detector at LEAR. The measured branching ratio is: BR ( p p → K + K − π 0 )=(2.37±0.15)×10 −3 . A partial wave analysis shows that this reaction is dominated by the π (K K ) S , K K ∗ (892) and π φ (1020) intermediate states. Weak signals are observed for π a 2 (1320), π f 2 (1270), π f 2 ′(1525) and K(Kπ) S . A satisfactory description of the Dalitz plot requires the introduction of π (K K ) P intermediate states with at least one pole.

An experimental study of the consolidation and associated grain growth kinetics of silicon carbide monofilaments sputter coated with nanocrystalline Ti6Al4V has been conducted. Bundles of coated fibers were consolidated using a hot isostatic press (HIP) equipped with an eddy current sensor for in situ measurement of the specimens' relative density. The experiments were conducted at temperatures of 760°, 840°, and 900°C using a variety of pressure cycles that resulted in both fully and partially consolidated composites. The sensor data was used to determine the densification-time response of the specimens and to construct experimental HIP maps. Cross-sections of the partially consolidated specimens were used to investigate the evolution of coated fiber-fiber contacts and interfiber void shapes. The analysis indicated that the initial packing density was approximately random with an average of only about two contacts per coated fiber at a relative density of 70%. The number of contacts was a linear function of relative density reaching a maximum of almost six contacts per coated fiber at the theoretical density. The pores were found to be cusp-shaped throughout the consolidation process, indicative of a densification rate that greatly exceeded the (pore rounding) rate of sintering.

Near net shape titanium and nickel matrix composites can be produced by the hot isostatic/vacuum hot pressing of alloy coated ceramic fibers. During the initial stage of consolidation, densification occurs by the inelastic deformation of metal-metal contacts. When the temperature is low and the consolidation pressure is high, the dominant mechanism of contact deformation is matrix plasticity. This densification process is investigated by analysing the elastic-plastic contact deformation of aligned fibers. Applying a methodology developed for modelling the consolidation of alloy powders and spray deposited composite monotapes, a contact yield criterion has been proposed and used to predict the dependence of the relative density upon process conditions and matrix mechanical properties. The resulting densification model contains unknown plastic flow (F) and contact area evolution (c) coefficients. A deformation theory elastic-plastic finite element analysis of a representative coated fiber unit cell loaded in compression is used to find these coefficients. The analysis shows the ceramic fiber significantly constrains plasticity in the alloy coating resulting in fiber volume fraction dependent coefficients and a fiber volume fraction dependent density-pressure relationship for coated fiber consolidation.

The Crystal Barrel Detector has been in operation since October 1989. Results on the analysis of the annihilation of protonium at rest into three pseudoscalars is presented. The π 0 π 0 π 0 final state confirms the existence of ƒ 2 (1520)→π 0 π 0 . In the ηη system of the π 0 ηη final state an isoscalar J PC = 0 ++ resonance with a mass of 1560 MeV/c 2 and a width of 245 MeV/c 2 is observed. The identification with ƒ 0 (1590) is doubtful since the ηη' decay is not observed with the corresponding strength. Our analysis yields an upper limit for the relative branching ratio BR(ƒ 0 (1560)→ηη') BR(ƒ 0 (1560)→ηη) .

We discuss φ production in p p annihilation at rest from the Asterix and Crystal Barrel experiments and compare the branching ratios to similar final states without strangeness. The ωπ 0 φπ 0 production ratio is unexpectedly low. In the search for new states, the φπ0 mass spectrum shows no evidence for a resonance in the 1450 MeV/c2 mass range but the K☆K0π0 Dalitz plot shows interesting structure.

Three different programs for protection of the oral mucosa were examined in 30 children and adolescents undergoing cytostatic therapy. The programs consisted of (a) a liquid of 0.1% Hexeditin + a soluble combination of an extract of rhubarb, salicylic acid and ethanol, (b) a liquid of 0.1% chlorhexidine digluconate and sugar-free chewing gum, and (c) a liquid of amino fluoride/tin fluoride and sugarfree chewing gum. All three programs seemed to protect the oral mucosa equally well The programs also protected the teeth from increased plaque coverage in 69–90% of all examinations. However, there were striking differences in the acceptance of the three programs. Those containing sugarfree chewing gum were preferred by 83% of the examined children, frequently because of the good taste and the easy way of application. A reason for some patients to decline a program was the painful biting taste that liquids sometimes had on irritable or ulcerative districts of the mucosa. Good compliance is important and essential for protecting the oral mucosa of an immunocompromised child. Different forms of oral disinfection work well, but their acceptance depends on their taste and painless application. The combination of a mild disinfective solution and sugarfree chewing gum is recommended.

Since every hypercode is finite, one may ask for the significance of the property that a language L admits a uniform upper bound on the size of hypercodes included in L . Such a language L is called h-bounded . We prove that a rational language L is h -bounded iff it is thin iff it is semi-discrete , i.e., L contains at most k words of any given length for some fixed k ∈ ℕ. Moreover, a representation of these languages by regular expressions is established. Concerning the general case, some properties of the syntactic monoid Synt( L ) of an h -bounded (semi-discrete) language are derived. If L is not disjunctive, then Synt( L ) contains a zero element. Every subgroup of Synt( L ) is a finite cyclic group. The idempotents of Synt( L )\{0, 1~ form an antichain with respect to the usual partial order.