Alterations in cell growth and signaling in ErbB3 binding protein-1 (Ebp1) deficient mice

<p>Abstract</p> <p>Background</p> <p>The ErbB3 binding protein-1 (Ebp1) belongs to a family of DNA/RNA binding proteins implicated in cell growth, apoptosis and differentiation. However, the physiological role of Ebp1 in the whole organism is not known. Therefore, we generated <it>Ebp1</it>-deficient mice carrying a gene trap insertion in intron 2 of the <it>Ebp1 (pa2g4) </it>gene.</p> <p>Results</p> <p>Ebp1^-/-mice were on average 30% smaller than wild type and heterozygous sex matched littermates. Growth retardation was apparent from Day 10 until Day 30. IGF-1 production and IGBP-3 and 4 protein levels were reduced in both embryo fibroblasts and adult knock-out mice. The proliferation of fibroblasts derived from Day 12.5 knock out embryos was also decreased as compared to that of wild type cells. Microarray expression analysis revealed changes in genes important in cell growth including members of the MAPK signal transduction pathway. In addition, the expression or activation of proliferation related genes such as AKT and the androgen receptor, previously demonstrated to be affected by Ebp1 expression <it>in vitro</it>, was altered in adult tissues.</p> <p>Conclusion</p> <p>These results indicate that Ebp1 can affect growth in an animal model, but that the expression of proliferation related genes is cell and context specific. The Ebp1^-/-mouse line represents a new <it>in vivo </it>model to investigate Ebp1 function in the whole organism.</p

Single flux quantum circuits with damping based on dissipative transmission lines

We propose and demonstrate the functioning of a special Rapid Single Flux Quantum (RSFQ) circuit with frequency-dependent damping. This damping is achieved by shunting individual Josephson junctions by pieces of open-ended RC transmission lines. Our circuit includes a toggle flip-flop cell, Josephson transmission lines transferring single flux quantum pulses to and from this cell, as well as DC/SFQ and SFQ/DC converters. Due to the desired frequency-dispersion in the RC line shunts which ensures sufficiently low noise at low frequencies, such circuits are well-suited for integrating with the flux/phase Josephson qubit and enable its efficient control.Comment: 6 pages incl. 6 figure

Jet formation and jet velocity fluctuations in a flue organ pipe

Flow visualization of the initial transient in a small recorderlike flue organ pipe is presented and the various stages of the jet formation are related to measurements of the acoustic response of the pipe. An initial acoustic signal, due to the unsteady volume flow of the jet, appears before the forming jet reaches the labium. This signal can easily be modeled using a low-frequency approximation. The initial trajectory of the jet makes a curve towards the exterior of the pipe. Under certain conditions, the jet may even, at first, miss the labium. This effect is related to the steepness of the pressure rise in the foot of the pipe. The initial impact of the jet with the labium appears to be a crucial factor in the triggering of the transient. Moving the labium towards the exterior of the pipe, using a steep pressure rise or putting ears around the mouth increase the chance that the jet will hit the labium. This initial impact is followed by an impulsive vortex shedding at the labium and subsequently a high-frequency varicoselike oscillation is observed on the jet. This oscillation is also observed without labium. After about three periods of the fundamental mode of the pipe, turbulence appears therefore destroying these coherent structures. Whereas the time dependency of the jet velocity dominates the first stage of the starting transient, the jet velocity fluctuations during steady-state result in a non-negligible damping. This loss mechanism is, for the fundamental mode of our experimental organ pipe, of the same order of magnitude as the radiation or visco-thermal damping.</p

Spatial organization in cyclic Lotka-Volterra systems

We study the evolution of a system of $N$ interacting species which mimics the dynamics of a cyclic food chain. On a one-dimensional lattice with N<5 species, spatial inhomogeneities develop spontaneously in initially homogeneous systems. The arising spatial patterns form a mosaic of single-species domains with algebraically growing size, $\ell(t)\sim t^\alpha$, where $\alpha=3/4$ (1/2) and 1/3 for N=3 with sequential (parallel) dynamics and N=4, respectively. The domain distribution also exhibits a self-similar spatial structure which is characterized by an additional length scale, ${\cal L}(t)\sim t^\beta$, with $\beta=1$ and 2/3 for N=3 and 4, respectively. For $N\geq 5$, the system quickly reaches a frozen state with non interacting neighboring species. We investigate the time distribution of the number of mutations of a site using scaling arguments as well as an exact solution for N=3. Some possible extensions of the system are analyzed.Comment: 18 pages, 10 figures, revtex, also available from http://arnold.uchicago.edu/~ebn

Trade unions and precariat in Europe : representative claims

Trade unions have been charged with neglecting labour market ‘outsiders’, while alternative actors have emerged to represent these. In response, unions have stepped up their claim to be representative of all workers, without distinction. We review the theoretical and policy debates on this issue, and argue that representation as such has been under-theorized. We draw on Saward’s concept of ‘representative claims’ to analyse the different grounds for competing assertions of representativeness. We identify four main forms of claims, and illustrate these with empirical examples. We conclude that these different claims are mutually reinforcing in stimulating attention to the outsiders, and in their interaction with institutional settings, they have a performative effect in defining new social actors

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

Firm heterogeneity and wages under different bargaining regimes : does a centralised union care for low-productivity firms?

This paper studies the relationship between wages and the degree of firm heterogeneity in a given industry under different wage setting structures. To derive testable hypotheses, we set up a theoretical model that analyses the sensitivity of wages to the variability in productivity conditions in a unionsised oligopoly framework. The model distinguishes centralised and decentralised wage determination. The theoretical results predict wages to be negatively associated with the degree of firm heterogeneity under centralised wage-setting, as unions internalise negative externalities of a wage increase for low-productivity firms. We test this prediction using a linked employeremployee panel data set from the German mining and manufacturing sector. Consistent with our hypotheses, the empirical results suggest that under industry-level bargaining workers in more heterogeneous sectors receive lower wages than workers in more homogeneous sectors. In contrast, the degree of firm heterogeneity is found to have no negative impact on wages in uncovered firms and under firm-level contracts

Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma

In this study, we demonstrate that vemurafenib but not dabrafenib reduces peripheral lymphocyte counts in melanoma patients while both agents show similar clinical efficacy. Within the lymphocyte compartment, vemurafenib selectively decreases circulating CD4+ T cells and changes their phenotype and function. This indicates that selective BRAFi need to be assessed individually for immunomodulatory effects, especially, when planning combinations with immunotherapie

546 Results from Phase Ib study of tebentafusp (tebe) in combination with durvalumab (durva) and/or tremelimumab (treme) in metastatic cutaneous melanoma (mCM)

BackgroundTebe, a T cell receptor fused to an anti-CD3 effector, can redirect T cells to target gp100+ cells and in Ph3, demonstrated overall survival (OS) benefit as monotherapy in metastatic uveal melanoma. In Ph2, any tumor shrinkage (44% of patients) was a better predictor of OS than response rate. In Ph1, Tebe had monotherapy activity in mCM, also a gp100+ tumor, with 1-year OS ~74% in PD-1 naïve mCM. A Ph1 dose escalation of tebe with durva (anti-PD-L1) and/or treme (anti-CTLA4) was conducted in pre-treated mCM [NCT02535078], with nearly all patients having prior PD1-treatment, and where recently reported therapies have 1-yr OS of ~55%.MethodsHeavily pre-treated HLA-A2+ mCM patients received weekly IV tebe alone (Arm 4) or with increasing doses of durva and/or treme (Arm 1–3) administered IV monthly starting day 15 of each cycle. Primary objective was to identify RP2D of combination therapy. Secondary objectives included adverse events (AE) and efficacy.Results112 pts received ≥1 tebe dose. Median age was 59, 77% were ECOG 0, and 37% were BRAFm (of which 71% received prior BRAFi/MEKi). 91% of pts were 2L+, while 74% were 3L+. 103 (92%) received prior PD-1 inhibitor, of which 87% also received prior ipilimumab. 43 pts received tebe + durva (Arm 1), 13 received tebe + treme (Arm 2), 29 received triplet therapy (Arm 3), and 27 received tebe alone (Arm 4). Maximum target doses of tebe (68 mcg) + durva (20 mg/kg) and treme (1 mg/kg) were tolerated. MTD was not formally identified for any arm. Two DLTs occurred: prolonged grade 3 rash (Arm 1) and grade 2 diarrhea leading to treatment delay (Arm 2). Related AEs that were Grade ≥3 or led to discontinuations were: 44%/0% (Arm 1), 23%/0% (Arm2), 38%/7% (Arm3), 26%/4% (Arm 4). There were no treatment-related deaths.In prior PD-1 pts, tumor shrinkage occurred in 36% and 1-yr OS was 68%. Of 51 evaluable PD-1 resistant pts (best response CR/PR/SD to prior PD1), tumor shrinkage occurred in 28% and 1-yr OS was 73% (figure 1). In 35 evaluable PD-1 refractory pts (prior best response PD), tumor shrinkage occurred in 49% and 1-yr OS was 61%. For 38 prior PD-1 pts who received ≥10mg/kg durva, 1-yr OS was 81%.Abstract 546 Figure 1% tumor change from baseline in evaluable patients with known response to prior PD1 exposureConclusionsTebe with anti-PD-L1 and/or anti-CTLA4 had an acceptable safety profile. Tebe + durva demonstrated durable tumor shrinkage and promising 1-yr OS rates in prior-PD1 treated mCM relative to recent reports.Trial RegistrationNCT02535078Ethics ApprovalThe institutional review board or independent ethics committee at each center approved the trial. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines