A conditional form of Bruton's tyrosine kinase is sufficient to activate multiple downstream signaling pathways via PLC Gamma 2 in B cells

BACKGROUND: Bruton's tyrosine kinase (Btk) is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-γ2 (PLCγ2) and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCγ2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCγ2-deficient DT40 B cell line. RESULTS: Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCγ2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCγ2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways, and apoptosis. In DT40 B cells deficient for PLCγ2, Btk:ER activation failed to induce the signaling events described above with the consequence that the cells failed to undergo apoptosis. CONCLUSIONS: These data suggest that Btk:ER regulates downstream signaling pathways primarily via PLCγ2 in B cells. While it is not known whether activated Btk:ER precisely mimics activated Btk, this conditional system will likely facilitate the dissection of the role of Btk and its family members in a variety of biological processes in many different cell types

Tidal dissipation in rotating giant planets

[Abridged] Tides may play an important role in determining the observed distributions of mass, orbital period, and eccentricity of the extrasolar planets. In addition, tidal interactions between giant planets in the solar system and their moons are thought to be responsible for the orbital migration of the satellites, leading to their capture into resonant configurations. We treat the underlying fluid dynamical problem with the aim of determining the efficiency of tidal dissipation in gaseous giant planets. In cases of interest, the tidal forcing frequencies are comparable to the spin frequency of the planet but small compared to its dynamical frequency. We therefore study the linearized response of a slowly and possibly differentially rotating planet to low-frequency tidal forcing. Convective regions of the planet support inertial waves, while any radiative regions support generalized Hough waves. We present illustrative numerical calculations of the tidal dissipation rate and argue that inertial waves provide a natural avenue for efficient tidal dissipation in most cases of interest. The resulting value of Q depends in a highly erratic way on the forcing frequency, but we provide evidence that the relevant frequency-averaged dissipation rate may be asymptotically independent of the viscosity in the limit of small Ekman number. In short-period extrasolar planets, if the stellar irradiation of the planet leads to the formation of a radiative outer layer that supports generalized Hough modes, the tidal dissipation rate can be enhanced through the excitation and damping of these waves. These dissipative mechanisms offer a promising explanation of the historical evolution and current state of the Galilean satellites as well as the observed circularization of the orbits of short-period extrasolar planets.Comment: 74 pages, 12 figures, submitted to The Astrophysical Journa

Pamela: development of the RF system for a non-relativistic non-scaling FFAG

The PAMELA project(Particle Accelerator For MEdical Applications) currently consists of the design of a particle therapy facility. The project, which is in the design phase, contains Non-Scaling FFAG, particle accelerator capable of rapid beam acceleration, giving a pulse repetition rate of 1kHz, far beyond that of a conventional synchrotron. To realise the repetition rate, a key component of the accelerator is the rf accelerating system. The combination of a high energy gain per turn and a high repetition rate is a significant challenge. In this paper, options for the rf system of the proton ring and the status of development are presented

Low-energy Coulomb excitation of 62^{62}Fe and 62^{62}Mn following in-beam decay of 62^{62}Mn

Sub-barrier Coulomb-excitation was performed on a mixed beam of $^{62}$Mn and $^{62}$Fe, following in-trap $\beta^{-}$ decay of $^{62}$Mn at REX-ISOLDE, CERN. The trapping and charge breeding times were varied in order to alter the composition of the beam, which was measured by means of an ionisation chamber at the zero-angle position of the Miniball array. A new transition was observed at 418~keV, which has been tentatively associated to a $(2^{+},3^{+})\rightarrow1^{+}_{g.s.}$ transition. This fixes the relative positions of the $\beta$-decaying $4^{+}$ and $1^{+}$ states in $^{62}$Mn for the first time. Population of the $2^{+}_{1}$ state was observed in $^{62}$Fe and the cross-section determined by normalisation to the $^{109}$Ag target excitation, confirming the $B(E2)$ value measured in recoil-distance lifetime experiments.Comment: 9 pages, 10 figure

Universal corrections to scaling for block entanglement in spin-1/2 XX chains

We consider the R\'enyi entropies $S_n(\ell)$ in the one dimensional spin-1/2 Heisenberg XX chain in a magnetic field. The case n=1 corresponds to the von Neumann ``entanglement'' entropy. Using a combination of methods based on the generalized Fisher-Hartwig conjecture and a recurrence relation connected to the Painlev\'e VI differential equation we obtain the asymptotic behaviour, accurate to order ${\cal O}(\ell^{-3})$, of the R\'enyi entropies $S_n(\ell)$ for large block lengths $\ell$. For n=1,2,3,10 this constitutes the 3,6,10,48 leading terms respectively. The o(1) contributions are found to exhibit a rich structure of oscillatory behaviour, which we analyze in some detail both for finite $n$ and in the limit $n\to\infty$.Comment: 25 pages, 5 figure

An Observational Study of the First Experience with Bevacizumab for the Treatment of Patients with Recurrent High-Grade Glioma in Two Belgian University Hospitals

Background. Bevacizumab (BEV), a humanized immunoglobulin G1 monoclonal antibody that inhibits VEGF has demonstrated activity against recurrent high-grade gliomas (HGG) in phase II clinical trials. Patients and Methods. Data were collected from patients with recurrent HGG who initiated treatment with BEV outside a clinical trial protocol at two Belgian university hospitals. Results. 19 patients (11 M/8 F) were administered a total of 138 cycles of BEV (median 4, range 1–31). Tumor response assessment by MRI was available for 15 patients; 2 complete responses and 3 partial responses for an objective response rate of 26% for the intent to treat population were observed on gadolinium-enhanced T1-weighted images; significant regressions on T2/FLAIR were documented in 10 out of 15 patients (67%). A reduced uptake on PET was documented in 3 out of 4 evaluable patients. The six-month progression-free survival was 21% (95% CI 2.7–39.5). Two patients had an ongoing tumor response and remained free from progression after 12 months of BEV treatment. Conclusions. The activity and tolerability of BEV were comparable to results from previous prospective phase II trials. Reduced uptake on PET suggests a metabolic response in addition to an antiangiogenic effect in some cases with favorable clinical outcome

Conceptual design of a nonscaling fixed field alternating gradient accelerator for protons and carbon ions for charged particle therapy

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.The conceptual design for a nonscaling fixed field alternating gradient accelerator suitable for charged particle therapy (the use of protons and other light ions to treat some forms of cancer) is described.EPSR

Relative Reactivity of the Metal-Amido versus Metal-Imido Bond in Linked Cp-Amido and Half-Sandwich Complexes of Vanadium

Treatment of (η5-C5H4C2H4NR)V(N-t-Bu)Me (R = Me, i-Pr) and CpV(N-p-Tol)(N-i-Pr2)Me (Cp = η5-C5H5) with B(C6F5)3 or [Ph3C][B(C6F5)4] results in formation of the corresponding cations, [(η5-C5H4C2H4NR)V(N-t-Bu)]+ and [CpV(N-p-Tol)(N-i-Pr2)]+. The latter could also be generated as its N,N-dimethylaniline adduct by treatment of the methyl complex with [PhNMe2H][BAr4] (Ar = Ph, C6F5). Instead, the analogous reaction with the linked Cp-amido precursor results in protonation of the imido-nitrogen atom. Sequential cyclometalation of the amide substituents gave cationic imine complexes [(η5-C5H4C2H4NCR'2)V(NH-t-Bu)]+ (R' = H, Me) and methane. Reaction of cationic [(η5-C5H4C2H4NR)V(N-t-Bu)]+ with olefins affords the corresponding olefin adducts, whereas treatment with 1 or 2 equiv of 2-butyne results in insertion of the alkyne into the vanadium-nitrogen single bond, affording the mono- and bis-insertion products [(η5-C5H4C2H4N(i-Pr)C2Me2)V(N-t-Bu)]+ and [(η5-C5H4C2H4N(i-Pr)C4Me4)V(N-t-Bu)]+. The same reaction with the half-sandwich compound [CpV(N-p-Tol)(N-i-Pr2)]+ results in a paramagnetic compound that, upon alcoholysis, affords sec-butylidene-p-tolylamine, suggesting an initial [2+2] cycloaddition reaction. The difference in reactivity between the V-N bond versus the V=N bond was further studied using computational methods. Results were compared to the isoelectronic titanium system CpTi(NH)(NH2). These studies indicate that the kinetic product in each system is derived from a [2+2] cycloaddition reaction. For titanium, this was found as the thermodynamic product as well, whereas the insertion reaction was found to be thermodynamically more favorable in the case of vanadium.