Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction

Somatic hypermutation specifically modifies rearranged immunoglobulin (Ig) genes in germinal center (GC) B cells. However, the bcl-6 gene can also acquire somatic mutations during the GC reaction, indicating that certain non-Ig genes can be targeted by the somatic hypermutation machinery. The CD95 gene, implicated in negative selection of B lymphocytes in GCs, is specifically expressed by GC B cells and was recently identified as a tumor suppressor gene being frequently mutated in (post) GC B cell lymphomas. In this study, the 5′ region (5′R) and/or the last exon coding for the death domain (DD) of the CD95 gene were investigated in naive, GC, and memory B cells from seven healthy donors. About 15% of GC and memory, but not naive, B cells carried mutations within the 5′R (mutation frequency 2.5 × 10−4 per basepair). Mutations within the DD were very rare but could be efficiently selected by inducing CD95-mediated apoptosis: in 22 apoptosis-resistant cells, 12 DD mutations were found. These results indicate that human B cells can acquire somatic mutations of the CD95 gene during the GC reaction, which potentially confers apoptosis resistance and may counteract negative selection through the CD95 pathway

Fast identification of folded human protein domains expressed in E. coli suitable for structural analysis

BACKGROUND: High-throughput protein structure analysis of individual protein domains requires analysis of large numbers of expression clones to identify suitable constructs for structure determination. For this purpose, methods need to be implemented for fast and reliable screening of the expressed proteins as early as possible in the overall process from cloning to structure determination. RESULTS: 88 different E. coli expression constructs for 17 human protein domains were analysed using high-throughput cloning, purification and folding analysis to obtain candidates suitable for structural analysis. After 96 deep-well microplate expression and automated protein purification, protein domains were directly analysed using 1D (1)H-NMR spectroscopy. In addition, analytical hydrophobic interaction chromatography (HIC) was used to detect natively folded protein. With these two analytical methods, six constructs (representing two domains) were quickly identified as being well folded and suitable for structural analysis. CONCLUSION: The described approach facilitates high-throughput structural analysis. Clones expressing natively folded proteins suitable for NMR structure determination were quickly identified upon small scale expression screening using 1D (1)H-NMR and/or analytical HIC. This procedure is especially effective as a fast and inexpensive screen for the 'low hanging fruits' in structural genomics

Radioactive 26Al and massive stars in the Galaxy

Gamma-rays from radioactive 26Al (half life ~7.2 10^5 yr) provide a 'snapshot' view of ongoing nucleosynthesis in the Galaxy. The Galaxy is relatively transparent to such gamma-rays, and emission has been found concentrated along the plane of the Galaxy. This led to the conclusion1 that massive stars throughout the Galaxy dominate the production of 26Al. On the other hand, meteoritic data show locally-produced 26Al, perhaps from spallation reactions in the protosolar disk. Furthermore, prominent gamma-ray emission from the Cygnus region suggests that a substantial fraction of Galactic 26Al could originate in localized star-forming regions. Here we report high spectral resolution measurements of 26Al emission at 1808.65 keV, which demonstrate that the 26Al source regions corotate with the Galaxy, supporting its Galaxy-wide origin. We determine a present-day equilibrium mass of 2.8 (+/-0.8) M_sol of 26Al. We use this to estimate that the frequency of core collapse (i.e. type Ib/c and type II) supernovae to be 1.9(+/- 1.1) events per century.Comment: accepted for publication in Nature, 24 pages including Online Supplements, 11 figures, 1 tabl

The GLAST Burst Monitor

The next large NASA mission in the field of gamma-ray astronomy, GLAST, is scheduled for launch in 2007. Aside from the main instrument LAT (Large-Area Telescope), a gamma-ray telescope for the energy range between 20 MeV and > 100 GeV, a secondary instrument, the GLAST burst monitor (GBM), is foreseen. With this monitor one of the key scientific objectives of the mission, the determination of the high-energy behaviour of gamma-ray bursts and transients can be ensured. Its task is to increase the detection rate of gamma-ray bursts for the LAT and to extend the energy range to lower energies (from ~10 keV to \~30 MeV). It will provide real-time burst locations over a wide FoV with sufficient accuracy to allow repointing the GLAST spacecraft. Time-resolved spectra of many bursts recorded with LAT and the burst monitor will allow the investigation of the relation between the keV and the MeV-GeV emission from GRBs over unprecedented seven decades of energy. This will help to advance our understanding of the mechanisms by which gamma-rays are generated in gamma-ray bursts.Comment: 8 pages, 7 figures, to appear in SPIE conference proceedings vol 5488, "UV-Gamma Ray Space Telescope Systems," Glasgow UK, 21-24 June 200

Diversity of critical behavior within a universality class

We study spatial anisotropy effects on the bulk and finite-size critical behavior of the O$(n)$ symmetric anisotropic $\phi^4$ lattice model with periodic boundary conditions in a $d$-dimensional hypercubic geometry above, at and below $T_c$. The absence of two-scale factor universality is discussed for the bulk order-parameter correlation function, the bulk scattering intensity, and for several universal bulk amplitude relations. For the confined system, renormalization-group theory within the minimal subtraction scheme at fixed dimension $d$ for $2<d<4$ is employed. For the case of cubic symmetry and for $n=1$ our perturbation approach yields excellent agreement with the Monte Carlo (MC) data for the finite-size amplitude of the free energy of the three-dimensional Ising model at $T_c$ by Mon [Phys. Rev. Lett. {\bf 54}, 2671 (1985)]. Below $T_c$ a minimum of the scaling function of the excess free energy is found. We predict a measurable dependence of this minimum on the anisotropy parameters. The relative anisotropy effect on the free energy is predicted to be significantly larger than that on the Binder cumulant. Our theory agrees quantitatively with the non-monotonic dependence of the Binder cumulant on the ferromagnetic next-nearest neighbor (NNN) coupling of the two-dimensional Ising model found by MC simulations of Selke and Shchur [J. Phys. {\bf A 38}, L739 (2005)]. Our theory also predicts a non-monotonic dependence for small values of the {\it antiferromagnetic} NNN coupling and the existence of a Lifschitz point at a larger value of this coupling. The nonuniversal anisotropy effects in the finite-size scaling regime are predicted to satisfy a kind of restricted universality. The tails of the large-$L$ behavior at $T \neq T_c$ violate both finite-size scaling and universality

Follow-up of the GHSG HD16 trial of PET-guided treatment in early-stage favorable Hodgkin lymphoma.

The primary analysis of the GHSG HD16 trial indicated a significant loss of tumor control with PET-guided omission of radiotherapy (RT) in patients with early-stage favorable Hodgkin lymphoma (HL). This analysis reports long-term outcomes. Overall, 1150 patients aged 18-75 years with newly diagnosed early-stage favorable HL were randomized between standard combined-modality treatment (CMT) (2x ABVD followed by PET/CT [PET-2] and 20 Gy involved-field RT) and PET-2-guided treatment omitting RT in case of PET-2 negativity (Deauville score [DS] < 3). The study aimed at excluding inferiority of PET-2-guided treatment and assessing the prognostic impact of PET-2 in patients receiving CMT. At a median follow-up of 64 months, PET-2-negative patients had a 5-year progression-free survival (PFS) of 94.2% after CMT (n = 328) and 86.7% after ABVD alone (n = 300; HR = 2.05 [1.20-3.51]; p = 0.0072). 5-year OS was 98.3% and 98.8%, respectively (p = 0.14); 4/12 documented deaths were caused by second primary malignancies and only one by HL. Among patients assigned to CMT, 5-year PFS was better in PET-2-negative (n = 353; 94.0%) than in PET-2-positive patients (n = 340; 90.3%; p = 0.012). The difference was more pronounced when using DS4 as cut-off (DS 1-3: n = 571; 94.0% vs. DS ≥ 4: n = 122; 83.6%; p < 0.0001). Taken together, CMT should be considered standard treatment for early-stage favorable HL irrespective of the PET-2-result

Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron

The CDF and D0 experiments at the Fermilab Tevatron have measured the asymmetry between yields of forward- and backward-produced top and antitop quarks based on their rapidity difference and the asymmetry between their decay leptons. These measurements use the full data sets collected in proton-antiproton collisions at a center-of-mass energy of $\sqrt s =1.96$ TeV. We report the results of combinations of the inclusive asymmetries and their differential dependencies on relevant kinematic quantities. The combined inclusive asymmetry is $A_{\mathrm{FB}}^{t\bar{t}} = 0.128 \pm 0.025$. The combined inclusive and differential asymmetries are consistent with recent standard model predictions