The histone H2B monoubiquitination regulatory pathway is required for differentiation of multipotent stem cells.

Extensive changes in posttranslational histone modifications accompany the rewiring of the transcriptional program during stem cell differentiation. However, the mechanisms controlling the changes in specific chromatin modifications and their function during differentiation remain only poorly understood. We show that histone H2B monoubiquitination (H2Bub1) significantly increases during differentiation of human mesenchymal stem cells (hMSCs) and various lineage-committed precursor cells and in diverse organisms. Furthermore, the H2B ubiquitin ligase RNF40 is required for the induction of differentiation markers and transcriptional reprogramming of hMSCs. This function is dependent upon CDK9 and the WAC adaptor protein, which are required for H2B monoubiquitination. Finally, we show that RNF40 is required for the resolution of the H3K4me3/H3K27me3 bivalent poised state on lineage-specific genes during the transition from an inactive to an active chromatin conformation. Thus, these data indicate that H2Bub1 is required for maintaining multipotency of hMSCs and plays a central role in controlling stem cell differentiation

REACCELERATION OF ION BEAMS FOR PARTICLE THERAPY

Abstract At the Heidelberg Ion-Beam Therapy Centre (HIT) more than 2000 cancer patients have been treated with ions using the raster-scanning method since 2009. The synchrotron provides pencil beams in therapy quality for more than 250 energy steps for each ion species allowing to vary the penetration depth and thus to irradiate the tumour slice-by-slice. So far, changing the beam energy necessitates a new synchrotron cycle, including all phases without beam extraction. As the number of ions that can be accelerated in the synchrotron usually exceeds the required number of ions for one energy slice, the duty cycle could be significantly reduced by reaccelerating or decelerating the remaining ions to the adjacent energy level. By alternating acceleration and extraction phases several slices could be irradiated with only short interruptions. This leads to a better duty cycle and a larger number of patients that can be treated in the same time. Therefore the behaviour of a reaccelerated but transversally blown up beam -due to the use of RF-knockout extraction -must be investigated in detail, beam losses have to be minimised. To estimate the potential benefit of such an operation mode, treatment time has been simulated and compared to the time achieved in the past. A reduction of more than 50 % is possible

Political integration by a detour? Ethnic communities and social capital of migrants in Berlin

This article investigates the impact of associational participation of migrants on their political integration in Berlin. Using survey data, we focus on the individual level to see whether migrants who are active in German and/or ethnic organisations are better integrated politically. We test the social capital argument that participation in voluntary organisations is beneficial for political integration and investigate the empirical side of the often normatively-based fear that ethnic self-organisation is a danger to the integration of ethnic groups in the receiving society. We could not find a clear-cut answer to this question. Participation in German organisations does indeed support integration, but the effects of participation in ethnic organisations are more ambiguous: migrants active in ethnic organisations are more politically active, but not more interested in German politics, than migrants who are not active in ethnic organisations. Furthermore, we conclude that the mechanisms behind the social capital argument are different for the ethnic groups under study. © 2004 Taylor and Francis Ltd

Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor

Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations is unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, finding that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and AML development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease