Description: Ribonuclease H2 plays an essential role for genome stability as it removes ribonucleotides misincorporated into genomic DNA by replicative polymerases and resolves RNA/DNA hybrids. Biallelic mutations in the genes encoding the three RNase H2 subunits cause Aicardi–Goutières syndrome (AGS), an early-onset inflammatory encephalopathy that phenotypically overlaps with the autoimmune disorder systemic lupus erythematosus. Here we studied the intracellular dynamics of RNase H2 in living cells during DNA replication and in response to DNA damage using confocal time-lapse imaging and fluorescence cross-correlation spectroscopy. We demonstrate that the RNase H2 complex is assembled in the cytosol and imported into the nucleus in an RNase H2B-dependent manner. RNase H2 is not only recruited to DNA replication foci, but also to sites of PCNA-dependent DNA repair. By fluorescence recovery after photobleaching, we demonstrate a high mobility and fast exchange of RNase H2 at sites of DNA repair and replication. We provide evidence that recruitment of RNase H2 is not only PCNA-dependent, mediated by an interaction of the B subunit with PCNA, but also PCNA-independent mediated via the catalytic domain of the A subunit. We found that AGS-associated mutations alter complex formation, recruitment efficiency and exchange kinetics at sites of DNA replication and repair suggesting that impaired ribonucleotide removal contributes to AGS pathogenesis.

Description: Magmatic activity in continental arcs is known to vary in a non-steady-state manner, with the mechanisms driving magmatic activity being a matter of ongoing discussion. Of particular importance is the question of what extent episodic magmatism in continental arcs is governed by external factors (e.g., plate motions) and internal factors (e.g., feedback processes in the upper plate). To test existing models for magmatic episodicity, which are mostly based on temporally and spatially limited records, this study uses large data sets of geochronological, geochemical, and plate kinematic data to document the Paleozoic to Mesozoic development of the North and South American Cordilleras in eight transects from British Columbia to Patagonia. The temporal distribution of U/Pb bedrock and detrital zircon ages, used as a proxy for timing of magmatic accretion, shows that some minima and maxima of zircon abundance are nearly synchronous for thousands of kilometers along the arc. Some age patterns are characterized by a periodicity of 50–80 Ma, suggesting a cyclic controlling mechanism. Other magmatic lulls or flare-ups find no equivalents in adjacent sectors, indicating that either discrete events or variable lag times may also be important in governing magmatic activity in continental arcs. Magma composition in Mexico, the Peninsular Ranges, and the Sierra Nevada varies episodically and proportionally with the temporal record of arc activity. During flare-up events, there is an increase in Sm/Yb, indicating deeper melting, and a decrease in Nd i , suggesting a higher degree of crustal assimilation. Geochemical scatter also increases during the initiation of flare-up events. Plate kinematic data provide a means of evaluating mantle heat input. The correlation between plate convergence rate and magmatic accretion varies for each sector, suggesting that different flare-ups or lulls likely reflect variable combinations of processes.

Description: Background We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. Patients and methods From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. Results Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%–100%. Conclusions Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.