The Arabidopsis BLAP75/Rmi1 Homologue Plays Crucial Roles in Meiotic Double-Strand Break Repair

In human cells and in Saccharomyces cerevisiae, BLAP75/Rmi1 acts together with BLM/Sgs1 and TopoIIIα/Top3 to maintain genome stability by limiting crossover (CO) formation in favour of NCO events, probably through the dissolution of double Holliday junction intermediates (dHJ). So far, very limited data is available on the involvement of these complexes in meiotic DNA repair. In this paper, we present the first meiotic study of a member of the BLAP75 family through characterisation of the Arabidopsis thaliana homologue. In A. thaliana blap75 mutants, meiotic recombination is initiated, and recombination progresses until the formation of bivalent-like structures, even in the absence of ZMM proteins. However, chromosome fragmentation can be detected as soon as metaphase I and is drastic at anaphase I, while no second meiotic division is observed. Using genetic and imunolocalisation studies, we showed that these defects reflect a role of A. thaliana BLAP75 in meiotic double-strand break (DSB) repair—that it acts after the invasion step mediated by RAD51 and associated proteins and that it is necessary to repair meiotic DSBs onto sister chromatids as well as onto the homologous chromosome. In conclusion, our results show for the first time that BLAP75/Rmi1 is a key protein of the meiotic homologous recombination machinery. In A. thaliana, we found that this protein is dispensable for homologous chromosome recognition and synapsis but necessary for the repair of meiotic DSBs. Furthermore, in the absence of BLAP75, bivalent formation can happen even in the absence of ZMM proteins, showing that in blap75 mutants, recombination intermediates exist that are stable enough to form bivalent structures, even when ZMM are absent

Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies

G-CSF is widely employed for the treatment of chemotherapy-induced neutropenia. Recently, neuroprotective effects of G-CSF in animal stroke models were discovered including infarct size reduction and enhancement of functional recovery. The underlying mechanisms of action of G-CSF in ischemia appear to be a direct anti-apoptotic activity in neurons and a neurogenesis inducing capacity. Additional effects may be based on the stimulation of new blood-vessel formation, the stimulation of immunocompetence and -modulation as well as on bone marrow mobilization. In addition to a discussion of these mechanisms, we will review the available preclinical studies and analyze their impact on the overall efficacy of G-CSF in experimental stroke

Multi-model evaluation of the sensitivity of the global energy budget and hydrological cycle to resolution

This study undertakes a multi-model comparison with the aim to describe and quantify systematic changes of the global energy and water budgets when the horizontal resolution of atmospheric models is increased and to identify common factors of these changes among models. To do so, we analyse an ensemble of twelve atmosphere-only and six coupled GCMs, with different model formulations and with resolutions spanning those of state-of-the-art coupled GCMs, i.e. from resolutions coarser than 100 km to resolutions finer than 25 km. The main changes in the global energy budget with resolution are a systematic increase in outgoing longwave radiation and decrease in outgoing shortwave radiation due to changes in cloud properties, and a systematic increase in surface latent heat flux; when resolution is increased from 100 to 25 km, the magnitude of the change of those fluxes can be as large as 5 W m−2. Moreover, all but one atmosphere-only model simulate a decrease of the poleward energy transport at higher resolution, mainly explained by a reduction of the equator-to-pole tropospheric temperature gradient. Regarding hydrological processes, our results are the following: (1) there is an increase of global precipitation with increasing resolution in all models (up to 40 × 103 km3 year−1) but the partitioning between land and ocean varies among models; (2) the fraction of total precipitation that falls on land is on average 10% larger at higher resolution in grid point models, but it is smaller at higher resolution in spectral models; (3) grid points models simulate an increase of the fraction of land precipitation due to moisture convergence twice as large as in spectral models; (4) grid point models, which have a better resolved orography, show an increase of orographic precipitation of up to 13 × 103 km3 year−1 which explains most of the change in land precipitation; (5) at the regional scale, precipitation pattern and amplitude are improved with increased resolution due to a better simulated seasonal mean circulation. We discuss our results against several observational estimates of the Earth's energy budget and hydrological cycle and show that they support recent high estimates of global precipitation

Immunological mechanism of action and clinical profile of disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials

Exploring new physics frontiers through numerical relativity

The demand to obtain answers to highly complex problems within strong-field gravity has been met with significant progress in the numerical solution of Einstein's equations - along with some spectacular results - in various setups. We review techniques for solving Einstein's equations in generic spacetimes, focusing on fully nonlinear evolutions but also on how to benchmark those results with perturbative approaches. The results address problems in high-energy physics, holography, mathematical physics, fundamental physics, astrophysics and cosmology