Wallertherkelsen1704

esponses. ClinicalTrials.gov no NCT03270085. Tracking variation in hosts' responses to parasitism across space in a metapopulation is critical to assess the current status of parasitism/anti-parasitism in a host-parasite system, which is also helpful to infer its coevolutionary history. The barn swallow Hirundo rustica is a tractable bird species to understand potential fine-tuned adaptations to avian brood parasitism across small geographic scales, both in the context of variation in its foreign-egg rejection pattern, and its widespread distribution in cuckoo-free urban areas and in cuckoo-present rural habitats, including reedbeds. Here we tested whether variation in co-occurrence between the host and its rare brood parasite, the common cuckoo Cuculus canorus (i.e., high level of co-occurrence in reed habitats, low in town habitats) at the metapopulation level predicts patterns of antiparasitic egg rejection behaviors in barn swallows in response to different types of model and natural eggs. Contrary to our predictions, higher parasite detectability in the reed habitat did not translate into higher parasitism rate and, in turn, we also found similarly low egg rejection rates across both sampled habitat types. These patterns implied a lack of fine-tuned increase of egg rejection rate in the reed-breeding population of barn swallows as a response to the increased perceived cuckoo encounter rate, perhaps because higher potential parasitism threat did not transfer into greater actual parasitism rate. It remains to be assessed whether the lack of small-scale geographic variation in barn swallows' egg rejection rates persists because this species responds to selection by parasitism as a spatially contiguous evolutionary unit. The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, while the paternal UBE3A gene is present but silenced specifically in neurons. Patients with AS present with severe neurodevelopmental delay, with pronounced motor deficits, absence of speech, intellectual disability, epilepsy, and sleep problems. The pathophysiology of AS is still unclear and a treatment is lacking. Animal models of AS recapitulate the genotypic and phenotypic features observed in AS patients, and have been invaluable for understanding the disease process as well as identifying apropriate drug targets. Using these AS mouse models we have learned that loss of UBE3A probably affects many areas of the brain, leading to increased neuronal excitability and a loss of synaptic spines, along with changes in a number of distinct behaviours. Inducible AS mouse models have helped to identify the critical treatment windows for the behavioral and physiological phenotypes. Additionally, AS mouse models indicate an important role for the predominantly nuclear UBE3A isoform in generating the characteristic AS pathology. Last, but not least, the AS mice have been crucial in guiding Ube3a gene reactivation treatments, which present a very promising therapy to treat AS. Two major processes tightly regulate protein synthesis, the initiation of mRNA translation and elongation phase that mediates the movement of ribosomes along the mRNA. The elongation phase is a high energy-consuming process, and is mainly regulated by the eukaryotic elongation factor 2 kinase (eEF2K) activity that phosphorylates and inhibits eEF2, the only known substrate of the kinase. eEF2K activity is closely regulated by several signaling pathways because the translation elongation phase strongly influences the cellular energy demand and can change the expression of specific proteins in different tissues. An increasing number of recent findings link eEF2k over activation to an array of human diseases, such as atherosclerosis, pulmonary arterial hypertension, progression of solid tumors, and some major neurological disorders. Several neurological studies suggest that eEF2K is a valuable target in treating epilepsy, depression and major neurodegenerative diseases. Despite eEF2k is an ubiquitous and conserved protein, it has been proved that its deletion does not affect development in animal models and in general cell viability. this website Therefore, it is possible to postulate that inhibiting its function may not cause serious side effects. In addition, eEF2K is a peculiar kinase molecularly different from most of other mammalian kinases and new compounds that inhibit eEF2K should not necessarily interfere with other important protein kinases. In this review we will critically summarize the evidence supporting the role of the altered eEF2K/eEF2 pathway in defined neurological diseases and its implications in curing these diseases in animal models, and possibly in humans, by targeting eEF2K activity. PURPOSE Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly collimated synchrotron beam into arrays of parallel microbeams depositing several hundred grays. It appears relevant to combine MRT with a conventional treatment course, preparing a treatment scheme for future patients in clinical trials. The efficiency of MRT delivered after several broad beam (BB) fractions to palliate of F98 brain tumors in rats in comparison with BB fractions alone was evaluated in this study. MATERIALS/METHODS Rats bearing 106 F98 cells implanted in the caudate nucleus were irradiated by 5 fractions in broad beam (BB) mode (3x6Gy + 2x8Gy BB) or by 2 boost fractions in MRT mode, of a total of 5 fractions (3x6Gy BB + MRT 2x8Gy valley dose; peak dose 181Gy (50/200μm)). Tumor growth was evaluated in vivo by MRI follow up at T-1, T7, T12 T15, T20, T25 days, after radiotherapy, and by histology and FACS studies. RESULTS MRT-boosted tumors displayed lower cell density and cell proliferation compared with BB-irradiated tumors. The MRT boost completely stopped tumor growth during ∼4 weeks and led to a significant increase in MST, while tumors treated with BB alone recurred within few days after the last radiation fraction. CONCLUSIONS The first evidence is presented that MRT, delivered as a boost of a conventional fractionated irradiation by orthovoltage broad X-ray beams, is feasible and more efficient than a conventional radiotherapy alone.