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Nonsense-mediated decay is well known by the lucid definition of being a RNA surveillance mechanism that ensures the speedy degradation of mRNAs containing premature translation termination codons. However, as we review here, NMD is far from being a simple quality control mechanism; it also regulates the stability of many wild-type transcripts. We summarise the abundance of research that has characterised each of the NMD factors and present a unified model for the recognition of NMD substrates. The contentious issue of how and where NMD occurs is also discussed, particularly with regard to P-bodies and SMG6-driven endonucleolytic degradation. In recent years, the discovery of additional functions played by several of the NMD factors has further complicated the picture. Therefore, we also review the reported roles of UPF1, SMG1 and SMG6 in other cellular processes.

Alpacas kept in Central Europe are often deficient in vitamin D3, which is supplemented orally or by injection by the owners or veterinarians. Vitamin D3 can be specified in two different units (IU and µg), which differ by a factor of 40. By mixing up these units, an overdosage can be induced. In this study, three alpaca crias were examined after vitamin D3 intoxication, with particular reference to kidney function. All three animals developed non-specific clinical alterations 1–2 weeks after a vitamin D3 overdose of approximately 40 times. Plasma of the animals revealed several alterations. The main findings were severe azotemia, hypercalcemia and hyperphosphatemia, 15 days after treatment. Kidney function analysis (endogenous creatinine clearance) in two of the crias revealed severe glomerular damage. All crias died despite intensive treatment within 23 days after vitamin D3 treatment. Necropsy revealed calcification in different organs, mainly the kidneys, lungs and liver. Since nine other crias in the same group were treated with comparable doses of vitamin D3 and no clinical signs were observed in these animals, it is concluded that individual animals show different levels of sensitivity to vitamin D3.

Results will provide a benchmark for subsequent trials in which combinations of interventions are assessed. Ignoring human movement during study design considerations would require an artificial increase in the expected effectiveness to achieve adequate power because every individual in a treatment cluster will be predicted to have the \"maximum\" effect. Insights from such trials will help guide the scaling up of effective dengue control strategies, whether vector control alone or in combination with vaccines, and will be applicable to other Ae. aegypti-borne viral infections of current public health concern, such as chikungunya and Zika viruses.

The Shackleton Range is a truncated Pan-African Orogen situated at the Weddell Sea margin of East Antarctica. It almost exclusively consists of basement rocks exposed at an elevated, escarpment-bound palaeosurface and is covered locally by patchy remnants of Ordovician, Permian and, controversially, Jurassic terrestrial deposits. This inventory does not match the geological record of any other place in Antarctica. Here we reconstruct the Phanerozoic evolution of the Shackleton Range by means of a multi-disciplinary approach combining petrological, geochemical and geochronological data with thermal history models of zircon and apatite fission track (ZFT, AFT) and (U-Th-Sm)/He (AHe) data. Petrographic, geochemical and 40Ar/39Ar analyses of a sedimentary cover sequence identify volcaniclastic rocks related to the Ferrar/Karoo magmatic event. Thermal history modelling of ZFT ages of 160-215 Ma, AFT ages of 124-225 Ma, AHe ages of 95-169 Ma and kinematic proxies in combination with geological information indicates a complex thermal history comprising at least three cooling episodes interrupted by reheating pulses. Thermal history refers to inversion of part of the Carboniferous-Triassic Transantarctic Basin prior to the 180 Ma Ferrar/Karoo Event and formation of an up to 3.4 km deep extensional Jurassic - Early Cretaceous basin due to Weddell Sea rifting. Basin depth was diminished by regional middle Cretaceous stress field changes. Final basin inversion and surface uplift were likely triggered by far-field tectonics and climatic influence. This history represents a typical example for the transition from an active to passive margin setting along the outer rim of Gondwana.

ABSTRACTRadiation-induced glioblastomas (RIGs) represent a significant proportion of glioblastomas (GBMs) seen in children and young adults and manifest poor prognosis. Little is known about their underlying biology, although limited studies have suggested no unique histologic or cytogenetic characteristics to distinguish them from de novo GBMs. In this study, we confirmed that a series of 5 RIGs showed no unique histologic or cytogenetic features compared with de novo pediatric GBMs, prompting us to further investigate RIGs using gene expression microarray profiling and Western blot analysis. Despite the inability of histologic and molecular genetic studies to identify distinguishing features between RIGs and pediatric GBMs, gene microarrays suggested significant differences between these 2 tumor types, at least those occurring in pediatric patients. Pediatric RIGs show greater homogeneity of gene expression than do de novo pediatric GBMs. Greater overlap was detected in gene expression patterns between RIGs and pilocytic astrocytomas than between RIGs and GBMs, medulloblastomas, ependymomas, atypical teratoid rhabdoid tumors, or rhabdomyosarcomas, suggesting a common precursor cell for RIG and pilocytic astrocytoma. Western blot analyses confirmed that ErbB3, Sox10, and platelet-derived growth factor receptor-α proteins were consistently expressed in RIGs but rarely in pediatric GBMs.

Pit-1 is a transcription factor that appears early in embryonic pituitary gland formation and is necessary for the development of somatotropes, lactotropes and thyrotropes. Steroidogenic factor-1 (SF-1) is another early appearing transcription factor that is involved in the development of gonadotropes. In this study we have compared RT-PCR analysis of hormone mRNA with traditional IHC for classification of 27 pituitary tumors and have evaluated the correlation of Pit-1 and SF-1 mRNA with hormone mRNA. RT-PCR detected concordant hormone mRNA in 100% of GH IHC positive, 100% of PRL IHC positive, 33% of TSH IHC positive, and 93% of gonadotropin IHC positive tumors. IHC, however, was concordant in only 71% of GH mRNA positive, 78% of PRL mRNA positive, 17% of TSH beta mRNA positive, and 76% of FSH beta mRNA positive tumors. Pit-1 mRNA was positive in 87% of tumors in which mRNA for GH, PRL or TSH beta was detected and in only 17% of GH, PRL and TSH beta mRNA negative tumors. SF-1 mRNA was positive in 94% of tumors in which mRNA for FSH beta was present and in no FSH beta mRNA negative tumors. We conclude that RT-PCR analysis of hormone mRNA may be more sensitive than traditional hormone IHC for classification of pituitary tumors. Furthermore, tumor Pit-1 mRNA positively correlates with GH, PRL and TSH beta mRNA while tumor SF-1 mRNA correlates well with FSH beta mRNA. Combined analysis of hormone and transcription factor mRNA in pituitary tumor tissue may therefore be a more meaningful approach to pituitary tumor characterization.