Regulation of PERK Signaling and Leukemic Cell Survival by a Novel Cytosolic Isoform of the UPR Regulator GRP78/BiP

The unfolded protein response (UPR) is an evolutionarily conserved mechanism to allow cells to adapt to stress targeting the endoplasmic reticulum (ER). Induction of ER chaperone GRP78/BiP increases protein folding capacity; as such it represents a major survival arm of UPR. Considering the central importance of the UPR in regulating cell survival and death, evidence is emerging that cells evolve feedback regulatory pathways to modulate the key UPR executors, however, the precise mechanisms remain to be elucidated. Here, we report the fortuitous discovery of GRP78va, a novel isoform of GRP78 generated by alternative splicing (retention of intron 1) and alternative translation initiation. Bioinformatic and biochemical analyses revealed that expression of GRP78va is enhanced by ER stress and is notably elevated in human leukemic cells and leukemia patients. In contrast to the canonical GRP78 which is primarily an ER lumenal protein, GRP78va is devoid of the ER signaling peptide and is cytosolic. Through specific knockdown of endogenous GRP78va by siRNA without affecting canonical GRP78, we showed that GRP78va promotes cell survival under ER stress. We further demonstrated that GRP78va has the ability to regulate PERK signaling and that GRP78va is able to interact with and antagonize PERK inhibitor P58IPK. Our study describes the discovery of GRP78va, a novel cytosolic isoform of GRP78/BiP, and the first characterization of the modulation of UPR signaling via alternative splicing of nuclear pre-mRNA. Our study further reveals a novel survival mechanism in leukemic cells and other cell types where GRP78va is expressed

Growth and metabolism in the Antarctic brachiopod Liothyrella uva

Summer and winter growth rates were assessed separately for a population of the Antarctic brachiopod Liothyrella uva between early January 1992 and December 1993. Annual shell growth rates (1.6-2.3 mm yr(-1) for a 5 mm individual; 0.96-1.44 mm (-1) for a 20 mm specimen) were two to six times slower than those reported for temperate species. Growth in specimens less than 20 mm in length was faster in 1992 than in 1993, although differences between years over the whole size range were not significant. Surprisingly, growth was much faster in winter periods than during the summers. A 5 mm long individual grew five times faster in winter than in summer, and for a 20 mm long specimen the difference was 13 times. This runs contrary to current ideas on the effects of seasonality on the biology of polar marine invertebrates, but may be an effect of maximizing the efficiency of resource utilization. Comparisons with previous work showed shell growth to be decoupled from periods of tissue mass increase, and also from the main period of phytoplankton productivity. Oxygen consumption of 75 of the specimens used in the growth study was measured to test the hypothesis that basal metabolic rates should be inversely correlated with growth rates. Unexpectedly, an analysis of residuals produced no significant relationship, positive or negative, between growth rate and basal metabolism (F = 1.37, p=0.25, n = 75). <br

Zebrafish larvae show negative phototaxis to near-infrared light.

Zebrafish larvae (Danio rerio) are among the most used model species to test biological effects of different substances in biomedical research, neuroscience and ecotoxicology. Most tests are based on changes in swimming activity of zebrafish larvae by using commercially available high-throughput screening systems. These systems record and analyse behaviour patterns using visible (VIS) and near-infrared (NIR) light sources, to simulate day (VIS) and night (NIR) phases, which allow continuous recording of the behaviour using a NIR sensitive camera. So far, however, the sensitivity of zebrafish larvae to NIR has never been tested experimentally, although being a critical piece of information for interpreting their behaviour under experimental conditions. Here, we investigated the swimming activity of 96 hpf (hours post fertilization) and 120 hpf zebrafish larvae under light sources of NIR at 860 nm and at 960 nm wavelength and under VIS light. A thermal source was simultaneously presented opposite to one of the light sources as control. We found that zebrafish larvae of both larval stages showed a clear negative phototactic response towards 860 nm NIR light and to VIS light, but not to 960 nm NIR light. Our results demonstrated that zebrafish larvae are able to perceive NIR at 860 nm, which is almost identical to the most commonly used light source in commercial screening systems (NIR at 850 nm) to create a dark environment. These tests, however, are not performed in the dark from the zebrafish´s point of view. We recommend testing sensitivity of the used test organism before assuming no interaction with the applied light source of commonly used biosensor test systems. Previous studies on biological effects of substances to zebrafish larvae should be interpreted with caution

Spatial dynamics of invasive Carduus thistles

Contains fulltext : 94183.pdf (preprint version ) (Open Access)MODSIM2011, 19th International Congress on Modelling and Simulation, Perth, Australia, 12–16 December 2011, 12 december 201