Protective Effect of Geranylgeranylacetone via Enhancement of HSPB8 Induction in Desmin-Related Cardiomyopathy

Background

An arg120gly (R120G) missense mutation in HSPB5 (α-β-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain.

Methodology/Principal Findings

In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice.

Conclusions/Significance

Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM.     

Saccadic Compression of Rectangle and Kanizsa Figures: Now You See It,Now You Don't

Background

Observers misperceive the location of points within a scene as compressed towards the goal of a saccade. However, recent studies suggest that saccadic compression does not occur for discrete elements such as dots when they are perceived as unified objects like a rectangle.

Methodology/Principal Findings

We investigated the magnitude of horizontal vs. vertical compression for Kanizsa figure (a collection of discrete elements unified into single perceptual objects by illusory contours) and control rectangle figures. Participants were presented with Kanizsa and control figures and had to decide whether the horizontal or vertical length of stimulus was longer using the two-alternative force choice method. Our findings show that large but not small Kanizsa figures are perceived as compressed, that such compression is large in the horizontal dimension and small or nil in the vertical dimension. In contrast to recent findings, we found no saccadic compression for control rectangles.

Conclusions

Our data suggest that compression of Kanizsa figure has been overestimated in previous research due to methodological artifacts, and highlight the importance of studying perceptual phenomena by multiple methods.     

Involvement of vesicular trafficking system in membrane targeting of the progeny influenza virus genome

The genome of influenza type A virus consists of single-stranded RNAs of negative polarity. Progeny viral RNA (vRNA) replicated in the nucleus is nuclear-exported, and finally transported to the budding site beneath the plasma membrane. However, the precise process of the membrane targeting of vRNA is unclear, although viral proteins and cytoskeleton are thought to play roles. Here, we have visualized the translocation process of progeny vRNA using fluorescence in situ hybridization method. Our results provide an evidence of the involvement of vesicular trafficking in membrane targeting of progeny vRNA independent of that of viral membrane proteins.     

A mutation in the uvi4 gene promotes progression of endo-reduplication and confers increased tolerance towards ultraviolet B light

We have isolated and characterized a new ultraviolet B (UV-B)-resistant mutant, uvi4 (UV-B-insensitive 4), of Arabidopsis. The fresh weight (FW) of uvi4 plants grown under supplemental UV-B light was more than twice that of the wild-type. No significant difference was found in their ability to repair the UV-B-induced cyclobutane pyrimidine dimers, or in the amount of UV-B absorptive compounds, both of which are well-known factors that contribute to UV sensitivity. Positional cloning revealed that the UVI4 gene encodes a novel basic protein of unknown function. We found that the hypocotyl cells in uvi4 undergo one extra round of endo-reduplication. The uvi4 mutation also promoted the progression of endo-reduplication during leaf development. The UVI4 gene is expressed mainly in actively dividing cells. In the leaves of P(UVI4)::GUS plants, the GUS signal disappeared in basipetal fashion as the leaf developed. The total leaf blade area was not different between uvi4 and the wild-type through leaf development, while the average cell area in the adaxial epidermis was considerably larger in uvi4, suggesting that the uvi4 leaves have fewer but larger epidermal cells. These results suggest that UVI4 is necessary for the maintenance of the mitotic state, and the loss of UVI4 function stimulated endo-reduplication. Tetraploid Arabidopsis was hyper-resistant to UV-B compared to diploid Arabidopsis, suggesting that the enhanced polyploidization is responsible for the increased UV-B tolerance of the uvi4 mutant.     

Caged gene-inducer spatially and temporally controls gene expression and plant development in transgenic Arabidopsis plant

Two new types of caged gene-inducers, caged 17beta-estradiol and caged dexamethazone, were synthesized. Caged gene-inducers were applied to transgenic Arabidopsis plants carrying a steroid hormone-inducible transactivation system. Light uncaged caged gene-inducers and controlled spatial and temporal expression of transgene in the transgenic plant. Furthermore, caged gene-inducers enabled the control of root development by light.