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Summary: The Muscleblind-like protein family (MBNL) plays an important role in regulating the transition between differentiation and pluripotency and in the pathogenesis of myotonic dystrophy type 1 (DM1), a CTG expansion disorder. How different MBNL isoforms contribute to the differentiation and are affected in DM1 has not been investigated. Here, we show that the MBNL1 cytoplasmic, but not nuclear, isoform promotes neurite morphogenesis and reverses the morphological defects caused by expanded CUG RNA. Cytoplasmic MBNL1 is polyubiquitinated by lysine 63 (K63). Reduced cytoplasmic MBNL1 in the DM1 mouse brain is consistent with the reduced extent of K63 ubiquitination. Expanded CUG RNA induced the deubiqutination of cytoplasmic MBNL1, which resulted in nuclear translocation and morphological impairment that could be ameliorated by inhibiting K63-linked polyubiquitin chain degradation. Our results suggest that K63-linked ubiquitination of MBNL1 is required for its cytoplasmic localization and that deubiquitination of cytoplasmic MBNL1 is pathogenic in the DM1 brain. : Wang et al. find that MBNL1 ubiquitination is required for cytoplasmic localization and promotion of neurite outgrowth. In myotonic dystrophy, expanded CUG repeat RNA leads to MBNL1 deubiquitination, resulting in nuclear-translocation-associated morphological defects that can be rescued by preventing degradation of lysine 63-linked polyubiquitin chains or enhancing MBNL1 ubiquitination. Keywords: MBNL1, polyubiquitination, myotonic dystrophy, nucleocytoplasmic localization, neurite outgrowth

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats in the 3' untranslated region (UTR) of the dystrophia myotonia protein kinase (DMPK) gene. Cognitive impairment associated with structural change in the brain is prevalent in DM1. How this histopathological abnormality during disease progression develops remains elusive. Nuclear accumulation of mutant DMPK mRNA containing expanded CUG RNA disrupting the cytoplasmic and nuclear activities of muscleblind-like (MBNL) protein has been implicated in DM1 neural pathogenesis. The association between MBNL dysfunction and morphological changes has not been investigated. We generated a mouse model for postnatal expression of expanded CUG RNA in the brain that recapitulates the features of the DM1 brain, including the formation of nuclear RNA and MBNL foci, learning disability, brain atrophy and misregulated alternative splicing. Characterization of the pathological abnormalities by a time-course study revealed that hippocampus-related learning and synaptic potentiation were impaired before structural changes in the brain, followed by brain atrophy associated with progressive reduction of axon and dendrite integrity. Moreover, cytoplasmic MBNL1 distribution on dendrites decreased before dendrite degeneration, whereas reduced MBNL2 expression and altered MBNL-regulated alternative splicing was evident after degeneration. These results suggest that the expression of expanded CUG RNA in the DM1 brain results in neurodegenerative processes, with reduced cytoplasmic MBNL1 as an early event response to expanded CUG RNA.

The ratio of ZnS to AgInS 2 is usually adjusted to tune the band gaps of this quaternary (Ag–In–Zn)S semiconductor to increase photocatalytic activity. In this study, the [Zn]/[Ag] ratio was kept constant. The hydrogen production rate was enhanced by increasing the content of indium sulfide. Compared to the steady H 2 evolution rate obtained with equal moles of indium and silver ([In]/[Ag] = 1, 0.64 L/m 2 h), that obtained with In-rich photocatalyst ([In]/[Ag] = 2, 3.75 L/m 2 h) is over 5.86 times higher. The number of nanostep structures, on which the Pt cocatalysts were loaded by photodeposition, increased with the content of indium. The indium-rich samples did not induce phase separation between Ag x In x Zn y S 2 x + y and AgIn 5 S 8 , instead forming a single-phase solid solution. Although the photocatalytic activity decreased slightly for bare In-rich photocatalysts, Pt loading played a critical role in the hydrogen production rate. This study demonstrates the significant effect of In 2 S 3 on this unique (Ag–In–Zn)S photocatalyst.

Chondroitin sulfate is a sulfated glycosaminoglycan that predominates in the ground substance of cartilage. Using monoclonal antichondroitin sulfate in 61 specimens of human otosclerotic lesions, we studied the distribution of this glucosaminoglycan in various stages of otosclerosis. Our findings show that chondroitin sulfate plays an important role in the development of otosclerosis. In addition, the distribution of chondroitin sulfate clearly delineates the stage of otosclerosis referred to as active into two distinct histologic stages. Dividing the active stage into "osteolytic" and "sponge-chondroid" would be reasonable based on our findings.