Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by a CTG trinucleotide repeat expansion (CTGexp) in the DMPK gene. In skeletal muscle, nuclear sequestration of the alternative splicing factor muscleblind-like 1 (MBNL1) explains the majority of the alternative splicing defects observed in the HSA
LR transgenic mouse model which expresses a pathogenic range CTGexp. In the present study, we addressed the possibility that MBNL1 sequestration by CUGexp RNA also contributes to splicing defects in the mammalian brain. We examined RNA from the brains of homozygous Mbnl1
ΔE3/ΔE3 knockout mice using splicing-sensitive microarrays. We used RT-PCR to validate a subset of alternative cassette exons identified by microarray analysis with brain tissues from Mbnl1
ΔE3/ΔE3 knockout mice and post-mortem DM1 patients. Surprisingly, splicing-sensitive microarray analysis of Mbnl1
ΔE3/ΔE3 brains yielded only 14 candidates for mis-spliced exons. While we confirmed that several of these splicing events are perturbed in both Mbnl1 knockout and DM1 brains, the extent of splicing mis-regulation in the mouse model was significantly less than observed in DM1. Additionally, several alternative exons, including Grin1 exon 4, App exon 7 and Mapt exons 3 and 9, which have previously been reported to be aberrantly spliced in human DM1 brain, were spliced normally in the Mbnl1 knockout brain. The sequestration of MBNL1 by CUGexp RNA results in some of the aberrant splicing events in the DM1 brain. However, we conclude that other factors, possibly other MBNL proteins, likely contribute to splicing mis-regulation in the DM1 brain.
Endocardial monophasic action potentials (MAPs) were recorded at the right ventricular apex in a patient with QTU prolongation and torsade de pointes (TdP) in association with marked bradycardia and hypokalemia. There was a distinct hump on phase 3 repolarization of the MAPs characteristic of early afterdepolarizations (EADs), which was associated with marked prolongation of the QTU interval on the surface electrocardiogram. EAD amplitude was bradycardia dependent, and there was a strong correlation (r = 0.91) between the preceding RR interval and the amplitude of the EAD (percent of MAP amplitude). Intravenous administration of lidocaine or right ventricular pacing suppressed the ventricular premature complexes and TdP in association with the suppression of the EADs on the MAPs. Furthermore, these EADs were not recorded on the MAPs 1 month later when the QTU prolongation and TdP had disappeared. These findings suggest that the TU abnormality and QTU prolongation responsible for TdP were due to bradycardia-dependent EADs.
Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to the sequestration of splicing factors such as muscleblind-like 1/2 (MBNL1/2) and aberrant splicing in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with amyotrophic lateral sclerosis (ALS, as disease controls), the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and ALS. In 7 out of the 15 examined splicing events, the level of PSI change between DM1 and ALS was significantly higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain.
Facilitated transport of molecular oxygen in membranes (poly (dimethyl siloxane), poly (butyl methacrylate), and poly(methyl methacrylate)) containing cobalt(II) or iron(II) a,a',a",a'"-meso-tetiakis(opivalamidophenyl)porphyrin as a fixed carrier of oxygen is studied by the combination of oxygen permeability in the membranes and oxygen-binding ability to the metalloporphyrin. The facilitation of oxygen transport is remarkable for the lower upstream pressure, which corresponds to a dual-mode transport model. The facilitation is more enhanced in the polymer matrix with the lower oxygen solubility (according to Henry's law). Although the oxygen-binding affinity of the iron porphyrin is larger than that of the cobalt porphyrin, the facilitation is lower because of its smaller oxygen-binding kinetic constant.
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