Numerical analysis of tsunami-induced inundation behind building along coasts

To evaluate the effects of impermeable rigid buildings located near vertical quay walls on the reduction of the inundation water volumes due to run-up tsunamis, a full-scale three-dimensional numerical analysis is performed using a three-dimensional coupled fluid-structure-sediment interaction model. Numerical results show that the inundation water volume can be reduced with an increase in the shielding ratio of the long-shore width of the buildings with respect to the total width of the coastline, and accordingly the buildings located along the coasts have the reduction effects of the inundation water volume. This suggests that countermeasures against tsunamis can be evaluated in a\ud comprehensive manner in terms of not only shore protection facilities for tsunamis at relatively high frequencies but also such buildings. Furthermore, the inundation depth at the seaward side of the buildings and the cross-shore bottom flow velocity at the gaps between the buildings increase with the shielding ratio, suggesting an increase in tsunami force and the onset of local scouring when the shielding ratio is large. Consequently, when designing buildings along the coasts, it is essential to consider an appropriate balance between the reduction effects of the inundation water volume and the instability of the buildings caused by the tsunami force and the local scouring

Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression

Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20111487/DC1.The development of cancer-specific therapeutics has been limited because most healthy cells and cancer cells depend on common pathways. Pyruvate kinase (PK) exists in M1 (PKM1) and M2 (PKM2) isoforms. PKM2, whose expression in cancer cells results in aerobic glycolysis and is suggested to bestow a selective growth advantage, is a promising target. Because many oncogenes impart a common alteration in cell metabolism, inhibition of the M2 isoform might be of broad applicability. We show that several small interfering (si) RNAs designed to target mismatches between the M2 and M1 isoforms confer specific knockdown of the former, resulting in decreased viability and increased apoptosis in multiple cancer cell lines but less so in normal fibroblasts or endothelial cells. In vivo delivery of siPKM2 additionally causes substantial tumor regression of established xenografts. Our results suggest that the inherent nucleotide-level specificity of siRNA can be harnessed to develop therapeutics that target isoform-specific exons in genes exhibiting differential splicing patterns in various cell types.MIT-Harvard Center for Cancer Nanotechnology ExcellenceNational Cancer Institute (U.S.) (Grant U54 CA151884)Marie D. and Pierre Casimir-Lambert FundNational Cancer Institute (U.S.) (Cancer Center Support (core) grant P30-CA14051

C9orf72 repeat expansions as genetic modifiers for depression in spinocerebellar ataxias

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142479/1/mds27258.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142479/2/mds27258_am.pd

Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells

Triplet-repeat expansions cause several inherited human diseases. Expanded triplet-repeats are unstable in somatic cells, and tissue-specific somatic instability contributes to disease pathogenesis. In mammalian cells instability of triplet-repeats is dependent on the location of the origin of replication relative to the repeat tract, supporting the ‘fork-shift’ model of repeat instability. Disease-causing triplet-repeats are transcribed, but how this influences instability remains unclear. We examined instability of the expanded (GAA•TTC)n sequence in mammalian cells by analyzing individual replication events directed by the SV40 origin from five different locations, in the presence and absence of doxycycline-induced transcription. Depending on the location of the SV40 origin, either no instability was observed, instability was caused by replication with no further increase due to transcription, or instability required transcription. Whereas contractions accounted for most of the observed instability, one construct showed expansions upon induction of transcription. These expansions disappeared when transcript stability was reduced via removal or mutation of a spliceable intron. These results reveal a complex interrelationship of transcription and replication in the etiology of repeat instability. While both processes may not be sufficient for the initiation of instability, transcription and/or transcript stability seem to further modulate the fork-shift model of triplet-repeat instability

Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8 % in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat

Video-assisted thoracoscopic resection for intralobar pulmonary sequestration.

Video-assisted thoracoscopic treatment of intralobar pulmonary sequestration in an obese (120 kg, body mass index 42) young man is described. Two aberrant arteries originating from the descending thoracic aorta were transected with a vascular stapler, and a left lower lobectomy was successfully performed thoracoscopically. Three-dimensional chest computed tomography was used to identify the aberrant vessels. Video-assisted thoracoscopic lobectomy is useful and minimally invasive for treating pulmonary sequestration, especially in obese patients.The original publication is available at www.springerlink.co

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

OBJECTIVE—Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis