Effects of progressive backward body weight supported treadmill training on gait ability in chronic stroke patients: A randomized controlled trial

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A Note on Vectorial AdS5_5/CFT4_4 Duality for Spin-jj Boundary Theory

The vectorial holographic correspondences between higher-spin theories in AdS$_5$ and free vector models on the boundary are extended to the cases where the latter is described by free massless spin-$j$ field. The dual higher-spin theory in the bulk does not include gravity and can only be defined on rigid AdS$_5$ background with $S^4$ boundary. We discuss various properties of these rather special higher-spin theories and calculate their one-loop free energies. We show that the result is proportional to the same quantity for spin-$j$ doubleton treated as if it is a AdS$_5$ field. Finally, we consider even more special case where the boundary theory itself is given by an infinite tower of massless higher-spin fields.Comment: 27 pages, version to appear in JHE

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

Direction of the oblique medial malleolar osteotomy for exposure of the talus

A medial malleolar osteotomy is often indicated for operative exposure of posteromedial osteochondral defects and fractures of the talus. To obtain a congruent joint surface after refixation, the oblique osteotomy should be directed perpendicularly to the articular surface of the tibia at the intersection between the tibial plafond and medial malleolus. The purpose of this study was to determine this perpendicular direction in relation to the longitudinal tibial axis for use during surgery. Using anteroposterior mortise radiographs and coronal computed tomography (CT) scans of 46 ankles (45 patients) with an osteochondral lesion of the talus, two observers independently measured the intersection angle between the tibial plafond and medial malleolus. The bisector of this angle indicated the osteotomy perpendicular to the tibial articular surface. This osteotomy was measured relative to the longitudinal tibial axis on radiographs. Intraclass correlation coefficients (ICC) were calculated to assess reliability. The mean osteotomy was 57.2 ± 3.2° relative to the tibial plafond on radiographs and 56.5 ± 2.8 on CT scans. This osteotomy corresponded to 30.4 ± 3.7° relative to the longitudinal tibial axis. The intraobserver (ICC, 0.90-0.93) and interobserver (ICC, 0.65-0.91) reliability of these measurements were good to excellent. A medial malleolar osteotomy directed at a mean 30° relative to the tibial axis enters the joint perpendicularly to the tibial cartilage, and will likely result in a congruent joint surface after reductio

Comparative analysis of somitogenesis related genes of the hairy/Enhancer of split class in Fugu and zebrafish

BACKGROUND: Members of a class of bHLH transcription factors, namely the hairy (h), Enhancer of split (E(spl)) and hairy-related with YRPW motif (hey) (h/E(spl)/hey) genes are involved in vertebrate somitogenesis and some of them show cycling expression. By sequence comparison, identified orthologues of cycling somitogenesis genes from higher vertebrates do not show an appropriate expression pattern in zebrafish. The zebrafish genomic sequence is not available yet but the genome of Fugu rubripes was recently published. To allow comparative analysis, the currently known Her proteins from zebrafish were used to screen the genomic sequence database of Fugu rubripes. RESULTS: 20 h/E(spl)/hey-related genes were identified in Fugu, which is twice the number of corresponding zebrafish genes known so far. A novel class of c-Hairy proteins was identified in the genomes of Fugu and Tetraodon. A screen of the human genome database with the Fugu proteins yielded 10 h/E(spl)/hey-related genes. By analysing the upstream sequences of the c-hairy class genes in zebrafish, Fugu and Tetraodon highly similar sequence stretches were identified that harbour Suppressor of hairless paired binding sites (SPS). This motif was also discovered in the upstream sequences of the her1 gene in the examined fish species. Here, the Su(h) sites are separated by longer intervening sequences. CONCLUSIONS: Our study indicates that not all her homologues in zebrafish have been isolated. Comparison to the human genome suggests a selective duplication of h/E(spl) genes in pufferfish or loss of members of these genes during evolution to the human lineage

TRAF6 Mediates IL-1β/LPS-Induced Suppression of TGF-β Signaling through Its Interaction with the Type III TGF-β Receptor

Transforming growth factor-β1 (TGF-β1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1β must overcome the anti-inflammatory effects of TGF-β to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1β or Lipopolysaccharide (LPS) suppresses TGF-β-induced anti-inflammatory signaling in a NF-κB-independent manner. TRAF6, a key molecule in IL-1β signaling, mediates this suppressive effect through interaction with the type III TGF-β receptor (TβRIII), which is TGF-β-dependent and requires type I TGF-β receptor (TβRI) kinase activity. TβRI phosphorylates TβRIII at residue S829, which promotes the TRAF6/TβRIII interaction and consequent sequestration of TβRIII from the TβRII/TβRI complex. Our data indicate that IL-1β enhances the pro-inflammatory response by suppressing TGF-βsignaling through TRAF6-mediated sequestration of TβRIII, which may be an important contributor to the early stages of tumor progression

P130Cas Attenuates Epidermal Growth Factor (EGF) Receptor Internalization by Modulating EGF-Triggered Dynamin Phosphorylation

BACKGROUND: Endocytosis controls localization-specific signal transduction via epidermal growth factor receptor (EGFR), as well as downregulation of that receptor. Extracellular matrix (ECM)-integrin coupling induces formation of macromolecular complexes that include EGFR, integrin, Src kinase and p130Cas, resulting in EGFR activation. In addition, cell adhesion to ECM increases EGFR localization at the cell surface and reduces EGFR internalization. The molecular mechanisms involved are not yet well understood. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the molecular mechanism by which p130Cas affects the endocytic regulation of EGFR. Biochemical quantification revealed that cell adhesion to fibronectin (FN) increases total EGFR levels and its phosphorylation, and that p130Cas is required for this process. Measurements of Texas Red-labeled EGF uptake and cell surface EGFR revealed that p130Cas overexpression reduces EGF-induced EGFR internalization, while p130Cas depletion enhances it. In addition, both FN-mediated cell adhesion and p130Cas overexpression reduce EGF-stimulated dynamin phosphorylation, which is necessary for EGF-induced EGFR internalization. Coimmunoprecipitation and GST pull-down assays confirmed the interaction between p130Cas and dynamin. Moreover, a SH3-domain-deleted form of p130Cas, which shows diminished binding to dynamin, inhibits dynamin phosphorylation and EGF uptake less effectively than wild-type p130Cas. CONCLUSIONS/SIGNIFICANCE: Our results show that p130Cas plays an inhibitory role in EGFR internalization via its interaction with dynamin. Given that the EGFR internalization process determines signaling density and specificity in the EGFR pathway, these findings suggest that the interaction between p130Cas and dynamin may regulate EGFR trafficking and signaling in the same manner as other endocytic regulatory proteins related to EGFR endocytosis

HDAC1 Inactivation Induces Mitotic Defect and Caspase-Independent Autophagic Cell Death in Liver Cancer

Histone deacetylases (HDACs) are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC), but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21WAF1/Cip1 and p27Kip1 expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21WAF1/Cip1 transcriptional activity through Sp1-binding sites in the p21WAF1/Cip1 promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy