GSK-3β phosphorylation of functionally distinct tau isoforms has differential, but mild effects

<p>Abstract</p> <p>Background</p> <p>Tau protein exists as six different isoforms that differ by the inclusion or exclusion of exons 2, 3 and 10. Exon 10 encodes a microtubule binding repeat, thereby resulting in three isoforms with three microtubule binding repeats (3R) and three isoforms that have four microtubule binding repeats (4R). In normal adult brain, the relative amounts of 3R tau and 4R tau are approximately equal. These relative protein levels are preserved in Alzheimer's disease, although in other neurodegenerative tauopathies such as progressive supranuclear palsy, corticobasal degeneration and Pick's disease, the ratio of 3R:4R is frequently altered. Because tau isoforms are not equally involved in these diseases, it is possible that they either have inherently unique characteristics owing to their primary structures or that post-translational modification, such as phosphorylation, differentially affects their properties.</p> <p>Results</p> <p>We have determined the effects of phosphorylation by a kinase widely believed to be involved in neurodegenerative processes, glycogen synthase kinase-3β (GSK-3β), on the microtubule binding and inducer-initiated polymerization of these isoforms in vitro. We have found that each isoform has a unique microtubule binding and polymerization profile that is altered by GSK-3β. GSK-3β phosphorylation had differential effects on the isoforms although there were similarities between isoforms and the effects were generally mild.</p> <p>Conclusion</p> <p>These results indicate that tau phosphorylation by a single kinase can have isoform specific outcomes. The mild nature of these changes, however, makes it unlikely that differential effects of GSK-3β phosphorylation on the isoforms are causative in neurodegenerative disease. Instead, the inherent differences in the isoform interactions themselves and local conditions in the diseased cells are likely the major determinant of isoform involvement in various neurodegenerative disorders.</p

Glycogen synthase kinase-3 inhibitor AR-A014418 suppresses pancreatic cancer cell growth via inhibition of GSK-3-mediated Notch1 expression

AbstractBackgroundGlycogen synthase kinase-3 (GSK-3) can act as either a tumour promoter or suppressor by its inactivation depending on the cell type. There are conflicting reports on the roles of GSK-3 isoforms and their interaction with Notch1 in pancreatic cancer. It was hypothesized that GSK-3α stabilized Notch1 in pancreatic cancer cells thereby promoting cellular proliferation.MethodsThe pancreatic cancer cell lines MiaPaCa2, PANC-1 and BxPC-3, were treated with 0–20 μM of AR-A014418 (AR), a known GSK-3 inhibitor. Cell viability was determined by the MTT assay and Live-Cell Imaging. The levels of Notch pathway members (Notch1, HES-1, survivin and cyclinD1), phosphorylated GSK-3 isoforms, and apoptotic markers were determined by Western blot. Immunoprecipitation was performed to identify the binding of GSK-3 specific isoform to Notch1.ResultsAR-A014418 treatment had a significant dose-dependent growth reduction (P< 0.001) in pancreatic cancer cells compared with the control and the cytotoxic effect is as a result of apoptosis. Importantly, a reduction in GSK-3 phosphorylation lead to a reduction in Notch pathway members. Overexpression of active Notch1 in AR-A014418-treated cells resulted in the negation of growth suppression. Immunoprecipitation analysis revealed that GSK-3α binds to Notch1.ConclusionsThis study demonstrates for the first time that the growth suppressive effect of AR-A014418 on pancreatic cancer cells is mainly mediated by a reduction in phosphorylation of GSK-3α with concomitant Notch1 reduction. GSK-3α appears to stabilize Notch1 by binding and may represent a target for therapeutic development. Furthermore, downregulation of GSK-3 and Notch1 may be a viable strategy for possible chemosensitization of pancreatic cancer cells to standard therapeutics

The Changing Presentation of Choledochal Cyst Disease: An Incidental Diagnosis

Background. Choledochal cysts are uncommon biliary lesions. Due to the evolution of imaging and laparoscopic surgery, we sought to describe our last 3 years experience with the presentation and management of choledochal cysts in adults. Methods. A retrospective review of a prospectively established database of adults who were managed for primary choledochal cyst disease between 2005 and 2008 was performed. Results. Between 8/2005 and 8/2008, 14 adults were managed for primary choledochal cyst disease. The average age was 41 years (range 17–86) and 79% were female. Presentations included biliary sepsis (3), pancreatitis (2), abdominal pain (3), or painless jaundice (1). Three patients had the cyst found during laparoscopic cholecystectomy, and two had an incidental finding after CT scan for an unrelated issue. The length of stay for those who had the cyst removed was 7.8 days (range 5–11). There were no operative or post-operative complications. Conclusions. Over the last 3 years 36% of our patients with choledochal cysts presented after incidental finding, either during a laparoscopic operation or after a CT scan for an unrelated problem. Increasing utilization of laparoscopy and CT scan for abdominal complaints has lead to a change in the pattern of presentation

Parallel block structured adaptive mesh refinement on graphics processing units.

Block-structured adaptive mesh refinement is a technique that can be used when solving partial differential equations to reduce the number of zones necessary to achieve the required accuracy in areas of interest. These areas (shock fronts, material interfaces, etc.) are recursively covered with finer mesh patches that are grouped into a hierarchy of refinement levels. Despite the potential for large savings in computational requirements and memory usage without a corresponding reduction in accuracy, AMR adds overhead in managing the mesh hierarchy, adding complex communication and data movement requirements to a simulation. In this paper, we describe the design and implementation of a native GPU-based AMR library, including: the classes used to manage data on a mesh patch, the routines used for transferring data between GPUs on different nodes, and the data-parallel operators developed to coarsen and refine mesh data. We validate the performance and accuracy of our implementation using three test problems and two architectures: an eight-node cluster, and over four thousand nodes of Oak Ridge National Laboratory’s Titan supercomputer. Our GPU-based AMR hydrodynamics code performs up to 4.87x faster than the CPU-based implementation, and has been scaled to over four thousand GPUs using a combination of MPI and CUDA

Yttrium-90 Radioembolization for Colorectal Cancer Liver Metastases: A Single Institution Experience

Purpose. We sought to evaluate our experience using yttrium-90 (90Y) resin microsphere hepatic radioembolization as salvage therapy for liver-dominant metastatic colorectal cancer (mCRC). Methods. A retrospective review of consecutive patients with unresectable mCRC who were treated with 90Y after failing first and second line systemic chemotherapy. Demographics, treatment dose, biochemical and radiographic response, toxicities, and survival were examined. Results. Fifty-one patients underwent 90Y treatments of which 69% were male. All patients had previously undergone extensive chemotherapy, 31% had undergone previous liver-directed therapy and 24% had a prior liver resection. Using RECIST criteria, either stable disease or a partial response was seen in 77% of patients. Overall median survival from the time of first 90Y treatment was 10.2 months (95% CI = 7.5–13.0). The absence of extrahepatic disease at the time of treatment with 90Y was associated with an improved survival, median survival of 17.0 months (95% CI = 6.4–27.6), compared to those with extrahepatic disease at the time of treatment with 90Y, 6.7 months (95% CI = 2.7–10.6 Conclusion: 90Y therapy is a safe locoregional therapy that provides an important therapeutic option to patients who have failed first and second line chemotherapy and have adequate liver function and performance status

A Kato type Theorem for the inviscid limit of the Navier-Stokes equations with a moving rigid body

The issue of the inviscid limit for the incompressible Navier-Stokes equations when a no-slip condition is prescribed on the boundary is a famous open problem. A result by Tosio Kato says that convergence to the Euler equations holds true in the energy space if and only if the energy dissipation rate of the viscous flow in a boundary layer of width proportional to the viscosity vanishes. Of course, if one considers the motion of a solid body in an incompressible fluid, with a no-slip condition at the interface, the issue of the inviscid limit is as least as difficult. However it is not clear if the additional difficulties linked to the body's dynamic make this issue more difficult or not. In this paper we consider the motion of a rigid body in an incompressible fluid occupying the complementary set in the space and we prove that a Kato type condition implies the convergence of the fluid velocity and of the body velocity as well, what seems to indicate that an answer in the case of a fixed boundary could also bring an answer to the case where there is a moving body in the fluid

ScalaTrace: Tracing, Analysis and Modeling of HPC Codes at Scale

Characterizing the communication behavior of large-scale applications is a difficult and costly task due to code/system complexity and their long execution times. An alternative to running actual codes is to gather their communication traces and then replay them, which facilitates application tuning and future procurements. While past approaches lacked lossless scalable trace collection, we contribute an approach that provides orders of magnitude smaller, if not near constant-size, communication traces regardless of the number of nodes while preserving structural information. We introduce intra- and inter-node compression techniques of MPI events, we develop a scheme to preserve time and causality of communication events, and we present results of our implementation for BlueGene/L. Given this novel capability, we discuss its impact on communication tuning and on trace extrapolation. To the best of our knowledge, such a concise representation of MPI traces in a scalable manner combined with time-preserving deterministic MPI call replay are without any precedence

Heat Shock Protein 70 Prevents both Tau Aggregation and the Inhibitory Effects of Preexisting Tau Aggregates on Fast Axonal Transport

Aggregation and accumulation of the microtubule-associated protein tau are associated with cognitive decline and neuronal degeneration in Alzheimer's disease and other tauopathies. Thus, preventing the transition of tau from a soluble state to insoluble aggregates and/or reversing the toxicity of existing aggregates would represent a reasonable therapeutic strategy for treating these neurodegenerative diseases. Here we demonstrate that molecular chaperones of the heat shock protein 70 (Hsp70) family are potent inhibitors of tau aggregation in vitro, preventing the formation of both mature fibrils and oligomeric intermediates. Remarkably, addition of Hsp70 to a mixture of oligomeric and fibrillar tau aggregates prevents the toxic effect of these tau species on fast axonal transport, a critical process for neuronal function. When incubated with preformed tau aggregates, Hsp70 preferentially associated with oligomeric over fibrillar tau, suggesting that prefibrillar oligomeric tau aggregates play a prominent role in tau toxicity. Taken together, our data provide a novel molecular basis for the protective effect of Hsp70 in tauopathies