Nuclear transport: what a kary-on!

AbstractCompartmentalisation in eukaryotic cells presents special problems in macromolecular transport. Here we use the recently determined X-ray structures of a number of components of the nuclear transport machinery as a framework to review current understanding of this fundamental biological process

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

Assessing transmission and translation of learning about evidence based policing by graduate trainee police officers

We examine transmission of Evidence Based Policing (EBP) principles through taught classroom sessions, a skills based Masterclass and enhanced infusion experienced by participants of the Police Now (PN) leadership development programme. We coded seventy-five presentations describing a live project delivered by 57 PN participants (probationer constables) at one of PN’s ‘100 Day Impact Events’. Benchmarking the content against extended EBP criteria revealed that graduates attempted to specify issues and engage in consultation, but made relatively limited use of concepts and theory, data analysis or statistical techniques. Rather than note this as a limitation of the PN programme, or ‘failures’ by the learners we argue that the findings open a wider discussion of what level of research sophistication can reasonably be expected of serving officers

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

Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation

Tau protein was scanned for highly amyloidogenic sequences in amphiphilic motifs (X)nZ, Z(X)nZ (n≥2) or (XZ)n (n≥2), where X is a hydrophobic residue and Z is a charged or polar residue. N-acetyl peptides homologous to these sequences were used to study aggregation. Transmission electron microscopy (TEM) showed 7 peptides, in addition to well known primary nucleating sequences c275VQIINK (AcPHF6*) and Ac306VQIVYK (AcPHF6), formed fibers, tubes, ribbons or rolled sheets. Of the peptides shown by TEM to form amyloid, Ac10VME, AcPHF6*, Ac375KLTFR, and Ac393VYK were found to enhance the fraction of β-structure of AcPHF6 formed at equilibrium, and Ac375KLTFR was found to inhibit AcPHF6 and AcPHF6* aggregation kinetics in a dose-dependent manner, consistent with its participation in a hybrid steric zipper model. Single site mutants were generated which transformed predicted amyloidogenic sequences in tau into non-amyloidogenic ones. A M11K mutant had fewer filaments and showed a decrease in aggregation kinetics and an increased lag time compared to wild type tau, while a F378K mutant showed significantly more filaments. Our results infer that sequences throughout tau, in addition to PHF6 and PHF6*, can seed amyloid formation or affect aggregation kinetics or thermodynamics

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

Mitochondrial DNA Manipulations Affect Tau Oligomerization

Background:Mitochondrial dysfunction and tau aggregation occur in Alzheimer’s disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau. Objective:To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations. Methods:Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects. Results:We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift. Conclusion:We conclude a cell’s mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance

Survival after Resection of Multiple Tumor Foci of Intrahepatic Cholangiocarcinoma

Background: Multiple tumor foci of intrahepatic cholangiocarcinoma (ICC) are often considered a contra-indication for resection. We sought to define long-term outcomes after resection of ICC in patients with multiple foci. Methods: Patients who underwent resection for ICC between 1990 and 2017 were identified from 12 major HPB centers. Outcomes of patients with solitary lesions, multiple lesions (ML), and oligometastases (OM) were compared. OM were defined as extrahepatic metastases spread to a single organ. Results: One thousand thirteen patients underwent resection of ICC. On final pathology, 185 patients (18.4%) had ML and 27 (2.7%) had OM. Median survival of patients with a solitary tumor was 43.2 months, while the median survival of patients with 2 tumors was 21.2 months; the median survival of patients with 3 or more tumors was 15.3 months (p < 0.001). Five-year survival was 43.3%, 28.0%, and 8.6%, respectively. The median survival of patients without OM was 37.8 months versus 14.9 months among patients with OM (p < 0.001); estimated 5-year survival was 39.3% and 10.6%, respectively. In multivariable analysis, the presence of two lesions was not an independent poor prognostic factor for OS (HR 1.19; 95%CI 0.90-1.57; p = 0.229). However, the presence of three or more tumors was an independent poor prognostic factor for OS (HR 1.97; 95%CI 1.48-2.64; p < 0.001). Conclusion: Resection of multiple liver tumors for patients with ICC did not preclude 5-year survival: in particular, estimated 5-year OS for resection of two tumors was 28.0%.info:eu-repo/semantics/publishedVersio

H1N1 2009 Pandemic Influenza Virus: Resistance of the I223R Neuraminidase Mutant Explained by Kinetic and Structural Analysis

Two classes of antiviral drugs, neuraminidase inhibitors and adamantanes, are approved for prophylaxis and therapy against influenza virus infections. A major concern is that antiviral resistant viruses emerge and spread in the human population. The 2009 pandemic H1N1 virus is already resistant to adamantanes. Recently, a novel neuraminidase inhibitor resistance mutation I223R was identified in the neuraminidase of this subtype. To understand the resistance mechanism of this mutation, the enzymatic properties of the I223R mutant, together with the most frequently observed resistance mutation, H275Y, and the double mutant I223R/H275Y were compared. Relative to wild type, KMvalues for MUNANA increased only 2-fold for the single I223R mutant and up to 8-fold for the double mutant. Oseltamivir inhibition constants (KI) increased 48-fold in the single I223R mutant and 7500-fold in the double mutant. In both cases the change was largely accounted for by an increased dissociation rate constant for oseltamivir, but the inhibition constants for zanamivir were less increased. We have used X-ray crystallography to better understand the effect of mutation I223R on drug binding. We find that there is shrinkage of a hydrophobic pocket in the active site as a result of the I223R change. Furthermore, R223 interacts with S247 which changes the rotamer it adopts and, consequently, binding of the pentoxyl substituent of oseltamivir is not as favorable as in the wild type. However, the polar glycerol substituent present in zanamivir, which mimics the natural substrate, is accommodate