Tus, an E. coli Protein, Contains Mammalian Nuclear Targeting and Exporting Signals

Shuttling of proteins between nucleus and cytoplasm in mammalian cells is facilitated by the presence of nuclear localization signals (NLS) and nuclear export signals (NES), respectively. However, we have found that Tus, an E. coli replication fork arresting protein, contains separate sequences that function efficiently as NLS and NES in mammalian cell lines, as judged by cellular location of GFP-fusion proteins. The NLS was localized to a short stretch of 9 amino acids in the carboxy-terminus of Tus protein. Alterations of any of these basic amino acids almost completely abolished the nuclear targeting. The NES comprises a cluster of leucine/hydrophobic residues located within 21 amino acids at the amino terminus of Tus. Finally, we have shown that purified GFP-Tus fusion protein or GFP-Tus NLS fusion protein, when added to the culture media, was internalized very efficiently into mammalian cells. Thus, Tus is perhaps the first reported bacterial protein to possess both NLS and NES, and has the capability to transduce protein into mammalian cells

CU++ET: An Object Oriented Tool for Accelerating Computational Fluid Dynamics Codes using Graphical Processing Units

The application of graphical processing units (GPU) to solve partial differential equations is gaining popularity with the advent of improved computer hardware. Various lower level interfaces exist that allow the user to access GPU specific functions. One such interface is NVIDIA's Compute Unified Device Architecture (CUDA) library. CUDA has been applied previously to solve the Three-Dimensional Euler equations, and a speed-up of the order of 500 has been reported in literature using multiple GPU units. However, porting existing codes to run on the GPU requires the user to write kernels that execute on multiple cores, in the form of Single Instruction Multiple Data (SIMD). In the present work, a higher level framework has been developed that uses object oriented programming techniques available in C++ such as polymorphism, operator overloading, and template meta programming. Using this approach, CUDA kernels can be generated automatically during compile time. Briefly, CU++ET allows a code developer with just C/C++ knowledge to write computer programs that will execute on the GPU without any knowledge of specific programming techniques in CUDA. It allows the user to reuse existing C/C++ CFD codes with minimal changes. This approach is tremendously beneficial for CFD code development because it mitigates the necessity of creating hundreds of GPU kernels for various purposes. In its current form, CU++ET provides a framework for parallel array arithmetic, simplified data structures to interface with the GPU, and smart array indexing. Using this framework, a higher-order 3D Euler solver (ARC3D-GPU) has been developed with a performance improvement of about 70x on a single GPU compared to traditional FORTRAN/CPU execution. An implementation of heterogeneous parallelism, i.e., utilizing multiple GPUs to simultaneously process a partitioned grid system with communication at the interfaces using MPI has been developed and tested. An unstructured version of CU++ET is also demonstrated with its application towards solving the incompressible Navier-Stokes equations

Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871

In-Situ Safeguards Verification of Low Burn-up Pressurized Water Reactor Spent Fuel Assemblies

A novel in-situ gross defect verification method for light water reactor spent fuel assemblies was developed and investigated by a Monte Carlo study. This particular method is particularly effective for old pressurized water reactor spent fuel assemblies that have natural uranium in their upper fuel zones. Currently there is no method or instrument that does verification of this type of spent fuel assemblies without moving the spent fuel assemblies from their storage positions. The proposed method uses a tiny neutron detector and a detector guiding system to collect neutron signals inside PWR spent fuel assemblies through guide tubes present in PWR assemblies. The data obtained in such a manner are used for gross defect verification of spent fuel assemblies. The method uses 'calibration curves' which show the expected neutron counts inside one of the guide tubes of spent fuel assemblies as a function of fuel burn-up. By examining the measured data in the 'calibration curves', the consistency of the operator's declaration is verified

Income and Poverty in a Developing Economy

We present a stochastic agent-based model for the distribution of personal incomes in a developing economy. We start with the assumption that incomes are determined both by individual labour and by stochastic effects of trading and investment. The income from personal effort alone is distributed about a mean, while the income from trade, which may be positive or negative, is proportional to the trader's income. These assumptions lead to a Langevin model with multiplicative noise, from which we derive a Fokker-Planck (FP) equation for the income probability density function (IPDF) and its variation in time. We find that high earners have a power-law income distribution while the low income groups have a Levy IPDF. Comparing our analysis with the Indian survey data (obtained from the world bank website) taken over many years we obtain a near-perfect data collapse onto our model's equilibrium IPDF. The theory quantifies the economic notion of "given other things". Using survey data to relate the IPDF to actual food consumption we define a poverty index, which is consistent with traditional indices, but independent of an arbitrarily chosen "poverty line" and therefore less susceptible to manipulation

Low Latency Geo-distributed Data Analytics

Low latency analytics on geographically distributed dat-asets (across datacenters, edge clusters) is an upcoming and increasingly important challenge. The dominant approach of aggregating all the data to a single data-center significantly inflates the timeliness of analytics. At the same time, running queries over geo-distributed inputs using the current intra-DC analytics frameworks also leads to high query response times because these frameworks cannot cope with the relatively low and variable capacity of WAN links. We present Iridium, a system for low latency geo-distri-buted analytics. Iridium achieves low query response times by optimizing placement of both data and tasks of the queries. The joint data and task placement op-timization, however, is intractable. Therefore, Iridium uses an online heuristic to redistribute datasets among the sites prior to queries ’ arrivals, and places the tasks to reduce network bottlenecks during the query’s ex-ecution. Finally, it also contains a knob to budget WAN usage. Evaluation across eight worldwide EC2 re-gions using production queries show that Iridium speeds up queries by 3 × − 19 × and lowers WAN usage by 15% − 64 % compared to existing baselines

Blockade of adenosine A2B receptors ameliorates murine colitis

Background and purpose: The adenosine 2B (A2B) receptor is the predominant adenosine receptor expressed in the colon. Acting through the A2B receptor, adenosine mediates chloride secretion, as well as fibronectin and interleukin (IL)-6 synthesis and secretion in intestinal epithelial cells. A2B receptor mRNA and protein expression are increased during human and murine colitis. However, the effect of the A2B receptor in the activation of the intestinal inflammatory response is not known. In this study, we examined the effect of A2B receptor antagonism on murine colitis. Experimental approach: Dextran sodium sulphate (DSS)-treated mice and piroxicam-treated IL-10/ mice were used as animal models of colitis. The A2B receptor-selective antagonist, ATL-801, was given in the diet. Key results: Mice fed ATL-801 along with DSS showed a significantly lower extent and severity of colitis than mice treated with DSS alone, as shown by reduced clinical symptoms, histological scores, IL-6 levels and proliferation indices. The administration of ATL-801 prevented weight loss, suppressed the inflammatory infiltrate into colonic mucosa and decreased epithelial hyperplasia in piroxicam-treated IL-10/ mice. IL-6 and keratinocyte-derived chemokine (KC) concentrations in the supernatants of colonic organ cultures from colitic mice were significantly reduced by ATL-801 administration. Conclusions and implications: Taken together, these data demonstrate that the intestinal epithelial A2B receptor is an important mediator of pro-inflammatory responses in the intestine and that A2B receptor blockade may be an effectiv

The Radish Gene Reveals a Memory Component with Variable Temporal Properties

Memory phases, dependent on different neural and molecular mechanisms, strongly influence memory performance. Our understanding, however, of how memory phases interact is far from complete. In Drosophila, aversive olfactory learning is thought to progress from short-term through long-term memory phases. Another memory phase termed anesthesia resistant memory, dependent on the radish gene, influences memory hours after aversive olfactory learning. How does the radish-dependent phase influence memory performance in different tasks? It is found that the radish memory component does not scale with the stability of several memory traces, indicating a specific recruitment of this component to influence different memories, even within minutes of learning