File and Object Replication in Data Grids

Data replication is a key issue in a Data Grid and can be managed in different ways and at different levels of granularity: for example, at the file level or object level. In the High Energy Physics community, Data Grids are being developed to support the distributed analysis of experimental data. We have produced a prototype data replication tool, the Grid Data Mirroring Package (GDMP) that is in production use in one physics experiment, with middleware provided by the Globus Toolkit used for authentication, data movement, and other purposes. We present here a new, enhanced GDMP architecture and prototype implementation that uses Globus Data Grid tools for efficient file replication. We also explain how this architecture can address object replication issues in an object-oriented database management system. File transfer over wide-area networks requires specific performance tuning in order to gain optimal data transfer rates. We present performance results obtained with GridFTP, an enhanced version of FTP, and discuss tuning parameters.     

A PAMPA Study of the Permeability‐Enhancing Effect of New Ceramide Analogues

There is a major need in drug discovery for quick, precise, and cost‐effective high‐throughput screening (HTS) systems in the early stages of drug research. The Parallel Artificial Membrane Permeability Assay (PAMPA) aims at predicting the passive membrane properties of drugs. Since 1998, model membranes have been developed to predict gastro‐intestinal absorption or transport through the blood–brain barrier. This paper presents recent results in a project aiming to improve the prediction of transdermal penetration. Using the PAMPA system, we investigated the effect of four newly synthetized ceramide analogues (certramides) on the permeability of three model compounds (ciprofloxacin, nifedipine, and verapamil). The certramides differ in the length of one alkyl chain, while the other alkyl chain and the head group remained the same. A relationship between the membrane concentration of certramides (from 0 to 100%) and the permeability of compounds was found, and the results of different certramides were compared. The strongest effect on permeability was caused by the ceramide analogue CTR(C₁₂–C₁₆). The reproducibility of the experiments and the impact of presence or absence of organic solvents (dodecane and CHCl₃) in the membrane were also investigated.     

A Distributed Multi-Storage Resource Architecture and I/O Performance Prediction for Scientific Computing

I/O intensive applications have posed great challenges to computational scientists. A major problem of these applications is that users have to sacrifice performance requirements in order to satisfy storage capacity requirements in a conventional computing environment. Further performance improvement is impeded by the physical nature of these storage media even when state-of-the-art I/O optimizations are employed.In this paper, we present a distributed multi-storage resource architecture, which can satisfy both performance and capacity requirements by employing multiple storage resources. Compared to a traditional single storage resource architecture, our architecture provides a more flexible and reliable computing environment. This architecture can bring new opportunities for high performance computing as well as inherit state-of-the-art I/O optimization approaches that have already been developed. It provides application users with high-performance storage access even when they do not have the availability of a single large local storage archive at their disposal. We also develop an Application Programming Interface (API) that provides transparent management and access to various storage resources in our computing environment. Since I/O usually dominates the performance in I/O intensive applications, we establish an I/O performance prediction mechanism which consists of a performance database and a prediction algorithm to help users better evaluate and schedule their applications. A tool is also developed to help users automatically generate performance data stored in databases. The experiments show that our multi-storage resource architecture is a promising platform for high performance distributed computing.     

Scalability of the surface-based DNA algorithm for 3-SAT

Since Adleman first proposed DNA computing for the Hamiltonian path problem, several authors have reported DNA computing for 3-SAT. Previous research presented DNA computing on surfaces and demonstrated how to solve a four-variable four-clause instance of 3-SAT, and claimed that the surface-based approach was designed to scale up to larger problems. In this paper we establish an error model for the incomplete "mark" and imperfect "destroy" operations. By using the error model we argue that no matter how large the "mark" and "destroy" rates are we can always give satisfiable instances of 3-SAT such that no DNA strands remain on the surface at the end of the computation. By the surface-based approach the satisfiable instances of 3-SAT would be misdetermined to be unsatisfiable. Thus, the error leads to an incorrect result of the SAT computation. Furthermore, given the "mark" rate p and the "not-destroy" rate rho, we find that the approach can only solve at most N-variable instances of 3-SAT problems, where N=[(2+beta(2)+2+2 square root beta (2))/beta(2)] in which beta=1-1/(p+rhoq) and q=1-p and [a] is the greatest integer less than a or equal to a.     

Sulfamoyl benzamides as novel CB2 cannabinoid receptor ligands

Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB₂ receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB₂ receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.     

Global computing for bioinformatics

Global computing, the collaboration of idle PCs via the Internet in a SETI@home style, emerges as a new way of massive parallel multiprocessing with potentially enormous CPU power. Its relations to the broader, fast-moving field of Grid computing are discussed without attempting a review of the latter. This review (i) includes a short table of milestones in global computing history, (ii) lists opportunities global computing offers for bioinformatics, (iii) describes the structure of problems well suited for such an approach, (iv) analyses the anatomy of successful projects and (v) points to existing software frameworks. Finally, an evaluation of the various costs shows that global computing indeed has merit, if the problem to be solved is already coded appropriately and a suitable global computing framework can be found. Then, either significant amounts of computing power can be recruited from the general public, or--if employed in an enterprise-wide Intranet for security reasons--idle desktop PCs can substitute for an expensive dedicated cluster.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Structural analysis of smooth muscle tropomyosin α and β isoforms

A large number of tropomyosin (Tm) isoforms function as gatekeepers of the actin filament, controlling the spatiotemporal access of actin-binding proteins to specialized actin networks. Residues ∼40–80 vary significantly among Tm isoforms, but the impact of sequence variation on Tm structure and interactions with actin is poorly understood, because structural studies have focused on skeletal muscle Tmα. We describe structures of N-terminal fragments of smooth muscle Tmα and Tmβ (sm-Tmα and sm-Tmβ). The 2.0-Å structure of sm-Tmα81 (81-aa) resembles that of skeletal Tmα, displaying a similar super-helical twist matching the contours of the actin filament. The 1.8-Å structure of sm-Tmα98 (98-aa) unexpectedly reveals an antiparallel coiled coil, with the two chains staggered by only 4 amino acids and displaying hydrophobic core interactions similar to those of the parallel dimer. In contrast, the 2.5-Å structure of sm-Tmβ98, containing Gly-Ala-Ser at the N terminus to mimic acetylation, reveals a parallel coiled coil. None of the structures contains coiled-coil stabilizing elements, favoring the formation of head-to-tail overlap complexes in four of five crystallographically independent parallel dimers. These complexes show similarly arranged 4-helix bundles stabilized by hydrophobic interactions, but the extent of the overlap varies between sm-Tmβ98 and sm-Tmα81 from 2 to 3 helical turns. The formation of overlap complexes thus appears to be an intrinsic property of the Tm coiled coil, with the specific nature of hydrophobic contacts determining the extent of the overlap. Overall, the results suggest that sequence variation among Tm isoforms has a limited effect on actin binding but could determine its gatekeeper function.