[3,3′-Dihy­droxy-3,3′-bis­(pyridin-3-yl-κN)-1,1′-(pyridine-2,6-di­yl)dipropan-1-one](nitrato-κ2 O,O′)silver(I)

In the title compound, a new macrocyclic metal complex, [Ag(NO3)(C21H15N3O4)], all non-H atoms are in a close-to-planar geometry (except for the nitrate anion), with a maximum out-of-plane deviation of 0.327 (6) Å for a pyridine C atom. The dihedral angle between the least-squares plane through the [3,3′-dihy­droxy-3,3′-bis­(pyridin-3-yl)-1,1′-(pyridine-2,6-di­yl)dipropan-1-one]silver(I) fragment and the nitrate anion is 31.29 (13)°. The mol­ecular structure is stabilized by several inter- and intra­molecular O—H⋯O and C—H⋯O hydrogen bonds. The AgI atom is coordinated by two pyridine N atoms and two O atoms of the nitrate anion in a geometry intermediate between tetrahedral and square-planar

sscMap: An extensible Java application for connecting small-molecule drugs using gene-expression signatures

Background: Connectivity mapping is a process to recognize novel pharmacological and toxicological properties in small molecules by comparing their gene expression signatures with others in a database. A simple and robust method for connectivity mapping with increased specificity and sensitivity was recently developed, and its utility demonstrated using experimentally derived gene signatures. Results: This paper introduces sscMap (statistically significant connections' map), a Java application designed to undertake connectivity mapping tasks using the recently published method. The software is bundled with a default collection of reference gene-expression profiles based on the publicly available dataset from the Broad Institute Connectivity Map 02, which includes data from over 7000 Affymetrix microarrays, for over 1000 small-molecule compounds, and 6100 treatment instances in 5 human cell lines. In addition, the application allows users to add their custom collections of reference profiles and is applicable to a wide range of other 'omics technologies. Conclusions: The utility of sscMap is two fold. First, it serves to make statistically significant connections between a user-supplied gene signature and the 6100 core reference profiles based on the Broad Institute expanded dataset. Second, it allows users to apply the same improved method to custom-built reference profiles which can be added to the database for future referencing. The software can be freely downloaded from http://purl.oclc.org/NET/sscMapComment: 3 pages, 1 table, 1 eps figur

3-(2-Bromo­benz­yl)-1-methyl-1H-imidazol-3-ium bromide

In the title compound, C11H12BrN2 +·Br−, the imidazole and phenyl rings are nearly perpendicular, making a dihedral angle of 87.71 (7)°. The crystal structure is stabilized by non-classical inter­molecular C—H⋯Br hydrogen bonds and inversion-related mol­ecules are linked through π–π inter­actions between the imidazole ring systems [centroid–centroid distance = 3.472 (6) Å]

Electromagnetic form factor of pion from N_f=2+1 dynamical flavor QCD

We present a calculation of the electromagnetic form factor of the pion in $N_f=2+1$ flavor lattice QCD. Calculations are made on the PACS-CS gauge field configurations generated using Iwasaki gauge action and Wilson-clover quark action on a $32^3\times64$ lattice volume with the lattice spacing estimated as $a=0.0907(13)$ fm at the physical point. Measurements of the form factor are made using the technique of partially twisted boundary condition to reach small momentum transfer as well as periodic boundary condition with integer momenta. Additional improvements including random wall source techniques and a judicious choice of momenta carried by the incoming and outgoing quarks are employed for error reduction. Analyzing the form factor data for the pion mass at $M_\pi \approx 411$ MeV and 296 MeV, we find that the NNLO SU(2) chiral perturbation theory fit yields $=0.441 \pm 0.046 {\rm fm}^2$ for the pion charge radius at the physical pion mass. Albeit the error is quite large, this is consistent with the experimental value of $0.452\pm 0.011 {\rm fm}^2$. Below $M_\pi\approx 300$ MeV, we find that statistical fluctuations in the pion two- and three-point functions become too large to extract statistically meaningful averages on a $32^3$ spatial volume. We carry out a sample calculation on a $64^4$ lattice with the quark masses close to the physical point, which suggests that form factor calculations at the physical point become feasible by enlarging lattice sizes to $M_\pi L\approx 4$.Comment: 28 pages, 14 figure

A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

Controlled interfacial assembly of 2D curved colloidal crystals and jammed shells

Assembly of colloidal particles on fluid interfaces is a promising technique for synthesizing two-dimensional micro-crystalline materials useful in fields as diverse as biomedicine1, materials science2, mineral flotation3 and food processing4. Current approaches rely on bulk emulsification methods, require further chemical and thermal treatments, and are restrictive with respect to the materials employed5-9. The development of methods that exploit the great potential of interfacial assembly for producing tailored materials have been hampered by the lack of understanding of the assembly process. Here we report a microfluidic method that allows direct visualization and understanding of the dynamics of colloidal crystal growth on curved interfaces. The crystals are periodically ejected to form stable jammed shells, which we refer to as colloidal armour. We propose that the energetic barriers to interfacial crystal growth and organization can be overcome by targeted delivery of colloidal particles through hydrodynamic flows. Our method allows an unprecedented degree of control over armour composition, size and stability.Comment: 18 pages, 5 figure

Non-linear soil behavior on freight vs passenger lines

Upgrading existing passenger-only railway lines to carry freight traffic is becoming increasingly desirable. This is challenging because freight trains have larger axle loads and thus can have a negative effect on track longevity, particularly on ballasted lines supported by sub-optimal ground conditions. These additional loads can cause large subgrade strains resulting in non-linear behaviour, which should be considered before permitting freight vehicles on passenger routes. To do so requires the modelling of non-linear soil behaviour which is challenging. Therefore, this paper presents a solution in the form of an equivalent non-linear, thin layer element soil model, coupled to an analytical track model. The model has low computational demand and can adjust subgrade stiffness depending upon strain levels. Therefore, it is well suited to computing track response induced by freight trains. This paper validates the model and then uses it to compare the differences between the response of a ballasted line to freight and passenger vehicles

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Biocompatibility of subretinal parylene-based Ti/Pt microelectrode array in rabbit for further artificial vision studies

To evaluate the biocompatibility of subretinal implanted parylene-based Ti/Pt microelectrode arrays (MEA). Eyes were enucleated 3 months after MEAs were implanted into the subretinal space of rabbits. Morphological changes of the retinas were investigated by H&E staining. Immunohistochemical staining for glial fibrillary acidic protein and opsin were performed to evaluate changes in Muller cells and photoreceptors in the retinas. Retina tissue around the array remained intact. Photoreceptor degeneration and glial cell activation were observed in the retina overlaying the MEA implant. However, the cells in the inner retinal layers were preserved. Photoreceptor degeneration and glial cell activation at the MEA–retina interface are expected to be a normal reaction to implantation. Material used in this experiment has good biocompatibility within the subretinal environment and is expected to be promising in the further retinal prosthesis studies