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Gary Parkinson Simon Gaisford Qian Ru Alastair Lockwood Ashkan Khalili Rose Sheridan Peng T. Khaw Steve Brocchini Hala M. Fadda 《AAPS PharmSciTech》2012,13(4):1063-1072
We are developing tablet dosage forms for implantation directly into the subconjunctival space of the eye. The matrix metalloproteinase inhibitor, ilomastat, has previously been shown to be efficacious at suppressing scarring following glaucoma filtration surgery (GFS). We report on the physical characterisation of ilomastat which is being developed for ocular implantation. Since ilomastat is being considered for implantation it is necessary to examine its polymorphs and their influence on aspects of the in vitro drug release profile. X-ray powder diffraction identified two polymorphs of ilomastat from different commercial batches of the compound. Tablets were prepared from the two different polymorphs. Isothermal perfusion calorimetry was used to show that amorphous content is not increased during tablet formulation. The melting points of the two polymorphs are 188 and 208°C as determined by differential scanning calorimetry. Utilising single crystal X-ray diffraction, the structural conformations and packing arrangements of the different polymorphs were determined. The orthorhombic crystal crystallised as a monohydrate while the second monoclinic crystal form is non-solvated. Ilomastat tablets prepared from the two different solid forms exhibited similar drug release profiles in vitro under conditions mimicking the aqueous composition, volume and flow of the subconjunctival space after GFS. This suggests that a reproducible dose at each time point during release after implantation should be achievable in vivo with ilomastat tablets prepared from the two polymorphs identified. 相似文献
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Pingzhao Hu Sarath Chandra Janga Mohan Babu J. Javier Díaz-Mejía Gareth Butland Wenhong Yang Oxana Pogoutse Xinghua Guo Sadhna Phanse Peter Wong Shamanta Chandran Constantine Christopoulos Anaies Nazarians-Armavil Negin Karimi Nasseri Gabriel Musso Mehrab Ali Nazila Nazemof Veronika Eroukova Ashkan Golshani Alberto Paccanaro Jack F Greenblatt Gabriel Moreno-Hagelsieb Andrew Emili 《PLoS biology》2009,7(4)
One-third of the 4,225 protein-coding genes of Escherichia coli K-12 remain functionally unannotated (orphans). Many map to distant clades such as Archaea, suggesting involvement in basic prokaryotic traits, whereas others appear restricted to E. coli, including pathogenic strains. To elucidate the orphans' biological roles, we performed an extensive proteomic survey using affinity-tagged E. coli strains and generated comprehensive genomic context inferences to derive a high-confidence compendium for virtually the entire proteome consisting of 5,993 putative physical interactions and 74,776 putative functional associations, most of which are novel. Clustering of the respective probabilistic networks revealed putative orphan membership in discrete multiprotein complexes and functional modules together with annotated gene products, whereas a machine-learning strategy based on network integration implicated the orphans in specific biological processes. We provide additional experimental evidence supporting orphan participation in protein synthesis, amino acid metabolism, biofilm formation, motility, and assembly of the bacterial cell envelope. This resource provides a “systems-wide” functional blueprint of a model microbe, with insights into the biological and evolutionary significance of previously uncharacterized proteins. 相似文献
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Xuemei Luo Maureen Mckeague Sylvain Pitre Michel Dumontier James Green Ashkan Golshani Maria C. Derosa Frank Dehne 《RNA (New York, N.Y.)》2010,16(11):2252-2262
It is well known that using random RNA/DNA sequences for SELEX experiments will generally yield low-complexity structures. Early experimental results suggest that having a structurally diverse library, which, for instance, includes high-order junctions, may prove useful in finding new functional motifs. Here, we develop two computational methods to generate sequences that exhibit higher structural complexity and can be used to increase the overall structural diversity of initial pools for in vitro selection experiments. Random Filtering selectively increases the number of five-way junctions in RNA/DNA pools, and Genetic Filtering designs RNA/DNA pools to a specified structure distribution, whether uniform or otherwise. We show that using our computationally designed DNA pool greatly improves access to highly complex sequence structures for SELEX experiments (without losing our ability to select for common one-way and two-way junction sequences). 相似文献
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Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet‐induced obesity
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Nataliya Zlotnikov Ashkan Javid Mijhgan Ahmed Azad Eshghi Tian Tian Tang Anoop Arya Anil Bansal Fatima Matar Maitry Parikh Rhodaba Ebady Adeline Koh Nupur Gupta Peng Song Yang Zhang Susan Newbigging Gary P. Wormser Ira Schwartz Robert Inman Michael Glogauer Tara J. Moriarty 《Cellular microbiology》2017,19(5)
Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high‐fat diet‐induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil‐ and macrophage‐based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi‐infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high‐fat diet, toll‐like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow‐derived macrophages from obese, B. burgdorferi‐infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice. 相似文献
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Electromagnetic cellular interactions 总被引:1,自引:0,他引:1
Michal Cifra Jeremy Z. Fields Ashkan Farhadi 《Progress in biophysics and molecular biology》2011,105(3):223-246
Chemical and electrical interaction within and between cells is well established. Just the opposite is true about cellular interactions via other physical fields. The most probable candidate for an other form of cellular interaction is the electromagnetic field. We review theories and experiments on how cells can generate and detect electromagnetic fields generally, and if the cell-generated electromagnetic field can mediate cellular interactions. We do not limit here ourselves to specialized electro-excitable cells. Rather we describe physical processes that are of a more general nature and probably present in almost every type of living cell. The spectral range included is broad; from kHz to the visible part of the electromagnetic spectrum. We show that there is a rather large number of theories on how cells can generate and detect electromagnetic fields and discuss experimental evidence on electromagnetic cellular interactions in the modern scientific literature. Although small, it is continuously accumulating. 相似文献
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Mohan Babu Roland Arnold Cedoljub Bundalovic-Torma Alla Gagarinova Keith S. Wong Ashwani Kumar Geordie Stewart Bahram Samanfar Hiroyuki Aoki Omar Wagih James Vlasblom Sadhna Phanse Krunal Lad Angela Yeou Hsiung Yu Christopher Graham Ke Jin Eric Brown Ashkan Golshani Philip Kim Gabriel Moreno-Hagelsieb Jack Greenblatt Walid A. Houry John Parkinson Andrew Emili 《PLoS genetics》2014,10(2)
Large-scale proteomic analyses in Escherichia coli have documented the composition and physical relationships of multiprotein complexes, but not their functional organization into biological pathways and processes. Conversely, genetic interaction (GI) screens can provide insights into the biological role(s) of individual gene and higher order associations. Combining the information from both approaches should elucidate how complexes and pathways intersect functionally at a systems level. However, such integrative analysis has been hindered due to the lack of relevant GI data. Here we present a systematic, unbiased, and quantitative synthetic genetic array screen in E. coli describing the genetic dependencies and functional cross-talk among over 600,000 digenic mutant combinations. Combining this epistasis information with putative functional modules derived from previous proteomic data and genomic context-based methods revealed unexpected associations, including new components required for the biogenesis of iron-sulphur and ribosome integrity, and the interplay between molecular chaperones and proteases. We find that functionally-linked genes co-conserved among γ-proteobacteria are far more likely to have correlated GI profiles than genes with divergent patterns of evolution. Overall, examining bacterial GIs in the context of protein complexes provides avenues for a deeper mechanistic understanding of core microbial systems. 相似文献
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Lakshmi Swarna Mukhi Pidugu J.C. Emmanuel Mbimba Muqeet Ahmad Edwin Pozharski Edward A. Sausville Ashkan Emadi Eric A. Toth 《BMC structural biology》2016,16(1):1