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"Lock, Peter"
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Characterization and formulation into solid dosage forms of a novel bacteriophage lytic against Klebsiella oxytoca
To isolate and characterize bacteriophage lytic for the opportunistic pathogen Klebsiella oxytoca and their formulation into a range of solid dosage forms for in-vitro testing.
We report the isolation, genomic and functional characterization of a novel bacteriophage lytic for Klebsiella oxytoca, which does not infect the closely related Klebsiella pneumoniae. This bacteriophage was formulated into suppositories and troches and shown to be released and lyse underlying Klebsiella oxytoca bacteria in an in-vitro model. These bacteriophage formulations were stable for at least 49 days at 4°C.
The successful in-vitro assay of these formulations here suggests that they could potentially be tested in-vivo to determine whether such a therapeutic approach could modulate the gut microbiome, and control Klebsiella oxytoca overgrowth, during antibiotic therapy regimes.
This study reports a novel bacteriophage specific for Klebsiella oxytoca which can be formulated into solid dosage forms appropriate for potential delivery in testing as a therapy to modulate gut microbiome during antibiotic therapies.
Journal Article
Space quest : jump to Jupiter
Learn about the features of Jupiter, the probes that have been sent there, and the scientists' theories about what the information sent back has revealed.
Book
Defining the role of cytoskeletal components in the formation of apoptopodia and apoptotic bodies during apoptosis
During apoptosis, dying cells undergo dynamic morphological changes that ultimately lead to their disassembly into fragments called apoptotic bodies (ApoBDs). Reorganisation of the cytoskeletal structures is key in driving various apoptotic morphologies, including the loss of cell adhesion and membrane bleb formation. However, whether cytoskeletal components are also involved in morphological changes that occur later during apoptosis, such as the recently described generation of thin apoptotic membrane protrusions called apoptopodia and subsequent ApoBD formation, is not well defined. Through monitoring the progression of apoptosis by confocal microscopy, specifically focusing on the apoptopodia formation step, we characterised the presence of F-actin and microtubules in a subset of apoptopodia generated by T cells and monocytes. Interestingly, targeting actin polymerisation and microtubule assembly pharmacologically had no major effect on apoptopodia formation. These data demonstrate apoptopodia as a novel type of membrane protrusion that could be formed in the absence of actin polymerisation and microtubule assembly.
Journal Article
Genetic Disruption of the Sh3pxd2a Gene Reveals an Essential Role in Mouse Development and the Existence of a Novel Isoform of Tks5
Tks5 is a scaffold protein and Src substrate involved in cell migration and matrix degradation through its essential role in invadosome formation and function. We have previously described that Tks5 is fundamental for zebrafish neural crest cell migration in vivo. In the present study, we sought to investigate the function of Tks5 in mammalian development by analyzing mice mutant for sh3pxd2a, the gene encoding Tks5. Homozygous disruption of the sh3pxd2a gene by gene-trapping in mouse resulted in neonatal death and the presence of a complete cleft of the secondary palate. Interestingly, embryonic fibroblasts from homozygous gene-trap sh3pxd2a mice lacked only the highest molecular weight band of the characteristic Tks5 triplet observed in protein extracts, leaving the lower molecular weight bands unaffected. This finding, together with the existence of two human Expressed Sequence Tags lacking the first 5 exons of SH3PXD2A, made us hypothesize about the presence of a second alternative transcription start site located in intron V. We performed 5'RACE on mouse fibroblasts and isolated a new transcript of the sh3pxd2a gene encoding a novel Tks5 isoform, that we named Tks5β. This novel isoform diverges from the long form of Tks5 in that it lacks the PX-domain, which confers affinity for phosphatidylinositol-3,4-bisphosphate. Instead, Tks5β has a short unique amino terminal sequence encoded by the newly discovered exon 6β; this exon includes a start codon located 29 bp from the 5'-end of exon 6. Tks5β mRNA is expressed in MEFs and all mouse adult tissues analyzed. Tks5β is a substrate for the Src tyrosine kinase and its expression is regulated through the proteasome degradation pathway. Together, these findings indicate the essentiality of the larger Tks5 isoform for correct mammalian development and the transcriptional complexity of the sh3pxd2a gene.
Journal Article
Functional and genomic characterization of a xenograft model system for the study of metastasis in triple-negative breast cancer
Triple-negative breast cancer represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes. Hence, new molecular targets for therapeutic intervention are necessary. Analyses of panels of human or mouse cancer lines derived from the same individual that differ in their cellular phenotypes but not in genetic background have been instrumental in defining the molecular players that drive the various hallmarks of cancer. To determine the molecular regulators of metastasis in triple-negative breast cancer, we completed a rigorous in vitro and in vivo characterization of four populations of the MDA-MB-231 human breast cancer line ranging in aggressiveness from non-metastatic to spontaneously metastatic to lung, liver, spleen and lymph node. Single nucleotide polymorphism (SNP) array analyses and genome-wide mRNA expression profiles of tumour cells isolated from orthotopic mammary xenografts were compared among the four lines to define both cell autonomous pathways and genes associated with metastatic proclivity. Gene set enrichment analysis demonstrated an unexpected association between both ribosome biogenesis and mRNA metabolism and metastatic capacity. Differentially expressed genes or families of related genes were allocated to one of four categories, associated with either metastatic initiation (for example CTSC, ENG, BMP2), metastatic virulence (e.g. ADAMTS1, TIE1) metastatic suppression (e.g. CST1, CST2, CST4, CST6, SCNNA1, BMP4) or metastatic avirulence (e.g. CD74). Collectively, this model system based on MDA-MB-231 cells should be useful for the assessment of gene function in the metastatic cascade and also for the testing of novel experimental therapeutics for the treatment of triple-negative breast cancer.
Journal Article
Marino Sanudo Torsello, The Book of the Secrets of the Faithful of the Cross
This is the first full translation of Marino Sanudo Torsello's Secreta fidelium Crucis to be made into English. The work itself is a piece of crusading propaganda following the fall of Acre in 1291, written between 1300 and 1321, but it includes much of historical relevance along with interesting observations on the early history of Jerusalem and the Crusader Kingdom. The translation is based upon the text edited by Jacques Bongars in 1611. There is an introduction that contextualises the book, its author, his sources and his audience. The notes provide essential information to clarify internal textual references and allusions, as well as the role of Biblical references in Sanudo's grand design. The index is designed to make this detailed text usable and accessible. In this, his major work, Sanudo advocated the conquest of Egypt as the means to regain Jerusalem for the Latins and worked through his points with considerable detail alongside references to 13th-century Mediterranean history, especially involving Louis IX of France and Charles of Anjou, king of Naples. Books I and II give considerable detailed discussion of the concept, plan and costs of his proposed crusade. Book III provides an outline history of the crusades and the crusader states. It is derived from a wide-reading of other sources especially of William of Tyre, and, for events after 1184 on the Eracles, the letters of James of Vitry, and Sanudo's own experiences in the east. Throughout, the work contains a staggering amount of cartographical, ethnographical, geographical, and nautical information, as well as numerous unique insights into historical events and personalities of the late 13th century, not only in Outremer but in Western Europe.
eBook
Isolation and characterization of bacteriophage NTR1 infectious for Nocardia transvalensis and other Nocardia species
We describe here the isolation and characterization of the bacteriophage, NTR1 from activated sludge. This phage is lytic for Nocardia transvalensis, Nocardia brasiliensis and Nocardia farcinica. NTR1 phage has a genome sequence of 65,275 bp in length, and its closest match is to the Skermania piniformis phage SPI1 sharing over 36% of its genome. The phage belongs to the Siphoviridae family, possessing a long non-contractile tail and icosahedral head. Annotation of the genome reveals 97 putative open reading frames arranged in the characteristic modular organization of Siphoviridae phages and contains a single tRNA-Met gene.
Journal Article
Expression of the adaptor protein Tks5 in human cancer: Prognostic potential
Tks5 (tyrosine kinase substrate with 5 SH3 domains) is an adaptor protein which cooperates with Src tyrosine kinase to promote the formation of protease-enriched, actin-based projections known as invadopodia, which are utilized by invasive cancer cells to degrade the extracellular matrix (ECM). We previously identified a Src-Tks5-Nck pathway which promotes invadopodium formation and ECM proteolysis in melanoma and breast cancer cells. We therefore sought to investigate the significance of Tks5 expression in human cancers. This was undertaken retrospectively through an immunohistochemical evaluation in tissue microarray cores and through data mining of the public database, Oncomine. Here we showed that Tks5 was expressed at higher levels in the microarray cores of breast, colon, lung and prostate cancer tissues compared to the levels in normal tissues. Importantly, mining of Oncomine datasets revealed a strong correlation between Tks5 mRNA overexpression in a number of cancers with increased metastatic events and a poorer prognosis. Collectively, these findings suggest a clinical association of Tks5 expression in human cancers. It identifies the importance for further investigations in examining the full potential of Tks5 as a relevant prognostic marker in a select number of cancers which may have implications for future targeted therapies.
Journal Article