DSpace Manual: Software version 1.5

DSpace is an open source software platform that enables organizations to: - Capture and describe digital material using a submission workflow module, or a variety of programmatic ingest options - Distribute an organization's digital assets over the web through a search and retrieval system - Preserve digital assets over the long term This system documentation includes a functional overview of the system, which is a good introduction to the capabilities of the system, and should be readable by nontechnical personnel. Everyone should read this section first because it introduces some terminology used throughout the rest of the documentation. For people actually running a DSpace service, there is an installation guide, and sections on configuration and the directory structure. Note that as of DSpace 1.2, the administration user interface guide is now on-line help available from within the DSpace system. Finally, for those interested in the details of how DSpace works, and those potentially interested in modifying the code for their own purposes, there is a detailed architecture and design section.

Characterisation of the role of canonical BMP-Smad 1/5/8 signalling in the development of ventral midbrain dopaminergic neurons

Ventral midbrain (VM) dopaminergic (DA) neurons, which project to the dorsal striatum via the nigrostriatal pathway, are progressively degenerated in Parkinson’s disease (PD). The identification of the instructive factors that regulate midbrain DA neuron development, and the subsequent elucidation of the molecular bases of their effects, is vital. Such an understanding would facilitate the generation of transplantable DA neurons from stem cells and the identification of developmentally-relevant neurotrophic factors, the two most promising therapeutic approaches for PD. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth/differentiation factor (GDF) 5, which signal via a canonical Smad 1/5/8 signalling pathway, have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo, and may function to regulate VM DA neuronal development. However, the molecular (signalling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects remain to be elucidated. The present thesis hypothesised that canonical Smad signalling mediates the direct effects of BMP2 and GDF5 on the development of VM DA neurons. By activating, modulating and/or inhibiting various components of the BMP-Smad signalling pathway, this research demonstrated that GDF5- and BMP2-induced neurite outgrowth from midbrain DA neurons is dependent on BMP type I receptor activation of the Smad signalling pathway. The role of glial cell-line derived neurotrophic factor (GDNF)-signalling, dynamin-dependent endocytosis and Smad interacting protein-1 (Sip1) regulation, in the neurotrophic effects of BMP2 and GDF5 were determined. Finally, the in vitro development of VM neural stem cells (NSCs) was characterised, and the ability of GDF5 and BMP2 to induce these VM NSCs towards DA neuronal differentiation was investigated. Taken together, these experiments identify GDF5 and BMP2 as novel regulators of midbrain DA neuronal induction and differentiation, and demonstrate that their effects on DA neurons are mediated by canonical BMPR-Smad signalling.

The persistence of the HgCl2 molecule in five new compounds in the system (NH4)(w)HgxCly(H2O)(z) with w : x : y : z=1 : 5 : 11 : 0, 2 : 3 : 8 : 1, 4 : 3 : 10 : 2, 2 : 1 : 4 : 1, and 10 : 3 : 16 : 0

Five new compounds in the system (NH4)Cl/HgCl2/H2O have been obtained as colourless single crystals, (NH4)Hg5Cl11, (NH4)(2)Hg3Cl8(H2O), (NH4)(4)Hg3Cl10(H2O)(2), (NH4)(2)HgCl4(H2O), and (NH4)(10)Hg3Cl16. In all of these, as in HgCl2 itself, (almost) linear HgCl2 molecules persist with Hg-Cl distances varying from 229 to 236 pm. In (NH4)(10)Hg3Cl16 there are also tetrahedra [HgCl4] with d(Hg-Cl) = 247 pm present. If larger Hg-Cl distances (of up to 340 pm) are considered as belonging to the coordination sphere of Hg-II, the structures may be described as consisting of isolated octahedra and tetrahedra as in (NH4)(10)Hg3Cl16, edge-connected chains as in (NH4)(2)HgCl4(H2O), edge-connected chains and layers of octahedra as in (NH4)(4)Hg3Cl10(H2O)(2), corrugated layers of edge-connected octahedra as in (NH4)(2)Hg3Cl8(H2O), and, finally, a three-dimensional network of connected six- and seven-coordinate Hg-Cl polyhedra as in (NH4)Hg5Cl11. The water molecules are never attached to Hg-II. The (NH4)(+) cations, and sometimes Cl- anions, play a role for electroneutrality only.

Study of the transamidative ring expansion of N--halogenoalkyl--lactams of alkyl chain lengths 2–12 in liquid ammonia and other liquid amines: syntheses of 7-, 8- and 9-membered 1,5-diaza cyclic ketones, including routes to (±)-dihydroperiphylline and (±)-celabenzine

N-(3-Halogenopropyl)-4-phenylazetidin-2-ones undergo amination in liquid ammonia followed by transamidative ring expansion to give the eight-membered 4-phenyl -1,5-diazacyclooctan-2-one in excellent yield. Ring expansion of the amines in liquid ammonia is found to be much more effective than in hydrocarbon solvents. Formation of 7-, 8-, and 9-membered azalactams from the requisite -halogenoalkyl--lactams is an excellent synthetic process, though it is not applicable to 10membered rings. In the cases of rings of 13-, 15- and 17-members, although amination and apparent expansion takes place, the large rings appear not to be stable to ammonia and the final products are acyclic amides. N-[4-Halogenobut-2(Z)-enyl]-4-phenylazetidin-2-one satisfactorily forms a 9-membered (Z)-olefinic azalactam, but the (E)-isomer gives an acyclic amino amide. By using alkyl-substituted -lactam side-chains, C-substituted medium rings can be obtained; the relative instability of N-acyl -lactams to ammonia, however, leads to acylamino amides rather than expanded rings.Employing ethylamine in place of ammonia, it is shown that N-ethylated azalactams are formed satisfactorily, and using allylamine, N-allyl medium rings capable of further elaboration are obtained. The chemistry of these systems is discussed. Using transamidation in liquid ammonia, a short synthesis of the 9-membered spermidine alkaloid (±)-dihydroperiphylline is reported. Synthesis of key intermediates, whose transformation into the 13-membered alkaloids of the celabenzine group has already been effected, has been carried out.X-Ray single-crystal structure determinations for 4-phenyl-1,5-diazacyclononan-2-one, trans-4-phenyl-8-methyl-1,5-diazacyclooctan-2-one and (Z)-4-phenyl-1,5-diazacyclonon-7-en-2-one are reported, and comment is made on certain conformational features.

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC(50) of 0.55 mu mol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV(II) genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH(2)-terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV(II) and ZAP-70(-) CLL cells but not in unmutated IgV(II) and ZAP-70(+) cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential.

Cosmological Constraints from Measurements of Type Ia Supernovae Discovered During the First 1.5 Yr of the Pan-STARRS1 Survey

We present griz_P1 light curves of 146 spectroscopically confirmed Type Ia supernovae (SNe Ia; 0.03 < z < 0.65) discovered during the first 1.5 yr of the Pan-STARRS1 Medium Deep Survey. The Pan-STARRS1 natural photometric system is determined by a combination of on-site measurements of the instrument response function and observations of spectrophotometric standard stars. We find that the systematic uncertainties in the photometric system are currently 1.2% without accounting for the uncertainty in the Hubble Space Telescope Calspec definition of the AB system. A Hubble diagram is constructed with a subset of 113 out of 146 SNe Ia that pass our light curve quality cuts. The cosmological fit to 310 SNe Ia (113 PS1 SNe Ia + 222 light curves from 197 low-z SNe Ia), using only supernovae (SNe) and assuming a constant dark energy equation of state and flatness, yields w = -1.120^+0.360_-0.206(Stat)^+0.269_0.291(Sys). When combined with BAO+CMB(Planck)+H₀, the analysis yields Ω_M = 0.280^+0.013_0.012 and w = -1.166^+0.072_-0.069 including all identified systematics. The value of w is inconsistent with the cosmological constant value of -1 at the 2.3σ level. Tension endures after removing either the baryon acoustic oscillation (BAO) or the H₀ constraint, though it is strongest when including the H₀ constraint. If we include WMAP9 cosmic microwave background (CMB) constraints instead of those from Planck, we find w = -1.124^+0.083_-0.065, which diminishes the discord to <2σ. We cannot conclude whether the tension with flat ΛCDM is a feature of dark energy, new physics, or a combination of chance and systematic errors. The full Pan-STARRS1 SN sample with ∼three times as many SNe should provide more conclusive results.

Investigation into the effect of molybdenum-site substitution on the performance of Sr2Fe1.5Mo0.5O6-δ for intermediate temperature solid oxide fuel cells

In this paper, niobium doping is evaluated as a means of enhancing the electrochemical performance of a Sr₂Fe_1.5Mo_0.5O_6-δ (SFM) perovskite structure cathode material for intermediate temperature solid oxide fuel cells (IT-SOFCs) applications. As the radius of Nb approximates that of Mo and exhibits +4/+5 mixed valences, its substitution is expected to improve material performance. A series of Sr₂Fe_1.5Mo_0.5-xNb_xO_6-δ (x = 0.05, 0.10, 0.15, 0.20) cathode materials are prepared and the phase structure, chemical compatibility, microstructure, electrical conductivity, polarization resistance and power generation are systematically characterized. Among the series of samples, Sr₂Fe_1.5Mo_0.4Nb_0.10O_6-δ (SFMNb_0.10) exhibits the highest conductivity value of 30 S cm^-1 at 550°C, and the lowest area specific resistance of 0.068 Ω cm² at 800°C. Furthermore, an anode-supported single cell incorporating a SFMNb_0.10 cathode presents a maximum power density of 1102 mW cm^-2 at 800°C. Furthermore no obvious performance degradation is observed over 15 h at 750°C with wet H₂(3% H₂O) as fuel and ambient air as the oxidant. These results demonstrate that SFMNb shows great promise as a novel cathode material for IT-SOFCs.

Investigation into the effect of Fe-site substitution on the performance of Sr2Fe1.5Mo0.5O6-δ anodes for SOFCs

Ni-substituted Sr₂Fe_1.5-xNi_xMo_0.5O_6-δ (SFNM) materials have been investigated as anode catalysts for intermediate temperature solid oxide fuel cells. Reduced samples (x = 0.05 and 0.1) maintained the initial perovskite structure after reduction in H₂, while metallic nickel particles were detected on the grain surface for x = 0.2 and 0.3 using transmission electron microscopy. Temperature programmed reduction results indicate that the stable temperature for SFNM samples under reduction conditions decreases with Ni content. In addition, X-ray photoelectron spectroscopy analysis suggests that the incorporation of Ni affects the conductivity of SFNM through changing the ratios of Fe³⁺/Fe²⁺ and Mo⁶⁺/Mo⁵⁺. Sr₂Fe_1.4Ni_0.1Mo_0.5O_6-δ shows the highest electrical conductivity of 20.6 S cm^-1 at 800 °C in H₂. The performance of this anode was further tested with electrolyte-supported cells, giving 380 mW cm^-2 at 750 °C in H₂, hence demonstrating that Ni doping in the B-site is beneficial for Sr₂Fe_1.5Mo_0.5O_6-δ anode performance. 

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tend to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce anti-proliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G2/M arrest. G2/M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of anti-apoptotic proteins Bcl-2 and Bcl-xL and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G2/M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-xL. Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOX-induced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer.

Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment

The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds. We thus characterised the apoptotic and cell cycle events associated with combination therapy of the PBOX compounds and flavopiridol and results showed a sequence dependent, synergistic enhancement of apoptosis in CML cells including those expressing the imatinib-resistant T315I mutant. Flavopiridol reduced the number of polyploid cells formed in response to PBOX treatment but only to a small extent, suggesting that inhibition of endoreplication was unlikely to play a major role in the mechanism by which flavopiridol synergistically enhanced PBOX-induced apoptosis. The addition of flavopiridol following PBOX-6 treatment did however result in an accelerated exit from the G2/M transition accompanied by an enhanced downregulation and deactivation of the CDK1/cyclin B1 complex and an enhanced degradation of the inhibitor of apoptosis protein (IAP) survivin. In conclusion, results from this study highlight the potential of these novel series of PBOX compounds, alone or in sequential combination with flavopiridol, as an effective therapy against CML.

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells

PURPOSE: The development of multi-drug resistance (MDR) due to the expression of members of the ATP binding cassette (ABC) transporter family is a major obstacle in cancer treatment. The broad range of substrate specificities associated with these transporters leads to the efflux of many anti-cancer drugs from tumour cells. Therefore, the development of new chemotherapeutic agents that are not substrates of these transporters is important. We have recently demonstrated that some members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds are microtubule-depolymerising agents that potently induce apoptosis in several cancer cell lines and impair growth of mouse breast tumours. The aim of this current study was to establish whether PBOXs were capable of inducing apoptosis in cancer cells expressing either P-glycoprotein or breast cancer resistance protein (BCRP), two of the main ABC transporters associated with MDR.

METHODS: We performed in vitro studies to assess the effects of PBOXs on cell proliferation, cell cycle and apoptosis in human cancer cell lines and their drug-resistant substrains expressing either P-glycoprotein or BCRP. In addition, we performed a preliminary molecular docking study to examine interactions between PBOXs and P-glycoprotein.

RESULTS: We established that three representative PBOXs, PBOX-6, -15 and -16 were capable of inducing apoptosis in drug-resistant HL60-MDR1 cells (expressing P-glycoprotein) and HL60-ABCG2 cells (expressing BCRP) with similar potencies as in parental human promyelocytic leukaemia HL60 cells. Likewise, resistance to PBOX-6 and -16 was not evident in P-glycoprotein-expressing A2780-ADR cells in comparison with parent human ovarian carcinoma A2780 cells. Finally, we deduced by molecular docking that PBOX-6 is not likely to form favourable interactions with the substrate binding site of P-glycoprotein.

CONCLUSION: Our results suggest that pro-apoptotic PBOX compounds may be potential candidates for the treatment of P-glycoprotein- or BCRP-associated MDR cancers.