Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy (1H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and 1H-MRS percentage change scores between scans were compared using one-way ANOVA and correlated with behavioural change scores. Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects were seen for any brain metabolites as measured with 1H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU. Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

Mathematical modelling of tumour-induced angiogenesis

The growth of solid tumours beyond a critical size is dependent upon angiogenesis, the formation of new blood vessels from an existing vasculature. Tumours may remain dormant at microscopic sizes for some years before switching to a mode in which growth of a supportive vasculature is initiated. The new blood vessels supply nutrients, oxygen, and access to routes by which tumour cells may travel to other sites within the host (metastasize). In recent decades an abundance of biological research has focused on tumour-induced angiogenesis in the hope that treatments targeted at the vasculature may result in a stabilisation or regression of the disease: a tantalizing prospect. The complex and fascinating process of angiogenesis has also attracted the interest of researchers in the field of mathematical biology, a discipline that is, for mathematics, relatively new. The challenge in mathematical biology is to produce a model that captures the essential elements and critical dependencies of a biological system. Such a model may ultimately be used as a predictive tool. In this thesis we examine a number of aspects of tumour-induced angiogenesis, focusing on growth of the neovasculature external to the tumour. Firstly we present a one-dimensional continuum model of tumour-induced angiogenesis in which elements of the immune system or other tumour-cytotoxins are delivered via the newly formed vessels. This model, based on observations from experiments by Judah Folkman et al., is able to show regression of the tumour for some parameter regimes. The modelling highlights a number of interesting aspects of the process that may be characterised further in the laboratory. The next model we present examines the initiation positions of blood vessel sprouts on an existing vessel, in a two-dimensional domain. This model hypothesises that a simple feedback inhibition mechanism may be used to describe the spacing of these sprouts with the inhibitor being produced by breakdown of the existing vessel's basement membrane. Finally, we have developed a stochastic model of blood vessel growth and anastomosis in three dimensions. The model has been implemented in C++, includes an openGL interface, and uses a novel algorithm for calculating proximity of the line segments representing a growing vessel. This choice of programming language and graphics interface allows for near-simultaneous calculation and visualisation of blood vessel networks using a contemporary personal computer. In addition the visualised results may be transformed interactively, and drop-down menus facilitate changes in the parameter values. Visualisation of results is of vital importance in the communication of mathematical information to a wide audience, and we aim to incorporate this philosophy in the thesis. As biological research further uncovers the intriguing processes involved in tumourinduced angiogenesis, we conclude with a comment from mathematical biologist Jim Murray, Mathematical biology is : : : the most exciting modern application of mathematics.

A study on the use of acoustic emission technique as a structural health monitoring tool

As civil infrastructures such as bridges age, there is a concern for safety and a need for cost-effective and reliable monitoring tool. Different diagnostic techniques are available nowadays for structural health monitoring (SHM) of bridges. Acoustic emission is one such technique with potential of predicting failure. The phenomenon of rapid release of energy within a material by crack initiation or growth in form of stress waves is known as acoustic emission (AE). AEtechnique involves recording the stress waves bymeans of sensors and subsequent analysis of the recorded signals,which then convey information about the nature of the source. AE can be used as a local SHM technique to monitor specific regions with visible presence of cracks or crack prone areas such as welded regions and joints with bolted connection or as a global technique to monitor the whole structure. Strength of AE technique lies in its ability to detect active crack activity, thus helping in prioritising maintenance work by helping focus on active cracks rather than dormant cracks. In spite of being a promising tool, some challenges do still exist behind the successful application of AE technique. One is the generation of large amount of data during the testing; hence an effective data analysis and management is necessary, especially for long term monitoring uses. Complications also arise as a number of spurious sources can giveAEsignals, therefore, different source discrimination strategies are necessary to identify genuine signals from spurious ones. Another major challenge is the quantification of damage level by appropriate analysis of data. Intensity analysis using severity and historic indices as well as b-value analysis are some important methods and will be discussed and applied for analysis of laboratory experimental data in this paper.

Genetic evidence for the vital function of osterix in cementogenesis

To date, attempts to regenerate a complete tooth, including the critical periodontal tissues associated with the tooth root, have not been successful. Controversy still exists regarding the origin of the cell source for cellular cementum (epithelial or mesenchymal). This disagreement may be partially due to a lack of understanding of the events leading to the initiation and development of the tooth roots and supportive tissues, such as the cementum. Osterix (OSX) is a transcriptional factor essential for osteogenesis, but its role in cementogenesis has not been addressed. In the present study, we first documented a close relationship between the temporal- and spatial-expression pattern of OSX and the formation of cellular cementum. We then generated 3.6 Col 1-OSX transgenic mice, which displayed accelerated cementum formation vs. WT controls. Importantly, the conditional deletion of OSX in the mesenchymal cells with two different Cre systems (the 2.3 kb Col 1 and an inducible CAG-CreER) led to a sharp reduction in cellular cementum formation (including the cementum mass and mineral deposition rate) and gene expression of dentin matrix protein 1 (DMP1) by cementocytes. However, the deletion of the OSX gene after cellular cementum formed did not alter the properties of the mature cementum as evaluated by backscattered SEM and resin-cast SEM. Transient transfection of Osx in the cementoblasts in vitro significantly inhibited cell proliferation and increased cell differentiation and mineralization. Taken together, these data support 1) the mesenchymal origin of cellular cementum (from PDL progenitor cells); 2) the vital role of OSX in controlling the formation of cellular cementum; and 3) the limited remodeling of cellular cementum in adult mice.

The complete mitochondrial genome of the gall-forming fly, Fergusonina taylori(Nelson and Yeates) (Diptera: Fergusoninidae)

The monogeneric family Fergusoninidae consists of gall-forming flies that, together with Fergusobia (Tylenchida: Neotylenchidae) nematodes, form the only known mutualistic association between insects and nematodes. In this study, the entire 16,000 bp mitochondrial genome of Fergusonina taylori Nelson and Yeates was sequenced. The circular genome contains one encoding region including 27 genes and one non-coding A þT-rich region. The arrangement of the proteincoding, ribosomal RNA (rRNA) and transfer RNA (tRNA) genes was the same as that found in the ancestral insect. Nucleotide composition is highly A þ T biased. All of the protein initiation codons are ATN, except for nad1 which begins with TTT. All 22 tRNA anticodons of F. taylori match those observed in Drosophila yakuba, and all form the typical cloverleaf structure except for tRNA-Ser (AGN) which lacks a dihydrouridine (DHU) arm. Secondary structural features of the rRNA genes of Fergusonina are similar to those proposed for other insects, with minor modifications. The mitochondrial genome of Fergusonina presented here may prove valuable for resolving the sister group to the Fergusoninidae, and expands the available mtDNA data sources for acalyptrates overall.

A fission yeast homolog of Int-6, the mammalian oncoprotein and eIF3 subunit, induces drug resistance when overexpressed

Through a screen to identify genes that induce multi-drug resistance when overexpressed, we have identified a fission yeast homolog of Int-6, a component of the human translation initiation factor eIF3. Disruption of the murine Int-6 gene by mouse mammary tumor virus (MMTV) has been implicated previously in tumorigenesis, although the underlying mechanism is not yet understood. Fission yeast Int6 was shown to interact with other presumptive components of eIF3 in vivo, and was present in size fractions consistent with its incorporation into a 43S translation preinitiation complex. Drug resistance induced by Int6 overexpression was dependent on the AP-1 transcription factor Pap1, and was associated with increased abundance of Pap1-responsive mRNAs, but not with Pap1 relocalization. Fission yeast cells lacking the int6 gene grew slowly. This growth retardation could be corrected by the expression of full length Int6 of fission yeast or human origin, or by a C-terminal fragment of the fission yeast protein that also conferred drug resistance, but not by truncated human Int-6 proteins corresponding to the predicted products of MMTV-disrupted murine alleles. Studies in fission yeast may therefore help to explain the ways in which Int-6 function can be perturbed during MMTV-induced mammary tumorigenesis.

Fatigue crack growth and fatigue life evaluation for welded steel bridge members with initial crack

Initial crack widely exists in the welded members of steel bridge induced by the welding procedure or by the fatigue damage crack initiation. The behavior of crack growth with a view to fatigue damage accumulation on the tip of cracks is discussed. Fatigue life of welded components with initial crack in bridges under traffic loading is investigated. Based on existing fatigue experiment results of welded members with initial crack and the fatigue experiment results of welded bridge members under constant stress cycles, the crack would keep semi-elliptical shape with variable ratio of a/c during the crack propagation. Based on the concept of continuum damage accumulated on the tip of fatigue cracks,the fatigue damage law suitable for steel bridge members under traffic loading is modified to consider the crack growth.The virtual crack growth method and the semi-elliptical crack shape assumption are proposed in this paper to deduce a new model of fatigue crack growth rate for welded bridge members under traffic loading. And the calculated method of the stress intensity factor necessary for evaluation of the fatigue life of welded bridge members with cracks is discussed.The proposed fatigue crack growth model is then applied to calculate the crack growth and the fatigue life of existing welded members with fatigue experimental results. The fatigue crack propagation computation results show that the ratio of crack depth to the half crack surface length a/c is variable during crack propagation process and the stress cycle increases with the increase of a0/c0 with certain a0/t0 .The calculated and measured fatigue lives are generally in good agreement,at some initial conditions of cracking, for welded members widely used in steel bridges.

Getting stuck in together : improving work integrated learning from an Australian institution and faculty perspective

According to a recent report Australian higher education is not in crisis. However, we could be doing it better. The report Mapping Australian Higher Education (Norton, 2012) highlights comparative weaknesses such as levels f student engagement; interactions between students and academic staff; and academic staff preferences for research over teaching. The report points out that despite these concerns most graduates continue to get good, well-paid jobs, student satisfaction is improving, and levels of public confidence in Australian higher education are high. It also stresses that ‘the promise of higher education is that it provides adaptable cognitive skills, not that it always provides the job specific skills graduates will need in their future employment’ (Norton, 2012, p.58). This is worth keeping in mind as we contribute to the significant growth in curriculum initiatives aimed at preparing graduates for the world of work. Work Integrated Learning (WIL) is not a new concept but there is increased pressure on higher education globally to address graduate employability skills. The sector is under pressure in an increasingly competitive environment to demonstrate the relevance of courses, accountability and effective use of public funds (Peach & Gamble, 2011). In the Australian context this also means responding to the skills shortage in areas such as engineering, health, construction and business (DEEWR, 2010). This paper provides a brief overview of collaborative efforts over several years to improve the activity of WIL at the Queensland University of Technology (QUT). These efforts have resulted in changes to curriculum, pedagogy, systems and processes, and the initiation of local, regional, national, and international networks. The willingness of students, staff, and industry partners to ‘get stuck in’ and try new approaches in these different contexts can be understood as a form of boundary spanning. That is, the development of the capability to mediate between different forms of expertise and the demands of different contexts in order to nurture student learning and improve the outcomes of higher education through WIL (Peach, Cates, Ilg, Jones, Lechleiter, 2011).

Damage quantification techniques in acoustic emission monitoring

Acoustic emission (AE) analysis is one of the several diagnostic techniques available nowadays for structural health monitoring (SHM) of engineering structures. Some of its advantages over other techniques include high sensitivity to crack growth and capability of monitoring a structure in real time. The phenomenon of rapid release of energy within a material by crack initiation or growth in form of stress waves is known as acoustic emission (AE). In AE technique, these stress waves are recorded by means of suitable sensors placed on the surface of a structure. Recorded signals are subsequently analysed to gather information about the nature of the source. By enabling early detection of crack growth, AE technique helps in planning timely retrofitting or other maintenance jobs or even replacement of the structure if required. In spite of being a promising tool, some challenges do still exist behind the successful application of AE technique. Large amount of data is generated during AE testing, hence effective data analysis is necessary, especially for long term monitoring uses. Appropriate analysis of AE data for quantification of damage level is an area that has received considerable attention. Various approaches available for damage quantification for severity assessment are discussed in this paper, with special focus on civil infrastructure such as bridges. One method called improved b-value analysis is used to analyse data collected from laboratory testing.

Semantic service discovery in the service ecosystem

Electronic services are a leitmotif in ‘hot’ topics like Software as a Service, Service Oriented Architecture (SOA), Service oriented Computing, Cloud Computing, application markets and smart devices. We propose to consider these in what has been termed the Service Ecosystem (SES). The SES encompasses all levels of electronic services and their interaction, with human consumption and initiation on its periphery in much the same way the ‘Web’ describes a plethora of technologies that eventuate to connect information and expose it to humans. Presently, the SES is heterogeneous, fragmented and confined to semi-closed systems. A key issue hampering the emergence of an integrated SES is Service Discovery (SD). A SES will be dynamic with areas of structured and unstructured information within which service providers and ‘lay’ human consumers interact; until now the two are disjointed, e.g., SOA-enabled organisations, industries and domains are choreographed by domain experts or ‘hard-wired’ to smart device application markets and web applications. In a SES, services are accessible, comparable and exchangeable to human consumers closing the gap to the providers. This requires a new SD with which humans can discover services transparently and effectively without special knowledge or training. We propose two modes of discovery, directed search following an agenda and explorative search, which speculatively expands knowledge of an area of interest by means of categories. Inspired by conceptual space theory from cognitive science, we propose to implement the modes of discovery using concepts to map a lay consumer’s service need to terminologically sophisticated descriptions of services. To this end, we reframe SD as an information retrieval task on the information attached to services, such as, descriptions, reviews, documentation and web sites - the Service Information Shadow. The Semantic Space model transforms the shadow's unstructured semantic information into a geometric, concept-like representation. We introduce an improved and extended Semantic Space including categorization calling it the Semantic Service Discovery model. We evaluate our model with a highly relevant, service related corpus simulating a Service Information Shadow including manually constructed complex service agendas, as well as manual groupings of services. We compare our model against state-of-the-art information retrieval systems and clustering algorithms. By means of an extensive series of empirical evaluations, we establish optimal parameter settings for the semantic space model. The evaluations demonstrate the model’s effectiveness for SD in terms of retrieval precision over state-of-the-art information retrieval models (directed search) and the meaningful, automatic categorization of service related information, which shows potential to form the basis of a useful, cognitively motivated map of the SES for exploratory search.

Development of a transformation system for sorghum (Sorghum bicolor L.)

Sorghum (Sorghum bicolor (L.) Moench) is the world’s fifth major cereal crop and holds importance as a construction material, food and fodder source. More recently, the potential of this plant as a biofuel source has been noted. Despite its agronomic importance, the use of sorghum production is being constrained by both biotic and abiotic factors. These challenges could be addressed by the use of genetic engineering strategies to complement conventional breeding techniques. However, sorghum is one of the most recalcitrant crops for genetic modification with the lack of an efficient tissue culture system being amongst the chief reasons. Therefore, the aim of this study was to develop an efficient tissue culture system for establishing regenerable embryogenic cell lines, micropropagation and acclimatisation for Sorghum bicolor and use this to optimise parameters for genetic transformation via Agrobacterium-mediated transformation and microprojectile bombardment. Using five different sorghum cultivars, SA281, 296B, SC49, Wray and Rio, numerous parameters were investigated in an attempt to establish an efficient and reproducible tissue culture and transformation system. Using immature embryos (IEs) as explants, regenerable embryogenic cell lines (ECLs) could only be established from cultivars SA281 and 296B. Large amounts of phenolics were produced from IEs of cultivars, SC49, Wary and Rio, and these compounds severely hindered callus formation and development. Cultivar SA281 also produced phenolics during regeneration. Attempts to suppress the production of these compounds in cultivars SA281 and SC49 using activated charcoal, PVP, ascorbic acid, citric acid and liquid filter paper bridge methods were either ineffective or had a detrimental effect on embryogenic callus formation, development and regeneration. Immature embryos sourced during summer were found to be far more responsive in vitro than those sourced during winter. In an attempt to overcome this problem, IEs were sourced from sorghum grown under summer conditions in either a temperature controlled glasshouse or a growth chamber. However, the performance of these explants was still inferior to that of natural summer-sourced explants. Leaf whorls, mature embryos, shoot tips and leaf primordia were found to be unsuitable as explants for establishing ECLs in sorghum cultivars SA281 and 296B. Using the florets of immature inflorescences (IFs) as explants, however, ECLs were established and regenerated for these cultivars, as well as for cultivar Tx430, using callus induction media, SCIM, and regeneration media, VWRM. The best in vitro responses, from the largest possible sized IFs, were obtained using plants at the FL-2 stage (where the last fully opened leaf was two leaves away from the flag leaf). Immature inflorescences could be stored at 25oC for up to three days without affecting their in vitro responses. Compared to IEs, the IFs were more robust in tissue culture and showed responses which were season and growth condition independent. A micropropagation protocol for sorghum was developed in this study. The optimum plant growth regulator (PGR) combination for the micropropagation of in vitro regenerated plantlets was found to be 1.0 mg/L BAP in combination with 0.5 mg/L NAA. With this protocol, cultivars 296B and SA281 produced an average of 57 and 13 off-shoots per plantlet, respectively. The plantlets were successfully acclimatised and developed into phenotypically normal plants that set seeds. A simplified acclimatisation protocol for in vitro regenerated plantlets was also developed. This protocol involved deflasking in vitro plantlets with at least 2 fully-opened healthy leaves and at least 3 roots longer than 1.5 cm, washing the media from the roots with running tap water, planting in 100 mm pots and placing in plastic trays covered with a clear plastic bag in a plant growth chamber. After seven days, the corners of the plastic cover were opened and the bags were completely removed after 10 days. All plantlets were successfully acclimatised regardless of whether 1:1 perlite:potting mix, potting mix, UC mix or vermiculite were used as potting substrates. Parameters were optimised for Agrobacterium-mediated transformation (AMT) of cultivars SA281, 296B and Tx430. The optimal conditions were the use of Agrobacterium strain LBA4404 at an inoculum density of 0.5 OD600nm, heat shock at 43oC for 3 min, use of the surfactant Pluronic F-68 (0.02% w/v) in the inoculation media with a pH of 5.2 and a 3 day co-cultivation period in dark at 22oC. Using these parameters, high frequencies of transient GFP expression was observed in IEs precultured on callus initiation media for 1-7 days as well as in four weeks old IE- and IF-derived callus. Cultivar SA281 appeared very sensitive to Agrobacterium since all tissue turned necrotic within two weeks post-exposure. For cultivar 296B, GFP expression was observed up to 20 days post co-cultivation but no stably transformed plants were regenerated. Using cultivar Tx430, GFP was expressed for up to 50 days post co-cultivation. Although no stably transformed plants of this cultivar were regenerated, this was most likely due to the use of unsuitable regeneration media. Parameters were optimised for transformation by particle bombardment (PB) of cultivars SA281, 296B and Tx430. The optimal conditions were use of 3-7 days old IEs and 4 weeks old IF callus, 4 hour pre- and post-bombardment osmoticum treatment, use of 0.6 µm gold microparticles, helium pressure of 1500 kPa and target distance of 15 cm. Using these parameters for PB, transient GFP expression was observed for up to 14, 30 and 50 days for cultivars SA281, 296B and Tx430, respectively. Further, the use of PB resulted in less tissue necrosis compared to AMT for the respective cultivars. Despite the presence of transient GFP expression, no stably transformed plants were regenerated. The establishment of regenerable ECLs and the optimization of AMT and PB parameters in this study provides a platform for future efforts to develop an efficient transformation protocol for sorghum. The development of GM sorghum will be an important step towards improving its agronomic properties as well as its exploitation for biofuel production.

Chemopreventive effect of PSP through targeting of prostate cancer stem cell-like population

Recent evidence suggested that prostate cancer stem/progenitor cells (CSC) are responsible for cancer initiation as well as disease progression. Unfortunately, conventional therapies are only effective in targeting the more differentiated cancer cells and spare the CSCs. Here, we report that PSP, an active component extracted from the mushroom Turkey tail (also known as Coriolus versicolor), is effective in targeting prostate CSCs. We found that treatment of the prostate cancer cell line PC-3 with PSP led to the down-regulation of CSC markers (CD133 and CD44) in a time and dose-dependent manner. Meanwhile, PSP treatment not only suppressed the ability of PC-3 cells to form prostaspheres under non-adherent culture conditions, but also inhibited their tumorigenicity in vivo, further proving that PSP can suppress prostate CSC properties. To investigate if the anti-CSC effect of PSP may lead to prostate cancer chemoprevention, transgenic mice (TgMAP) that spontaneously develop prostate tumors were orally fed with PSP for 20 weeks. Whereas 100% of the mice that fed with water only developed prostate tumors at the end of experiment, no tumors could be found in any of the mice fed with PSP, suggesting that PSP treatment can completely inhibit prostate tumor formation. Our results not only demonstrated the intriguing anti-CSC effect of PSP, but also revealed, for the first time, the surprising chemopreventive property of oral PSP consumption against prostate cancer.

Inhibitors of human immunodeficiency virus type 1 reverse transcriptase target distinct phases of early reverse transcription

Early HIV-1 reverse transcription can be separated into initiation and elongation phases. Here we show, using PCR analysis of negative-strand strong-stop DNA [(−)ssDNA] synthesis in intact virus, that different reverse transcriptase (RT) inhibitors affect distinct phases of early natural endogenous reverse transcription (NERT). The effects of nevirapine on NERT were consistent with a mechanism of action including both specific and nonspecific binding events. The nonspecific component of this inhibition targeted the elongation reaction, whereas the specific effect seemed principally to be directed at very early events (initiation or the initiation-elongation switch). In contrast, foscarnet and the nucleoside analog ddATP inhibited both early and late (−)ssDNA synthesis in a similar manner. We also examined compounds that targeted other viral proteins and found that Ro24-7429 (a Tat antagonist) and rosmarinic acid (an integrase inhibitor) also directly inhibited RT. Our results indicate that NERT can be used to identify and evaluate compounds that directly target the reverse transcription complex.

Effective discrimination of acoustic emission source signals for structural health monitoring

Acoustic emission (AE) is the phenomenon where stress waves are generated due to rapid release of energy within a material caused by sources such as crack initiation or growth. AE technique involves recording the stress waves by means of sensors and subsequent analysis of the recorded signals to gather information about the nature of the source. Though AE technique is one of the popular non destructive evaluation (NDE) techniques for structural health monitoring of mechanical, aerospace and civil structures; several challenges still exist in successful application of this technique. Presence of spurious noise signals can mask genuine damage‐related AE signals; hence a major challenge identified is finding ways to discriminate signals from different sources. Analysis of parameters of recorded AE signals, comparison of amplitudes of AE wave modes and investigation of uniqueness of recorded AE signals have been mentioned as possible criteria for source differentiation. This paper reviews common approaches currently in use for source discrimination, particularly focusing on structural health monitoring of civil engineering structural components such as beams; and further investigates the applications of some of these methods by analyzing AE data from laboratory tests.