Functional Interleukin-17 Receptor A is Expressed in Central Nervous System Glia and Upregulated in Experimental Autoimmune Encephalomyelitis

Background: Interleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood. Methods: EAE was induced in C57Bl/6 mice by immunization with myelin oligodendroglial glycoprotein. IL-17RA expression in the CNS was compared between control and EAE mice using RT-PCR, in situ hybridization, and immunohistochemistry. Cell-type specific expression was examined in isolated astrocytic and microglial cell cultures. Cytokine and chemokine production was measured in IL-17A treated cultures to evaluate the functional status of IL-17RA. Results: Here we report increased IL-17RA expression in the CNS of mice with EAE, and constitutive expression of functional IL-17RA in mouse CNS tissue. Specifically, astrocytes and microglia express IL-17RA in vitro, and IL-17A treatment induces biological responses in these cells, including significant upregulation of MCP-1, MCP-5, MIP-2 and KC chemokine secretion. Exogenous IL-17A does not significantly alter the expression of IL-17RA in glial cells, suggesting that upregulation of chemokines by glial cells is due to IL-17A signaling through constitutively expressed IL-17RA. Conclusion: IL-17RA expression is significantly increased in the CNS of mice with EAE compared to healthy mice, suggesting that IL-17RA signaling in glial cells can play an important role in autoimmune inflammation of the CNS and may be a potential pathway to target for therapeutic interventions. © 2009 Sarma et al; licensee BioMed Central Ltd.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P-SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. Molecular Psychiatry (2009) 14, 774-785; doi:10.1038/mp.2008.135; published online 30 December 2008

A survey of molecular line emission towards ultracompact HII regions

We have used the JCMT to survey molecular line emission towards 14 ultracompact HII regions (G5.89, G9.62, G10.30, G10.47, G12.21, G13.87, G29.96, G31.41, G34.26, G43.89, G45.12, G45.45, G45.47, and G75.78). For each source, we observed up to ten 1 GHz bands between 200 and 350 GHz, covering lines of more than 30 species including multiple transitions of CO isotopes, CH3OH, CH3CCH, CH3CN and HCOOCH3, and sulphuretted molecules. The number of transitions detected varied by a factor of 20 between sources; which were chosen following observations of high-excitation ammonia (Cesaroni et al. 1994a) and methyl cyanide (Olmi et al. 1993). In half our sample (the line-poor sources), only (CO)-O-17: (CO)-O-18, SO, (CS)-S-34 and CH3OH were detected. In the line-rich sources, we detected over 150 lines, including high excitation lines of CH3CN, HCOOCH3; C2H5CN, CH3OH, and CH3CCH. We have calculated the physical conditions of the molecular gas. To reproduce the emission from the line-rich sources requires both a hot, dense compact core and an ambient cloud consisting of less dense, cooler gas. The hot cores, which are less than 0.1 pc in size; reach densities of at least 10(8) cm(-3) and temperatures of more than 80 K. The line-poor sources can be modelled without a hot core by a 20-30 K, 10(5) cm(-3) cloud. We find no correlation between the size of the HII region and the current physical conditions in the molecular environment. A comparison with chemical models (Millar et al. 1997) confirms that grain surface chemistry is important in hot cores.

Consistent effects of consumer species loss across different habitats

Our knowledge of the effects of consumer species loss on ecosystem functioning is limited by a paucity of manipulative field studies, particularly those that incorporate inter-trophic effects. Further, given the ongoing transformation of natural habitats by anthropogenic activities, studies should assess the relative importance of biodiversity for ecosystem processes across different environmental contexts by including multiple habitat types. We tested the context-dependency of the effects of consumer species loss by conducting a 15-month field experiment in two habitats (mussel beds and rock pools) on a temperate rocky shore, focussing on the responses of algal assemblages following the single and combined removals of key gastropod grazers (Patella vulgata, P. ulyssiponensis, Littorina littorea and Gibbula umbilicalis). In both habitats, the removal of limpets resulted in a larger increase in macroalgal richness than that of either L. littorea or G. umbilicalis. Further, by the end of the study, macroalgal cover and richness were greater following the removal of multiple grazer species compared to single species removals. Despite substantial differences in physical properties and the structure of benthic assemblages between mussel beds and rock pools, the effects of grazer loss on macroalgal cover, richness, evenness and assemblage structure were remarkably consistent across both habitats. There was, however, a transient habitat-dependent effect of grazer removal on macroalgal assemblage structure that emerged after three months, which was replaced by non-interactive effects of grazer removal and habitat after 15 months. This study shows that the effects of the loss of key consumers may transcend large abiotic and biotic differences between habitats in rocky intertidal systems. While it is clear that consumer diversity is a primary driver of ecosystem functioning, determining its relative importance across multiple contexts is necessary to understand the consequences of consumer species loss against a background of environmental change.

Improving E-Assessment Systems With A focus On Adaptive Feedback And Marking

Institutions involved in the provision of tertiary education across Europe are feeling the pinch. European universities, and other higher education (HE) institutions, must operate in a climate where the pressure of government spending cuts (Garben, 2012) is in stark juxtaposition to the EU’s strategy to drive forward and maintain a growth of student numbers in the sector (eurostat, 2015).

In order to remain competitive, universities and HE institutions are making ever-greater use of electronic assessment (E-Assessment) systems (Chatzigavriil et all, 2015; Ferrell, 2012). These systems are attractive primarily because they offer a cost-effect and scalable approach for assessment. In addition to scalability, they also offer reliability, consistency and impartiality; furthermore, from the perspective of a student they are most popular because they can offer instant feedback (Walet, 2012).

There are disadvantages, though.

First, feedback is often returned to a student immediately on competition of their assessment. While it is possible to disable the instant feedback option (this is often the case during an end of semester exam period when assessment scores must be can be ratified before release), however, this option tends to be a global ‘all on’ or ‘all off’ configuration option which is controlled centrally rather than configurable on a per-assessment basis.

If a formative in-term assessment is to be taken by multiple groups of
students, each at different times, this restriction means that answers to each question will be disclosed to the first group of students undertaking the assessment. As soon as the answers are released “into the wild” the academic integrity of the assessment is lost for subsequent student groups.

Second, the style of feedback provided to a student for each question is often limited to a simple ‘correct’ or ‘incorrect’ indicator. While this type of feedback has its place, it often does not provide a student with enough insight to improve their understanding of a topic that they did not answer correctly.

Most E-Assessment systems boast a wide range of question types including Multiple Choice, Multiple Response, Free Text Entry/Text Matching and Numerical questions. The design of these types of questions is often quite restrictive and formulaic, which has a knock-on effect on the quality of feedback that can be provided in each case.

Multiple Choice Questions (MCQs) are most prevalent as they are the most prescriptive and therefore most the straightforward to mark consistently. They are also the most amenable question types, which allow easy provision of meaningful, relevant feedback to each possible outcome chosen.
Text matching questions tend to be more problematic due to their free text entry nature. Common misspellings or case-sensitivity errors can often be accounted for by the software but they are by no means fool proof, as it is very difficult to predict in advance the range of possible variations on an answer that would be considered worthy of marks by a manual marker of a paper based equivalent of the same question.

Numerical questions are similarly restricted. An answer can be checked for accuracy or whether it is within a certain range of the correct answer, but unless it is a special purpose-built mathematical E-Assessment system the system is unlikely to have computational capability and so cannot, for example, account for “method marks” which are commonly awarded in paper-based marking.

From a pedagogical perspective, the importance of providing useful formative feedback to students at a point in their learning when they can benefit from the feedback and put it to use must not be understated (Grieve et all, 2015; Ferrell, 2012).

In this work, we propose a number of software-based solutions, which will overcome the limitations and inflexibilities of existing E-Assessment systems.

Optical observations of 23 distant Jupiter Family Comets, including 36P/Whipple at multiple phase angles

We present photometry on 23 Jupiter Family Comets (JFCs) observed at large heliocentric distance, primarily using the 2.5-m Isaac Newton Telescope (INT). Snapshot images were taken of 17 comets, of which five were not detected, three were active and nine were unresolved and apparently inactive. These include 103P/Hartley 2, the target of the NASA Deep Impact extended mission, EPOXI. For six comets we obtained time-series photometry and use this to constrain the shape and rotation period of these nuclei. The data are not of sufficient quantity or quality to measure precise rotation periods, but the time-series do allow us to measure accurate effective radii and surface colours. Of the comets observed over an extended period, 40P/Väisälä 1, 47P/Ashbrook-Jackson and P/2004 H2 (Larsen) showed faint activity which limited the study of the nucleus. Light curves for 94P/Russell 4 and 121P/Shoemaker-Holt 2 reveal rotation periods of around 33 and 10h, respectively, although in both cases these are not unique solutions. 94P was observed to have a large range in magnitudes implying that it is one of the most elongated nuclei known, with an axial ratio a/b >= 3. 36P/Whipple was observed at five different epochs, with the INT and ESO's 3.6-m NTT, primarily in an attempt to confirm the preliminary short rotation period apparent in the first data set. The combined data set shows that the rotation period is actually longer than 24h. A measurement of the phase function of 36P's nucleus gives a relatively steep ß = 0.060 +/- 0.019. Finally, we discuss the distribution of surface colours observed in JFC nuclei, and show that it is possible to trace the evolution of colours from the Kuiper Belt Object (KBO) population to the JFC population by applying a `dereddening' function to the KBO colour distribution.

Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies

BACKGROUND: While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease.

RESULTS: We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations.

Using hypnosis to facilitate direct observation of multiple tics and self-monitoring in a typically developing teenager

A hypnotic induction technique was used to facilitate direct observation of multiple tics in a typically developing teenager in a home setting. A comprehensive habit reversal program then was implemented, including awareness training, competing response training, relaxation training, self-monitoring, social support and contingency management. Duration of relaxation was then self-monitored using a changing criterion design. The procedure eliminated multiple tics and achieved long-term maintenance of treatment gains. Implications for assessing and treating tics are discussed.

PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma

Summary Bortezomib (formerly PS-341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21-d cycles of PAD, comprising bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1–4, 8–11 and 15–18 during cycle 1 and days 1–4 during cycles 2–4. During days 1–4, patients also received 0, 4·5 or 9 mg/m2 of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high-dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention-to-treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials.

Bradykinin-related peptides, including a novel structural variant, (Val1)-bradykinin, from the skin secretion of Guenther's frog, Hylarana guentheri and their molecular precursors.

Multiple bradykinin-related peptides including a novel bradykinin structural variant, (Val1)-bradykinin, have been identified from the defensive skin secretion of Guenther's frog, Hylarana guentheri by a tandem mass spectrometry method. Subsequently, four different preprobradykinin cDNAs, which encoded multiple bradykinin copies and its structural variants, were consistently cloned from a skin derived cDNA library. These preprobradykinin cDNAs showed little structural similarity with mammalian kininogens and the kininogens from the skin of toads, but have regions that are highly conserved in the kininogens from another ranid frog, Odorrana schmackeri. Alignment of these preprobradykinins revealed that preprobradykinin 1, 2 and 3 may derive from a single gene by alternative exon splicing.

Advances in protein kinase B signalling: AKTion on multiple fronts

The role of the serine/threonine protein kinase B (PKB, also known as Akt) is becoming increasingly more evident to researchers investigating diverse cellular processes such as glucose uptake, cell-cycle progression, apoptosis and transcriptional regulation. New roles for PKB/Akt have been described in various organisms and biological processes. From the regulation of ovarian ecdysteroid production in the humble mosquito (Aedes aegypti), through the seasonal, tissue-specific regulation of PKB/Akt during the hibernation of yellow-bellied marmots (Marmota flaviventris), to the control of glucose metabolism and insulin signalling in the mouse (Mus musculus), our knowledge of the function of this protein kinase has expanded greatly in recent years. Significant advances in all aspects of PKB/Akt signalling have occurred in the past 2 years, including biological insights, novel substrates and newly discovered regulatory mechanisms of PKB/Akt. Collectively, these data expand the current models of PKB/Akt signalling and highlight potential directions for PKB/Akt research in the future.

Flexible Natural Language Generation in Multiple Contexts

We present a practical approach to Natural Language Generation (NLG) for spoken dialogue systems. The approach is based on small template fragments (mini-templates). The system’s object architecture facilitates generation of phrases across pre-defined business domains and registers, as well as into different languages. The architecture simplifies NLG in well-understood application contexts, while providing the flexibility for a developer and for the system, to vary linguistic output according to dialogue context, including any intended affective impact. Mini-templates are used with a suite of domain term objects, resulting in an NLG system (MINTGEN – MINi-Template GENerator) whose extensibility and ease of maintenance is enhanced by the sparsity of information devoted to individual domains. The system also avoids the need for specialist linguistic competence on the part of the system maintainer.

Developing a conceptual model of lead performance measurement and benchmarking: A multiple case analysis

Purpose: Environmental turbulence including rapid changes in technology and markets has resulted in the need for new approaches to performance measurement and benchmarking. There is a need for studies that attempt to measure and benchmark upstream, leading or developmental aspects of organizations. Therefore, the aim of this paper is twofold. The first is to conduct an in-depth case analysis of lead performance measurement and benchmarking leading to the further development of a conceptual model derived from the extant literature and initial survey data. The second is to outline future research agendas that could further develop the framework and the subject area.

Design/methodology/approach: A multiple case analysis involving repeated in-depth interviews with managers in organisational areas of upstream influence in the case organisations.

Findings: It was found that the effect of external drivers for lead performance measurement and benchmarking was mediated by organisational context factors such as level of progression in business improvement methods. Moreover, the legitimation of the business improvement methods used for this purpose, although typical, had been extended beyond their original purpose with the development of bespoke sets of lead measures.

Practical implications: Examples of methods and lead measures are given that can be used by organizations in developing a programme of lead performance measurement and benchmarking.

Originality/value: There is a paucity of in-depth studies relating to the theory and practice of lead performance measurement and benchmarking in organisations.

Discovery of multiple neuropeptide families in the phylum Platyhelminthes

Available evidence shows that short amidated neuropeptides are widespread and have important functions within the nervous systems of all flatworms (phylum Platyhelminthes) examined, and could therefore represent a starting point for new lead drug compounds with which to combat parasitic helminth infections. However, only a handful of these peptides have been characterised, the rigorous exploration of the flatworm peptide signalling repertoire having been hindered by the dearth of flatworm genomic data. Through searches of both expressed sequence tags and genomic resources using the basic local alignment search tool (BLAST), we describe 96 neuropeptides on 60 precursors from 10 flatworm species. Most of these (51 predicted peptides on 14 precursors) are novel and are apparently restricted to flatworms; the remainder comprise nine recognised peptide families including FMRFamide-like (FLPs), neuropeptide F (NPF)-like, myomodulin-like, buccalin-like and neuropeptide FF (NPFF)-like peptides; notably, the latter have only previously been reported in vertebrates. Selected peptides were localised immunocytochemically to the Schistosoma mansoni nervous system. We also describe several novel flatworm NPFs with structural features characteristic of the vertebrate neuropeptide Y (NPY) superfamily, previously unreported characteristics which support the common ancestry of flatworm NPFs with the NPY-superfamily. Our dataset provides a springboard for investigation of the functional biology and therapeutic potential of neuropeptides in flatworms, simultaneously launching flatworm neurobiology into the post-genomic era. (C) 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.