Personal development planning in the first year

The approach to quality and standards in higher education (HE) in Scotland is enhancement led and learner centred. It was developed through a partnership of the Scottish Funding Council (SFC), Universities Scotland, the National Union of Students in Scotland (NUS Scotland) and the Quality Assurance Agency for Higher Education (QAA) Scotland. The Higher Education Academy has also joined that partnership. The Enhancement Themes are a key element of a five-part framework, which has been designed to provide an integrated approach to quality assurance and enhancement. The Enhancement Themes support learners and staff at all levels in further improving higher education in Scotland; they draw on developing innovative practice within the UK and internationally The five elements of the framework are: z a comprehensive programme of subject-level reviews undertaken by higher education institutions (HEIs) themselves; guidance is published by the SFC (www.sfc.ac.uk) z enhancement-led institutional review (ELIR), run by QAA Scotland (www.qaa.ac.uk/reviews/ELIR) z improved forms of public information about quality; guidance is provided by the SFC (www.sfc.ac.uk) z a greater voice for students in institutional quality systems, supported by a national development service - student participation in quality scotland (sparqs) (www.sparqs.org.uk) z a national programme of Enhancement Themes aimed at developing and sharing good practice to enhance the student learning experience, facilitated by QAA Scotland (www.enhancementthemes.ac.uk). The topics for the Enhancement Themes are identified through consultation with the sector and implemented by steering committees whose members are drawn from the sector and the student body. The steering committees have the task of establishing a programme of development activities, which draw on national and international good practice. Publications emerging from each Theme are intended to provide important reference points for HEIs in the ongoing strategic enhancement of their teaching and learning provision. Full details of each Theme, its steering committee, the range of research and development activities as well as the outcomes are published on the Enhancement Themes website (www.enhancementthemes.ac.uk). To further support the implementation and embedding of a quality enhancement culture within the sector - including taking forward the outcomes of the Enhancement Themes - an overarching committee, the Scottish Higher Education Enhancement Committee (SHEEC), chaired by Professor Kenneth Miller, Vice-Principal, University of Strathclyde, has the important dual role of supporting the overall approach of the Enhancement Themes, including the five-year rolling plan, as well as institutional enhancement strategies and management of quality. SHEEC, working with the individual topic-based Enhancement Themes' steering committees, will continue to provide a powerful vehicle for progressing the enhancement-led approach to quality and standards in Scottish higher education

Beyond blood brain barrier breakdown – in vivo detection of occult neuroinflammatory foci by magnetic nanoparticles in high field MRI

BACKGROUND: Gadopentate dimeglumine (Gd-DTPA) enhanced magnetic resonance imaging (MRI) is widely applied for the visualization of blood brain barrier (BBB) breakdown in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Recently, the potential of magnetic nanoparticles to detect macrophage infiltration by MRI was demonstrated. We here investigated a new class of very small superparamagnetic iron oxide particles (VSOP) as novel contrast medium in murine adoptive-transfer EAE. METHODS: EAE was induced in 17 mice via transfer of proteolipid protein specific T cells. MR images were obtained before and after application of Gd-DTPA and VSOP on a 7 Tesla rodent MR scanner. The enhancement pattern of the two contrast agents was compared, and correlated to histology, including Prussian Blue staining for VSOP detection and immunofluorescent staining against IBA-1 to identify macrophages/microglia. RESULTS: Both contrast media depicted BBB breakdown in 42 lesions, although differing in plaques appearances and shapes. Furthermore, 13 lesions could be exclusively visualized by VSOP. In the subsequent histological analysis, VSOP was localized to microglia/macrophages, and also diffusely dispersed within the extracellular matrix. CONCLUSION: VSOP showed a higher sensitivity in detecting BBB alterations compared to Gd-DTPA enhanced MRI, providing complementary information of macrophage/microglia activity in inflammatory plaques that has not been visualized by conventional means

Short- and long-range interactions in the HIV-1 5′ UTR regulate genome dimerization and packaging

RNA dimerization is the noncovalent association of two human immunodeficiency virus-1 (HIV-1) genomes. It is a conserved step in the HIV-1 life cycle and assumed to be a prerequisite for binding to the viral structural protein Pr55Gag during genome packaging. Here, we developed functional analysis of RNA structure-sequencing (FARS-seq) to comprehensively identify sequences and structures within the HIV-1 5′ untranslated region (UTR) that regulate this critical step. Using FARS-seq, we found nucleotides important for dimerization throughout the HIV-1 5′ UTR and identified distinct structural conformations in monomeric and dimeric RNA. In the dimeric RNA, key functional domains, such as stem-loop 1 (SL1), polyadenylation signal (polyA) and primer binding site (PBS), folded into independent structural motifs. In the monomeric RNA, SL1 was reconfigured into long- and short-range base pairings with polyA and PBS, respectively. We show that these interactions disrupt genome packaging, and additionally show that the PBS–SL1 interaction unexpectedly couples the PBS with dimerization and Pr55Gag binding. Altogether, our data provide insights into late stages of HIV-1 life cycle and a mechanistic explanation for the link between RNA dimerization and packaging.Peer Reviewe

THINK Back: KNowledge-based Interpretation of High Throughput data

Results of high throughput experiments can be challenging to interpret. Current approaches have relied on bulk processing the set of expression levels, in conjunction with easily obtained external evidence, such as co-occurrence. While such techniques can be used to reason probabilistically, they are not designed to shed light on what any individual gene, or a network of genes acting together, may be doing. Our belief is that today we have the information extraction ability and the computational power to perform more sophisticated analyses that consider the individual situation of each gene. The use of such techniques should lead to qualitatively superior results

Mast Cells and Gastrointestinal Dysmotility in the Cystic Fibrosis Mouse

BACKGROUND: Cystic fibrosis (CF) has many effects on the gastrointestinal tract and a common problem in this disease is poor nutrition. In the CF mouse there is an innate immune response with a large influx of mast cells into the muscularis externa of the small intestine and gastrointestinal dysmotility. The aim of this study was to evaluate the potential role of mast cells in gastrointestinal dysmotility using the CF mouse (Cftr(tm1UNC), Cftr knockout). METHODOLOGY: Wild type (WT) and CF mice were treated for 3 weeks with mast cell stabilizing drugs (ketotifen, cromolyn, doxantrazole) or were treated acutely with a mast cell activator (compound 48/80). Gastrointestinal transit was measured using gavage of a fluorescent tracer. RESULTS: In CF mice gastric emptying at 20 min post-gavage did not differ from WT, but was significantly less than in WT at 90 min post-gavage. Gastric emptying was significantly increased in WT mice by doxantrazole, but none of the mast cell stabilizers had any significant effect on gastric emptying in CF mice. Mast cell activation significantly enhanced gastric emptying in WT mice but not in CF mice. Small intestinal transit was significantly less in CF mice as compared to WT. Of the mast cell stabilizers, only doxantrazole significantly affected small intestinal transit in WT mice and none had any effect in CF mice. Mast cell activation resulted in a small but significant increase in small intestinal transit in CF mice but not WT mice. CONCLUSIONS: The results indicate that mast cells are not involved in gastrointestinal dysmotility but their activation can stimulate small intestinal transit in cystic fibrosis

A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Lithium is an effective treatment for Bipolar Disorder (BD) and significantly reduces suicide risk, though the molecular basis of lithium's effectiveness is not well understood. We seek to improve our understanding of this effectiveness by posing hypotheses based on new experimental data as well as published data, testing these hypotheses in silico, and posing new hypotheses for validation in future studies. We initially hypothesized a gene-by-environment interaction where lithium, acting as an environmental influence, impacts signal transduction pathways leading to differential expression of genes important in the etiology of BD mania.</p> <p>Results</p> <p>Using microarray and rt-QPCR assays, we identified candidate genes that are differentially expressed with lithium treatment. We used a systems biology approach to identify interactions among these candidate genes and develop a network of genes that interact with the differentially expressed candidates. Notably, we also identified cocaine as having a potential influence on the network, consistent with the observed high rate of comorbidity for BD and cocaine abuse. The resulting network represents a novel hypothesis on how multiple genetic influences on bipolar disorder are impacted by both lithium treatment and cocaine use. Testing this network for association with BD and related phenotypes, we find that it is significantly over-represented for genes that participate in signal transduction, consistent with our hypothesized-gene-by environment interaction. In addition, it models related pharmacogenomic, psychiatric, and chemical dependence phenotypes.</p> <p>Conclusions</p> <p>We offer a network model of gene-by-environment interaction associated with lithium's effectiveness in treating BD mania, as well as the observed high rate of comorbidity of BD and cocaine abuse. We identified drug targets within this network that represent immediate candidates for therapeutic drug testing. Posing novel hypotheses for validation in future work, we prioritized SNPs near genes in the network based on functional annotation. We also developed a "concept signature" for the genes in the network and identified additional candidate genes that may influence the system because they are significantly associated with the signature.</p

Electrostatically stabilized magnetic nanoparticles – an optimized protocol to label T cells for in vivo MRI in a mouse model of multiple sclerosis

Die MS ist eine Erkrankung, die zu einer frühen Invalidität der Patienten führen kann und daher gravierende Konsequenzen für Patienten und ihre Angehörigen birgt. Die therapeutischen Möglichkeiten sind bislang sehr limitiert. Dies liegt nicht zuletzt am mangelnden Verständnis der Pathogenese. Bei der MS handelt es sich um eine Autoimmunerkrankung, die vermutlich durch autoreaktive T-Zellen initiiert wird. Die Rolle von T-Zellen in der Erkrankungsentwicklung ist bisher nicht hinreichend geklärt. Ziel dieser Arbeit ist es, eine neue Methode zu etablieren, die die nicht-invasive Verfolgung von T-Zellen in vivo ermöglicht. Sie soll eingesetzt werden, um einen Beitrag zur Aufklärung pathogenetischer Mechanismen der Neuroinflammation und Neurodegeneration zunächst im Rahmen der EAE, letztendlich aber auch für andere Krankheitsmodelle, zu liefern. Obwohl die Markierung und das in vivo Zelltracking von Makrophagen und Stammzellen schon weitestgehend optimiert sind, stellen T-Zellen auf Grund der fehlenden phagozytotischen Kapazität weiterhin eine große Herausforderung dar. Daher wurde in der hier vorliegenden Arbeit eine neuartige Gruppe von Partikeln eingesetzt, die eine sehr viel effizientere Aufnahme in die Zellen ermöglichen soll. Repräsentant dieser von Zitrat umhüllten Partikel ist das sogenannte VSOP (very small iron oxide particle). Gekoppelt an Protaminsulfat, einem vielfach bewährten Transfektionsagens, soll sich die Transfektionskapazität der VSOP-Partikel potenzieren und dadurch auch die Beladung von Zellen ermöglichen, die kaum phagozytotische Kapazitäten besitzen. Das aus der Konjugation von VSOP und Protaminsulfat hervorgehende VProt wurde hinsichtlich seiner Beladungsfähigkeit, sowie dem potentiellen Einfluss auf Vitalität und Funktion der beladenen Zellen eingehend untersucht und mit nativen VSOP verglichen. Im in vitro System wurde zunächst ein effizientes Beladungsprotokoll mit VProt für die humanen HeLa-Zellen erstellt, um vorab eine Einschätzung von Beladungszeiten und -konzentrationen zu ermöglichen, die bei effektiver Partikelaufnahme eine möglichst geringe Toxizität gewährleisten. Im Anschluss wurden die gewonnen Erkenntnisse auf frische enzephalitogene T-Zellen von SJL/J-Mäusen übertragen, um ein Methodenprotokoll für die effiziente Beladung von T-Zellen mit VProt zu etablieren. Daraufhin wurden die beladenen T-Zellen in vivo in einem Mausmodell der MS, der experimentellen autoimmunen Enzephalomyelitis (EAE), auf den Erhalt ihres enzephalitogenen Potenzials untersucht. Die Applikation von Gadolinium-DTPA diente dazu, in der MRT Permeabilitätsstörungen der Blut-Hirn-Schranke in T1-gewichteten Sequenzen sichtbar zu machen. Darüberhinaus wurde die intrathekale Injektion VProt enthaltender T-Zellen angewendet, um schließlich die Fähigkeit dieser T-Zellen zur Signalgebung im MRT zu ermitteln. Die Transition dieser Methode von „Bench to Bedside“ in den humanen Organismus soll zu einem späteren Zeitpunkt die Übertragbarkeit auf die MS, sowie ein weites Spektrum weiterer Pathologien ermöglichen. Durch das auf diesem Wege erlangte bessere Verständnis der Pathogenese können gezielt therapeutische Möglichkeiten ausgelotet und durch Verkürzung des Zeitraums bis zur Diagnosestellung zukünftig auch ein früheres therapeutisches Eingreifen erreicht werden.We present a novel highly efficient protocol to magnetically label T cells applying electrostatically stabilized very small superparamagnetic iron oxide particles (VSOP) in combination with protamine, that we developed in preparation of future magnetic resonance imaging (MRI) in vivo studies on cell migration, e.g. in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Encephalitogenic T cells an HeLa cells were co- incubated with VSOP, or with protamine-complexed VSOP (VProt), respectively, at different conditions, optimizing concentrations and incubation times. Labelling efficacy was determined by atomic absorption spectrometry as well as histologically and by relaxometry, and evaluated on a 7 Tesla MR system. Furthermore, we investigated effects on t cell functionality by observing gadolinium leakage in pEAE mice after transfer of VProt labeled T cells. Results: T cell co-incubation with VSOP resulted in an efficient cellular iron uptake. T2 times of labeled cells dropped significantly, resulting in prominent hypointensity on T2*-weighted scans. Optimal labelling efficacy was achieved by VProt. Conclusions: VProt yields a highly efficient T cell labelling, adapted for applications in future in vivo trials