The Design of Student Training Resources to Enhance the Student Voice in Academic Quality Assurance and Quality Enhancement Processes

Without appropriate training and recognition, students – in particular Class Representatives – often struggle to engage fully with a University’s quality assurance and quality enhancement processes. Through the “Our Student Voice” project in Technological University Dublin (TU Dublin), a suite of digital training resources were designed to provide training for students to help develop the requisite knowledge and skills for effective participation there processes, thus strengthening student engagement and enhancing the student voice. The resources are organised into thirteen accessible episodes that each commence with an animated scenario that sets out key messages. The remainder of the episode provides detailed guidance for students and learning activities to help students develop their skillset. Upon completion of the learning activities, and having satisfactorily undertaken one of three specific student role in the quality processes, students can apply for recognition through a digital badge. The training resources and digital badges have been co-designed by a project team comprised of staff and students from across the University guided by best practice internationally. This paper describes the co-design process and presents a set of lessons learned that may assist other higher education institutions in enabling impactful student engagement in their academic quality assurance and quality enhancement processes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

MicroRNA-21 Limits Uptake of Listeria monocytogenes by Macrophages to Reduce the Intracellular Niche and Control Infection.

MiRNAs are important post-transcriptional regulators of gene expression. MiRNA expression is a crucial part of host responses to bacterial infection, however there is limited knowledge of their impact on the outcome of infections. We investigated the influence of miR-21 on macrophage responses during infection with Listeria monocytogenes, which establishes an intracellular niche within macrophages. MiR-21 is induced following infection of bone marrow-derived macrophages (BMDMs) with Listeria. MiR-21-/- macrophages display an increased bacterial burden with Listeria at 30 min and 2 h post-infection. This phenotype was reversed by the addition of synthetic miR-21 mimics to the system. To assess the immune response of wildtype (WT) and miR-21-/- macrophages, BMDMs were treated with bacterial LPS or infected with Listeria. There was no difference in IL-10 and IL-6 between WT and miR-21-/- BMDMs in response to LPS or Listeria. TNF-? was increased in miR-21-/- BMDMs stimulated with LPS or Listeria compared to WT macrophages. We next assessed the production of nitric oxide (NO), a key bactericidal factor in Listeria infection. There was no significant difference in NO production between WT and miR-21-/- cells, indicating that the increased bacterial burden may not be due to impaired killing. As the increased bacterial load was observed early following infection (30 min), we questioned whether this is due to differences in uptake of Listeria by WT and miR-21-/- macrophages. We show that miR-21-deficiency enhances uptake of FITC-dextran and FITC-Escherichia coli bioparticles by macrophages. The previously observed Listeria burden phenotype was ablated by pre-treatment of cells with the actin polymerization inhibitor cytochalasin-D. From analysis of miR-21 targets, we selected the pro-phagocytic regulators myristoylated alanine-rich C-kinase substrate (MARCKS) and Ras homolog gene family, member B (RhoB) for further investigation. MARCKS and RhoB are increased in miR-21-/- BMDMs, correlating with increased uptake of Listeria. Finally, intra-peritoneal infection of mice with Listeria led to increased bacterial burden in livers of miR-21-/- mice compared to WT mice. These findings suggest a possible role for miR-21 in regulation of phagocytosis during infection, potentially by repression of MARCKS and RhoB, thus serving to limit the availability of the intracellular niche of pathogens like L. monocytogenes

Loss of microRNA-21 influences the gut microbiota causing reduced susceptibility in a murine model of colitis

Background and aims: microRNAs regulate gene expression and influence the pathogenesis of human diseases. The present study investigated the role of microRNA-21 [miR-21] in the pathogenesis of intestinal inflammation, because miR-21 is highly expressed in inflammatory bowel disease. Inflammatory bowel disease is associated with intestinal barrier dysfunction and an altered gut microbiota. Recent studies have demonstrated that host microRNAs can shape the microbiota. Thus, we determined the influence of miR-21 on the gut microbiota and observed the subsequent impact in a dextran sodium sulphate [DSS]-induced colitis model. Methods: The influence of miR-21 on the gut microbiota and inflammation was assessed in wild-type [WT] and miR-21-/- mice, in co-housed mice, following antibiotic depletion of the microbiota, or by colonization of germ-free [GF] mice with fecal homogenate, prior to DSS administration. We carried out 16S rRNA sequencing on WT and miR-21-/- mice to dissect potential differences in the gut microbiota. Results: miR-21-/- mice have reduced susceptibility to DSS-induced colitis compared with WT mice. Co-housing conferred some protection to WT mice, while GF mice colonized with fecal homogenate from miR-21-/- were protected from DSS colitis compared with those colonized with WT homogenate. Further supporting a role for the microbiota in the observed phenotype, the protection afforded by miR-21 depletion was lost when mice were pre-treated with antibiotics. The 16S rRNA sequencing revealed significant differences in the composition of WT and miR-21-/- intestinal microbiota. Conclusions: These findings suggest that miR-21 influences the pathogenesis of intestinal inflammation by causing propagation of a disrupted gut microbiota

Giving Student Groups a Stronger Voice: Using Participatory Research and Action (PRA) to Initiate Change to a Curriculum

Traditional student feedback mechanisms have been criticised for being teacher-centered in design and in particular, for their absence of transparent follow-up actions. In contrast, this study describes the process and the evaluation of a participatory research and action (PRA) approach used in an undergraduate Physiotherapy degree. This approach aimed to give students a stronger voice in order to identify the issues they felt were most important and to involve them in the subsequent actions to change or influence their curriculum. Using group consensus, key areas were identified by the students using a variety of PRA techniques, solutions were recommended and some actions implemented. Both students and staff maintained that the process had gone some way to empowering students and had begun a ripple effect in relation to student involvement in on-going curriculum design and debate

Both TLR2 and TRIF contribute to interferon-? production during Listeria infection.

Synthesis of interferon-? (IFN-?) is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-? synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-? production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, ?pgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-? gene, requiring TLR2 and bacterial internalization. Induction of IFN-? was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived macrophages. The novelty of our findings thus lies in the first description of TLR2 and TRIF as two critical components leading to the induction of the IFN-? gene and in uncovering that individual macrophage populations adopt different strategies to link pathogen recognition signals to IFN-? gene expression

Promyelocytic leukemia protein interacts with the apoptosis-associated speck-like protein to limit inflammasome activation

The apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1? production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively, our data indicate that PML limits ASC function, retaining ASC in the nucleus

MyD88 adaptor-like (Mal) functions in the epithelial barrier and contributes to intestinal integrity via protein kinase C

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer

Protective role for caspase-11 during acute experimental murine colitis.

Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1? and IL-18. Noncanonical inflammasome activity occurs during host defense against Gram-negative bacteria and in models of acute septic shock. We propose that the noncanonical inflammasome is activated in mice during acute intestinal inflammation elicited by dextran sodium sulfate (DSS), a model of experimental colitis. We find that caspase-11?/? mice display enhanced susceptibility to DSS, because of impaired IL-18 production. The impaired IL-18 levels observed are shown to result in reduced intestinal epithelial cell proliferation and increased cell death. We also suggest that a novel type II IFN?dependent, type I IFN-TRIF?independent signaling pathway is required for in vivo caspase-11 production in intestinal epithelial cells during DSS colitis. Collectively, these data suggest that IFN-??mediated caspase-11 expression has a key role maintaining intestinal epithelial barrier integrity in vivo during experimentally induced acute colitis