Heterogeneous agendas around public engagement in stem cell research:The case for maintaining plasticity

Although public engagement is now part of the business of doing science, there is considerable divergence about what the term means and what public engagement ought to be doing. This paper refl ects on these heterogeneous meanings and agendas through an analysis of focus group data from research on public engagement in stem cell research. Three broad visions of public engagement are identifi ed: as education and information provision; as dialogue; and as participation in policy making. In analysing the implications of these visions three dimensions are highlighted: weakly and strongly structured visions of public engagement; the co production of roles and relationships; and the framing of what is at stake. Each of these has the potential to include or exclude some groups in public engagement. We conclude that social scientists should seek to maintain the plasticity of public engagement as a necessary condition for greater participation and reflexivity in science policy, practice and governance

Helicobacter hepaticus cytolethal distending toxin promotes intestinal carcinogenesis in 129Rag2‐deficient mice

Multiple pathogenic Gram-negative bacteria produce the cytolethal distending toxin (CDT) with activity of DNase I; CDT can induce DNA double-strand breaks (DSBs), G2/M cell cycle arrest, and apoptosis in cultured mammalian cells. However, the link of CDT to in vivo tumorigenesis is not fully understood. In this study, 129/SvEv Rag2−/−mice were gavaged with wild-type Helicobacter hepatics 3B1(Hh) and its isogenic cdtB mutant HhcdtBm7, followed by infection for 10 and 20 weeks (WPI). HhCDT deficiency did not affect cecal colonization levels of HhcdtBm7, but attenuated severity of cecal pathology in HhcdtBm7-infected mice. Of importance, preneoplasic dysplasia was progressed to cancer from 10 to 20 WPI in the Hh-infected mice but not in the HhcdtBm7-infected mice. In addition, the loss of HhCDT significantly dampened transcriptional upregulation of cecal Tnfα and Il-6, but elevated Il-10 mRNA levels when compared to Hh at 10 WPI. Furthermore, the presence of HhCDT increased numbers of lower bowel intestinal γH2AX-positive epithelial cells (a marker of DSBs) at both 10 and 20 WPI and augmented phospho-Stat3 foci[superscript +] intestinal crypts (activation of Stat3) at 20 WPI. Our findings suggest that CDT promoted Hh carcinogenesis by enhancing DSBs and activation of the Tnfα/Il-6-Stat3 signaling pathway.National Institutes of Health (U.S.) (Grant R01-OD01141)National Institutes of Health (U.S.) (Grant T32-OD010978)National Institutes of Health (U.S.) (Grant P01 CA28842

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Abstract Helicobacter pylori infection promotes male-predominant gastric adenocarcinoma in humans. Estrogens reduce gastric cancer risk and previous studies demonstrated that prophylactic 17ɴ-estradiol (E2) in INS-GAS mice decreases H. pylori-induced carcinogenesis. We examined the effect of E2 and Tamoxifen, on H. pylori-induced gastric cancer in male and female INS-GAS mice. After confirming robust gastric pathology at 16 weeks post-infection (WPI), mice were implanted with E2

Experiences as a clinical teaching fellow: interviews with clinical teaching fellows in the West Midlands

BackgroundThe majority of junior doctors in the UK do not proceed directly into specialty training after completing mandatory foundation training but instead take a year out of training. A common post undertaken during a year out of training is a clinical teaching fellow (CTF) role which is used to provide undergraduate medical student teaching. There is only a small amount of literature available regarding CTF posts, and very little of this explores experiences or reasons for taking up such as post. An understanding of the reasons why doctors are choosing to work as CTFs and what their experiences are in post will contribute to how the role is further developed and utilised within the NHS. This study aimed to explore the experiences of CTFs employed in the West Midlands at NHS hospital Trusts.MethodsCTFs working in Trusts in the West Midlands region registered as students on the Education for Healthcare Professionals Post Graduate Certificate course at the University of Birmingham in August 2019 and 2020 who were enrolled in a longitudinal study were invited to take part in an individual interview asking about their experiences as CTFs.ResultsNine CTFs participated in an interview. Five main themes were identified which related to their experiences in post and plans for future careers. Participants reported choosing to undertake a CTF role due to wanting a break from clinical work and having previously enjoyed delivering teaching. Positive experiences in post included lifestyle related benefits and self-development opportunities. Challenges identified with the role included the impact of COVID-19 and volume of students.ConclusionThis is the first study to use interview methodology to explore experiences of CTFs, and has provided a valuable insight into the experiences of those in post in the West Midlands region. Understanding why doctors chose this job and what their experiences are could help to further develop and refine the role. To guarantee demands for teaching staff are met those employing CTFs should be aware of reasons why doctors apply for the post and ensure the post remains a desirable option

Multivariate Modeling Identifies Neutrophil- and Th17-Related Factors as Differential Serum Biomarkers of Chronic Murine Colitis

Background: Diagnosis of chronic intestinal inflammation, which characterizes inflammatory bowel disease (IBD), along with prediction of disease state is hindered by the availability of predictive serum biomarker. Serum biomarkers predictive of disease state will improve trials for therapeutic intervention, and disease monitoring, particularly in genetically susceptible individuals. Chronic inflammation during IBD is considered distinct from infectious intestinal inflammation thereby requiring biomarkers to provide differential diagnosis. To address whether differential serum biomarkers could be identified in murine models of colitis, immunological profiles from both chronic spontaneous and acute infectious colitis were compared and predictive serum biomarkers identified via multivariate modeling.Methodology/Principal Findings: Discriminatory multivariate modeling of 23 cytokines plus chlorotyrosine and nitrotyrosine (protein adducts from reactive nitrogen species and hypochlorite) in serum and tissue from two murine models of colitis was performed to identify disease-associated biomarkers. Acute C. rodentium-induced colitis in C57BL/6J mice and chronic spontaneous Helicobacter-dependent colitis in TLR4−/− x IL-10−/− mice were utilized for evaluation. Colon profiles of both colitis models were nearly identical with chemokines, neutrophil- and Th17-related factors highly associated with intestinal disease. In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon. In contrast, the discriminatory predictive serum factors for chronic colitis were neutrophil- and Th17-related factors (KC, IL-12/23p40, IL-17, G-CSF, and chlorotyrosine) that were also elevated in colon tissue. Chronic colitis serum biomarkers were specific to chronic colitis as they were not discriminatory for acute colitis.Conclusions/Significance: Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis. Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.</p

Multivariate Modeling Identifies Neutrophil- and Th17-Related Factors as Differential Serum Biomarkers of Chronic Murine Colitis

Diagnosis of chronic intestinal inflammation, which characterizes inflammatory bowel disease (IBD), along with prediction of disease state is hindered by the availability of predictive serum biomarker. Serum biomarkers predictive of disease state will improve trials for therapeutic intervention, and disease monitoring, particularly in genetically susceptible individuals. Chronic inflammation during IBD is considered distinct from infectious intestinal inflammation thereby requiring biomarkers to provide differential diagnosis. To address whether differential serum biomarkers could be identified in murine models of colitis, immunological profiles from both chronic spontaneous and acute infectious colitis were compared and predictive serum biomarkers identified via multivariate modeling.Discriminatory multivariate modeling of 23 cytokines plus chlorotyrosine and nitrotyrosine (protein adducts from reactive nitrogen species and hypochlorite) in serum and tissue from two murine models of colitis was performed to identify disease-associated biomarkers. Acute C. rodentium-induced colitis in C57BL/6J mice and chronic spontaneous Helicobacter-dependent colitis in TLR4(-/-) x IL-10(-/-) mice were utilized for evaluation. Colon profiles of both colitis models were nearly identical with chemokines, neutrophil- and Th17-related factors highly associated with intestinal disease. In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon. In contrast, the discriminatory predictive serum factors for chronic colitis were neutrophil- and Th17-related factors (KC, IL-12/23p40, IL-17, G-CSF, and chlorotyrosine) that were also elevated in colon tissue. Chronic colitis serum biomarkers were specific to chronic colitis as they were not discriminatory for acute colitis.Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis. Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers

Meeting report: GARNet/OpenPlant CRISPR-Cas workshop

Targeted genome engineering has been described as a “game-changing technology” for fields as diverse as human genetics and plant biotechnology. One technique used for precise gene editing utilises the CRISPR-Cas system and is an effective method for genetic engineering in a wide variety of plants. However, many researchers remain unaware of both the technical challenges that emerge when using this technique or of its potential benefits. Therefore in September 2015, GARNet and OpenPlant organized a two-day workshop at the John Innes Centre that provided both background information and hands-on training for this important technology

Helicobacter hepaticus Infection Promotes Hepatitis and Preneoplastic Foci in Farnesoid X Receptor (FXR) Deficient Mice

Farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid metabolism and transport. Mice lacking expression of FXR (FXR KO) have a high incidence of foci of cellular alterations (FCA) and liver tumors. Here, we report that Helicobacter hepaticus infection is necessary for the development of increased hepatitis scores and FCA in previously Helicobacter-free FXR KO mice. FXR KO and wild-type (WT) mice were sham-treated or orally inoculated with H. hepaticus. At 12 months post-infection, mice were euthanized and liver pathology, gene expression, and the cecal microbiome were analyzed. H. hepaticus induced significant increases hepatitis scores and FCA numbers in FXR KO mice (P<0.01 and P<0.05, respectively). H. hepaticus altered the beta diversity of cecal microbiome in both WT and FXR KO mice compared to uninfected mice (P<0.05). Significant upregulation of β-catenin, Rela, Slc10a1, Tlr2, Nos2, Vdr, and Cyp3a11 was observed in all FXR KO mice compared to controls (P<0.05). Importantly, H. hepaticus and FXR deficiency were necessary to significantly upregulate Cyp2b10 (P<0.01). FXR deficiency was also a potent modulator of the cecal microbiota, as observed by a strong decrease in alpha diversity. A significant decrease in Firmicutes, particularly members of the order Clostridiales, was observed in FXR KO mice (P<0.05 and FDR<5%, ANOVA). While FXR deficiency strongly affects expression of genes related to immunity and bile acid metabolism, as well as the composition of the microbiome; however, its deficiency was not able to produce significant histopathological changes in the absence of H. hepaticus infection.National Institutes of Health (U.S.) (NIH R01 OD011141)National Institutes of Health (U.S.) (NIH T32 OD010978)National Institutes of Health (U.S.) (NIH P30 ES002109)National Institutes of Health (U.S.) (P01 CA026731

Regulation of dendrimer/dextran material performance by altered tissue microenvironment in inflammation and neoplasia

available in PMC 2015 October 30A “one material fits all” mindset ignores profound differences in target tissues that affect their responses and reactivity. Yet little attention has been paid to the role of diseased tissue on material performance, biocompatibility, and healing capacity. We assessed material-tissue interactions with a prototypical adhesive material based on dendrimer/dextran and colon as a model tissue platform. Adhesive materials have high sensitivity to changes in their environment and can be exploited to probe and quantify the influence of even subtle modifications in tissue architecture and biology. We studied inflammatory colitis and colon cancer and found not only a difference in adhesion related to surface chemical interactions but also the existence of a complex interplay that determined the overall dendrimer/dextran biomaterial compatibility. Compatibility was contextual, not simply a constitutive property of the material, and was related to the extent and nature of immune cells in the diseased environment present before material implantation. We then showed how to use information about local alterations of the tissue microenvironment to assess disease severity. This in turn guided us to an optimal dendrimer/dextran formulation choice using a predictive model based on clinically relevant conditions.National Institutes of Health (U.S.) (NIH grant R01 GM-49039)Deshpande Center for Technological Innovatio