Hyperproliferation and Dysregulation ofIL-4 Expression in NF-ATp-Deficient Mice

AbstractNF-ATp is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells. They also display early defects in the transcription of multiple genes encoding cytokines and cell surface receptors, including CD40L and FasL. A striking defect in early IL-4 production was observed after ligation of the TCR complex by treatment with anti-CD3 in vivo. The transcription of other cytokines including IL-13, GM–CSF, and TNFα was also affected, though to a lesser degree. Interestingly, the cytokines IL-2 and IFNγ were minimally affected. Despite this early defect in IL-4 transcription, Th2 development was actually enhanced at later timepoints as evidenced by increased IL-4 production and IgE levels in situations that favor the formation of Th2 cells both in vitro and in vivo. These data suggest that NF-ATp may be involved in cell growth, and that it is important for the balanced transcription of the IL-4 gene during the course of an immune response.BDY

The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis

Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor

Proof of principle for a high sensitivity search for the electric dipole moment of the electron using the metastable a(1)[^3\Sigma^+] state of PbO

The metastable a(1)[^3\Sigma^+] state of PbO has been suggested as a suitable system in which to search for the electric dipole moment (EDM) of the electron. We report here the development of experimental techniques allowing high-sensitivity measurements of Zeeman and Stark effects in this system, similar to those required for an EDM search. We observe Zeeman quantum beats in fluorescence from a vapor cell, with shot-noise limited extraction of the quantum beat frequencies, high counting rates, and long coherence times. We argue that improvement in sensitvity to the electron EDM by at least two orders of magnitude appears possible using these techniques.Comment: 5 pages, 3 figure

UWE Science Communication Postgraduate Papers

ForewordThis second volume in the Postgraduate Papers series has been produced as part of the celebrations of ten years of Science Communication postgraduate programmes in the Faculty of Health and Applied Sciences, University of the West of England, Bristol.Every year, some fifteen to twenty students undertake a Master’s level project as part of their MSc studies. These papers represent just a small selection of the projects carried out between 2009 and 2013 but they persuasively demonstrate the wide range of subjects tackled by our students and the innovative research they conduct.Bonnie Buckley, Jennifer Garrett and Melanie Davies looked at aspects of science communication in science centres and museums. Bonnie examined the motivations that lead people to be volunteers in science centres; Jennifer investigated how science centres can play a role in communicating environmental sustainability and Melanie explored how science centres can use a range of activities to sustain and develop creativity. The Internet offers new modes and new routes for dialogue and science communication. Felicity Liggins, Mathieu Ranger and Robin Longdin undertook projects in this dynamic medium. Felicity explored attitudes to blogging in the UK Met Office, while Mathieu looked at the particular challenges faced by science bloggers and Robin investigated whether online interaction with scientists could positively affect school students’ attitudes to science.Amy Seakins, Maya Herbolzheimer and Sarah Venugopal’s projects were all based in the lively and diverse world of festivals. Spanning the worlds of traditional and online communication, Amy considered how citizen science projects could make the most effective use of the media; Maya investigated the effectiveness of a Festival of Nature in engaging a wide range of attendees with nature conservation, while Sarah examined the relationship between arts and science at a science event embedded in an arts festival.The final two papers, by Michal Jane Filtness and Alexander Brown defy grouping but clearly illustrate the variety of audiences our students address. Michal investigated researchers’ views of the Pathways to Impact tool created by the UK Research Councils to increase the public impact of research, while Alexander evaluated the impact on school students’ attitudes to science among young people who had undertaken work experience placements at a UK research council. We want to congratulate those graduates whose research is included in this volume and thank them for the time and care they have taken in creating their contributions. Thanks should also go to the graduates’ academic supervisors, who are the co-authors on these papers; in particular Dr Karen Bultitude and Dr Helen Featherstone, who are now based at other institutions. We would also like to thank the many organisations whose support made these projects possible.We are honoured to share in our graduates’ success and delighted to have this opportunity to open up their work to a wider audience. We wish all our graduates every success in their careers as science communicators

Inhibitory Function of Two NFAT Family Members in Lymphoid Homeostasis and Th2 Development

AbstractNuclear factor of activated T cells (NFAT) is a critical regulator of early gene transcription in response to TCR-mediated signals. Here, we show that mice lacking both NFATp and NFAT4 develop a profound lymphoproliferative disorder likely due to a lowered threshold for TCR signaling coupled with increased resistance to apoptosis secondary to defective FasL expression. NFAT mutant mice also have allergic blepharitis, interstitial pneumonitis, and a 103 to 104 fold increase in serum IgG1 and IgE levels, secondary to a dramatic and selective increase in Th2 cytokines. This phenotype may be ascribed to unopposed occupancy of the IL-4 promoter by NFATc. Our data demonstrate that lymphoid homeostasis and Th2 activation require a critical balance among NFAT family members

Association between changes in gene signatures expression and disease activity among patients with systemic lupus erythematosus

Abstract Background We assessed the stability of BAFF, interferon, plasma cell and LDG neutrophil gene expression signatures over time, and whether changes in expression coincided with changes in SLE disease activity. Methods Two hundred forty-three patients with SLE were evaluated for disease activity, serological parameters and peripheral blood gene signatures in clinic visits (2 or more per patient) that occurred between 2009 and 2012. Levels of the BAFF gene transcript, plasma cell signature, Interferon (IFN) signature and the low density granulocytes (LDG)-associated neutrophil gene signature were assessed in PAX-gene-preserved peripheral blood by global microarray. The stability of repeated measures of gene expression was quantified using intra-class correlation coefficients. SLE disease activity was measured using the Physicians Global Assessment and the SELENA-SLEDAI index and its components. Using a mixed effects regression model we assessed: 1) the association between a patient’s average gene signature expression over time and disease activity, and 2) the association between a patient’s changes in gene expression over time and changes in disease activity. Results Gene expression signatures showed more within-person stability than systolic blood pressure. The IFN signature exhibited the most stability. Patients with high levels of BAFF and IFN transcripts tended to have significantly higher levels of musculoskeletal disease, skin disease, anti-dsDNA, and erythrocyte sedimentation rate, and lower levels of complement. However, changes in BAFF or IFN gene signatures were not associated with changes in disease activity. Similar associations were seen between the LDG gene signature and disease activity. However, when LDG increased, complement tended to increase. Patients with high levels of plasma cell gene signature tended to have higher levels of anti-dsDNA and lower levels of complement. However, unlike the other gene signatures, changes in plasma cell gene signature significantly coincided with changes in anti-dsDNA and complement. Conclusions The gene expression signatures were relatively stable within patients over time. BAFF and interferon gene expression were markers of patients with generally higher disease activity, but changes in these gene signatures did not coincide with changes in disease activity. Plasma Cell gene signature expression tracked with the traditional SLE serologic markers of anti-dsDNA and complement

Clinical Application of a Modular Genomics Technique in Systemic Lupus Erythematosus: Progress towards Precision Medicine

Monitoring disease activity in a complex, heterogeneous disease such as lupus is difficult. Both over- and undertreatment lead to damage. Current standard of care serologies are unreliable. Better measures of disease activity are necessary as we move into the era of precision medicine. We show here the use of a data-driven, modular approach to genomic biomarker development within lupus—specifically lupus nephritis