The Binding Site for TRAF2 and TRAF3 but Not for TRAF6 Is Essential for CD40-Mediated Immunoglobulin Class Switching

AbstractTo define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40ΔTRAF6), TRAF2 and TRAF3 (CD40ΔTRAF2/3), or both (CD40ΔTRAFs) into B cells of CD40−/− mice. The in vivo isotype switch defect in CD40−/− mice was fully corrected by WT and CD40ΔTRAF6, partially by CD40ΔTRAF2/3, and not at all by CD40ΔTRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, and NFκB in B cells were normal in WT and CD40ΔTRAF6 mice, severely impaired in CD40ΔTRAF2/3, and absent in CD40ΔTRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential for CD40 isotype switching and activation in B cells

Venture capital on a shoestring: Bioventures’ pioneering life sciences fund in South Africa

<p>Abstract</p> <p>Background</p> <p>Since 2000, R&D financing for global health has increased significantly, with innovative proposals for further increases. However, although venture capital (VC) funding has fostered life sciences businesses across the developed world, its application in the developing world and particularly in Africa is relatively new. Is VC feasible in the African context, to foster the development and application of local health innovation?</p> <p>As the most industrially advanced African nation, South Africa serves as a test case for life sciences venture funding. This paper analyzes Bioventures, the first VC company focused on life sciences investment in sub-Saharan Africa. The case study method was used to analyze the formation, operation, and investment support of Bioventures, and to suggest lessons for future health venture funds in Africa that aim to develop health-oriented innovations.</p> <p>Discussion</p> <p>The modest financial success of Bioventures in challenging circumstances has demonstrated a proof of concept that life sciences VC can work in the region. Beyond providing funds, support given to investees included board participation, contacts, and strategic services. Bioventures had to be proactive in finding and supporting good health R&D.</p> <p>Due to the fund’s small size, overhead and management expenses were tightly constrained. Bioventures was at times unable to make follow-on investments, being forced instead to give up equity to raise additional capital, and to sell health investments earlier than might have been optimal. With the benefit of hindsight, the CFO of Bioventures felt that partnering with a larger fund might benefit similar future funds. Being better linked to market intelligence and other entrepreneurial investors was also seen as an unmet need.</p> <p>Summary</p> <p>BioVentures has learned lessons about how the traditional VC model might evolve to tackle health challenges facing Africa, including how to raise funds and educate investors; how to select, value, and support investments; and how to understand the balance between financial and social returns. The experience of the fund suggests that future health funds targeting ailments of the poor might require investors that accept health benefits as part of their overall “return.” Learning from Bioventures may help develop health innovation funding for sub-Saharan African that has combined health, financial, and economic development impacts.</p

BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway

By diversifying antibody biological effector functions, class switch DNA recombination has a central role in the maturation of the antibody response. Here we show that BCR-signalling synergizes with Toll-like receptor (TLR) signalling to induce class switch DNA recombination. BCR-signalling activates the non-canonical NF-κB pathway and enhances the TLR-dependent canonical NF-κB pathway, thereby inducing activation-induced cytidine deaminase (AID), which is critical for class switch DNA recombination. Escherichia coli lipopolysaccharide (LPS) triggers dual TLR4/BCR-signalling and induces hallmarks of BCR-signalling, including CD79a phosphorylation and Ca2+ mobilization, and activates both the NF-κB pathways to induce AID and class switch DNA recombination in a PI(3)K p85α-dependent fashion. CD40-signalling activates the two NF-κB pathways to induce AID and class switch DNA recombination independent of BCR-signalling. Finally, dual BCR/TLR-engaging NP–lipopolysaccharide effectively elicits class-switched NP-specific IgG3 and IgG2b in mice. Thus, by integrating signals of the non-canonical and canonical NF-κB pathways, BCR and TLRs synergize to induce AID and T-cell-independent class switch DNA recombination

Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory gd T cell subsets

Two distinct subsets of γδ T cells that produce interleukin 17 (IL-17) (CD27(-) γδ T cells) or interferon-γ (IFN-γ) (CD27(+) γδ T cells) develop in the mouse thymus, but the molecular determinants of their functional potential in the periphery remain unknown. Here we conducted a genome-wide characterization of the methylation patterns of histone H3, along with analysis of mRNA encoding transcription factors, to identify the regulatory networks of peripheral IFN-γ-producing or IL-17-producing γδ T cell subsets in vivo. We found that CD27(+) γδ T cells were committed to the expression of Ifng but not Il17, whereas CD27(-) γδ T cells displayed permissive chromatin configurations at loci encoding both cytokines and their regulatory transcription factors and differentiated into cells that produced both IL-17 and IFN-γ in a tumor microenvironment

HIV-1 Populations in Semen Arise through Multiple Mechanisms

HIV-1 is present in anatomical compartments and bodily fluids. Most transmissions occur through sexual acts, making virus in semen the proximal source in male donors. We find three distinct relationships in comparing viral RNA populations between blood and semen in men with chronic HIV-1 infection, and we propose that the viral populations in semen arise by multiple mechanisms including: direct import of virus, oligoclonal amplification within the seminal tract, or compartmentalization. In addition, we find significant enrichment of six out of nineteen cytokines and chemokines in semen of both HIV-infected and uninfected men, and another seven further enriched in infected individuals. The enrichment of cytokines involved in innate immunity in the seminal tract, complemented with chemokines in infected men, creates an environment conducive to T cell activation and viral replication. These studies define different relationships between virus in blood and semen that can significantly alter the composition of the viral population at the source that is most proximal to the transmitted virus

Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence

background: Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder in women of reproductive age. Although patients with PCOS are typically characterized by increased numbers of oocytes retrieved during IVF, they are often of poor quality, leading to lower fertilization, cleavage and implantation rates, and a higher miscarriage rate. methods: For this review, we searched the database MEDLINE (1950 to January 2010) and Google for all full texts and/or abstract articles published in English with content related to oocyte maturation and embryo developmental competence. results: The search showed that alteration of many factors may directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions, resulting in a lower pregnancy rate in patients with PCOS. The extra-ovarian factors identified included gonadotrophins, hyperandrogenemia and hyperinsulinemia, although intra-ovarian factors included members of the epidermal, fibroblast, insulin-like and neurotrophin families of growth factors, as well as the cytokines. conclusions: Any abnormality in the extra- and/or intra-ovarian factors may negatively affect the granulosa cell-oocyte interaction, oocyte maturation and potential embryonic developmental competence, contributing to unsuccessful outcomes for patients with PCOS who are undergoing assisted reproduction.Obstetrics &amp; GynecologyReproductive BiologySCI(E)PubMed49REVIEW117-331

The additional value of patient-reported health status in predicting 1-year mortality after invasive coronary procedures: A report from the Euro Heart Survey on Coronary Revascularisation

Objective: Self-perceived health status may be helpful in identifying patients at high risk for adverse outcomes. The Euro Heart Survey on Coronary Revascularization (EHS-CR) provided an opportunity to explore whether impaired health status was a predictor of 1-year mortality in patients with coronary artery disease (CAD) undergoing angiographic procedures. Methods: Data from the EHS-CR that included 5619 patients from 31 member countries of the European Society of Cardiology were used. Inclusion criteria for the current study were completion of a self-report measure of health status, the EuroQol Questionnaire (EQ-5D) at discharge and information on 1-year follow-up, resulting in a study population of 3786 patients. Results: The 1-year mortality was 3.2% (n = 120). Survivors reported fewer problems on the five dimensions of the EQ-5D as compared with non-survivors. A broad range of potential confounders were adjusted for, which reached a p<0.10 in the unadjusted analyses. In the adjusted analyses, problems with self-care (OR 3.45; 95% CI 2.14 to 5.59) and a low rating (≤ 60) on health status (OR 2.41; 95% CI 1.47 to 3.94) were the most powerful independent predictors of mortality, among the 22 clinical variables included in the analysis. Furthermore, patients who reported no problems on all five dimensions had significantly lower 1-year mortality rates (OR 0.47; 95% CI 0.28 to 0.81). Conclusions: This analysis shows that impaired health status is associated with a 2-3-fold increased risk of all-cause mortality in patients with CAD, independent of other conventional risk factors. These results highlight the importance of including patients' subjective experience of their own health status in the evaluation strategy to optimise risk stratification and management in clinical practice