Tyrosine Phosphorylation and Structural Requirements Mediate Toll-Like Receptor 9 Function

Upon invasion of microbial pathogens, cells of the innate immune system respond through the activation of pattern recognition receptors (PRRs) that recognize pattern associated molecular patterns (PAMPs). Once these receptors bind ligand, they initiate a signaling cascade culminating in the expression of proinflammatory and antiviral cytokines, costimulatory molecules, and antimicrobial agents, all of which contribute to pathogen clearance and host defense. However, excessive signaling through these receptors can lead to inflammatory conditions resulting in damage to the host. Therefore, understanding the signaling events downstream of PRR activation is critical for gaining insight into targeting specific mediators for therapeutic intervention to combat infection and to limit host pathology. Canonically, Toll-like receptors (TLRs), one class of PRR, have been thought to signal through serine threonine kinases following ligand recognition. However, there is emerging evidence for the role of protein tyrosine kinases regulating TLR function, but their role is not entirely clear. We sought to understand how TLR9 function is affected by a conserved tyrosine residue in its cytoplasmic domain and by activation of the protein tyrosine kinase Syk. We initially hypothesized that Syk might be participating in tyrosine phosphorylation of TLR9 to induce downstream signaling following receptor activation with CpG DNA. Utilizing genetic deletion of Syk in dendritic cells in vivo and genetic knockdown in a macrophage cell line, here we demonstrate that Syk is important for the intracellular trafficking and exocytosis of the proinflammatory cytokine TNFa, but not IL-6, following CpG stimulation. This secretion event involved activation of calcium signaling and calcium calmodulin kinase II (CaMKII) downstream of Syk. Syk-deficient cells exhibited normal CpG-induced activation of the canonical TLR9 signaling machinery, suggesting that Syk mediates a signaling cascade to promote cytokine exocytosis independent of cytokine transcription and translation, a role unexpected based on its function downstream of ITAM-bearing receptors. These data implicate this signaling pathway in a novel role of cytokine sorting and may have broader implications for release of other cytokines downstream of various pattern recognition receptors

BAICE Thematic Forum:Challenging deficit discourses in international education and development

Research and policy in international education has o en been framed in terms of a deficit discourse. For instance, policy debates on women’s literacy and education have begun by positioning women as a group who need to ‘catch up’ on certain skills in order to become more active in development. Rather than recognising the skills and knowledge that participants already have and prac se in their everyday lives, researchers who adopt this deficit perspective on learning and education may find that the research agenda and questions will already be shaped to a large extent by the providers’/ policy makers’ standpoint. This BAICE Thematic Forum aimed to deepen understanding around how deficit discourses have shaped the questions and objectives of international educational research. As well as deconstructing and gaining greater knowledge into why and how these dominant deficit discourses have influenced the research agenda, we also set out to investigate and propose alternative conceptual models through two linked seminars. The seminars were intended to explore and challenge dominant deficit discourses that have shaped the way researchers/policy makers look at specific groups in development and thematic policy areas

Dialoguer avec la radio

On croit souvent que la radio est un média unidirectionnel ; African Farm Radio Research Initiative cherche au contraire à utiliser les TIC pour recueillir du contenu et diffuser ces informations aux communautés agricoles de toute l'Afrique rurale

Talking back to radio

Radio is often considered to be a one-way medium, but the African Farm Radio Research Initiative is investigating ways of combining radio and ICTs to gather content and to share information among farming communities throughout rural Africa

Interactive radio’s promising role in climate information services: Farm Radio International concept paper

This paper focuses on how interactive radio programming can increase the reach of weather and seasonal climate information and related advisory services. In doing so, they can enhance small-scale farmers’ capacity to make optimal decisions and manage risks based on a better understanding of probabilistic seasonal forecasts. The objective is to outline strategy that could vastly and affordably expand the number of small-scale farmers that are reached by and benefit from weather and climate information and related advisory services. Building on Farm Radio International’s (FRI) pioneering African Farm Radio Research Initiative (AFRRI), we assess the opportunities for interactive radio to provide integrated climate and advisory information while increasing farmers’ equitable access to salient and legitimate programming. We describe a number of practical strategies that can be used to make radio-based climate communication interactive, outline elements of a successful interactive radio service targeting rural communities, and discuss costs and other issues required for sustainability

International development volunteering as transformational feminist practice for gender equality

Abstract: International and transnational commitments to gender equality require strategies that tackle root causes and prevailing attitudes that perpetuate disparities. In this article, we examine the role and impact of international development volunteers (IDV) as development actors who are well-placed for feminist transformational change, as they work in transnational spaces to influence, support, or reinforce changes in attitudes and behaviors towards gender equality and women’s empowerment (GEWE). This qualitative study analyses data collected from 45 interviews in three countries (Malawi, Kenya and Uganda) to document partner organization perspectives on relational dynamics emerging from interactions with IDVs. Partner organization staff highlighted several notable positive and negative contributions to GEWE outcomes arising from day-to-day interactions with IDVs. These interactions shaped their understandings of GEWE, enhanced confidence for GEWE programming, and provided exposure to role models who can shape alternative attitudes and behaviors to gender equality. While the study revealed varying degrees of challenges and benefits for partner organizations working with volunteers specifically on gender equality, partner organization staff highlighted contributions made by IDVs to transnational spatial relations, as well as the transformational interactions that shaped these relations. Insights provided by partner country staff members offer subaltern perspectives and rich insights into the contributions of IDVs in gender equality programming and shed new light on the challenges and opportunities for fostering transnational feminist spaces of knowledge sharing, relationship building, and alternative practices

Delivering climate services for farmers and pastoralists through interactive radio

A scoping study to assess demand, opportunities and potential for the use of interactive radio to deliver climate services at scale for farmers and pastoralists was conducted by CCAFS in partnership with Farm Radio International in Tanzania, and Farm Radio Trust in Malawi in late 2014. Over 1280 individuals were interviewed in an audience research activity, while a desk survey, key informant interviews and knowledge partner engagement activities were undertaken to validate audience research and assess the wider context. The study reveals that for both Malawi and Tanzania, there is clear demand for climate information services via radio and mobile phone. Both radio and mobile phones are in common use, and are rated by farmers and pastoralists to have great potential as effective and trusted channels where they can access various climate information services. Surveyed farmers and pastoralists noted that radio programs, backed up by ICT services, would serve them best. Rainfall patterns, temperature data and forecasting services – both weekly and daily – were mentioned as particular needs. In general, farmers would trust climate information received via their preferred radio stations, and would use it in decision-making on their farms. Women and men differed in time spent listening to radio, in mobile phone airtime purchased, and in Malawi, phone ownership; but larger location differences masked any gender differences in preferences about information content, delivery channels, or expectations about user and benefit. As a response to farmer articulated demand, Farm Radio International and Farm Radio Trust propose working with key institutions and radio station partners to develop interactive programming for rural climate services as part of their implementation of the GFCS Adaptation Programme in Africa. Interactive climate services radio programming would respond to farmers’ ongoing climate information needs, and will engage them in program design, broadcast, monitoring and evaluation – together with partner radio stations. Interactive climate services radio programming will consist of short weekly radio programs, with the option of daily forecasts or interpretations, and will be complemented with ICT services via mobile phone. Programs will be continuously monitored and assessed by audiences and project staff to ensure relevance, usefulness, level of use and accuracy

Large-scale antibody immune response mapping of splenic B cells and bone marrow plasma cells in a transgenic mouse model

Molecular characterization of antibody immunity and human antibody discovery is mainly carried out using peripheral memory B cells, and occasionally plasmablasts, that express B cell receptors (BCRs) on their cell surface. Despite the importance of plasma cells (PCs) as the dominant source of circulating antibodies in serum, PCs are rarely utilized because they do not express surface BCRs and cannot be analyzed using antigen-based fluorescence-activated cell sorting. Here, we studied the antibodies encoded by the entire mature B cell populations, including PCs, and compared the antibody repertoires of bone marrow and spleen compartments elicited by immunization in a human immunoglobulin transgenic mouse strain. To circumvent prior technical limitations for analysis of plasma cells, we applied single-cell antibody heavy and light chain gene capture from the entire mature B cell repertoires followed by yeast display functional analysis using a cytokine as a model immunogen. We performed affinity-based sorting of antibody yeast display libraries and large-scale next-generation sequencing analyses to follow antibody lineage performance, with experimental validation of 76 monoclonal antibodies against the cytokine antigen that identified three antibodies with exquisite double-digit picomolar binding affinity. We observed that spleen B cell populations generated higher affinity antibodies compared to bone marrow PCs and that antigen-specific splenic B cells had higher average levels of somatic hypermutation. A degree of clonal overlap was also observed between bone marrow and spleen antibody repertoires, indicating common origins of certain clones across lymphoid compartments. These data demonstrate a new capacity to functionally analyze antigen-specific B cell populations of different lymphoid organs, including PCs, for high-affinity antibody discovery and detailed fundamental studies of antibody immunity

The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins

Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers