Rapid CD4⁺ T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9

Toll‐like receptors (TLRs) can recognize microbial patterns and utilize adaptor molecules, such as‐MyD88 or (TRIF TIR‐domain‐containing adapter‐inducing interferon‐β), to initiate downstream signaling that ultimately affects the initiation of adaptive immunity. In addition to this inflammatory role, TLR5 expression on dendritic cells can favor antigen presentation of flagellin peptides and thus increase the sensitivity of flagellin‐specific T‐cell responses in vitro and in vivo. Here, we examined the role of alternative signaling pathways that might regulate flagellin antigen presentation in addition to MyD88. These studies suggest a requirement for spleen tyrosine kinase, a noncanonical TLR‐signaling adaptor molecule, and its downstream molecule CARD9 in regulating the sensitivity of flagellin‐specific CD4⁺ T‐cell responses in vitro and in vivo. Thus, a previously unappreciated signaling pathway plays an important role in regulating the dominance of flagellin‐specific T‐cell responses

Indigenous knowledges and development: a postcolonial caution

As a result of the failure of formal top-down development, there has recently been increased interest in the possibilities of drawing upon the indigenous knowledges of those in the communities involved, in an attempt to produce more effective development strategies. The concept of indigenous knowledge calls for the inclusion of local voices and priorities, and promises empowerment through ownership of the process. However, there has been little critical examination of the ways in which indigenous knowledges have been included in the development process. Drawing upon postcolonial theory, this article suggests that indigenous knowledges are often drawn into development by both theorists and development institutions in a very limited way, failing to engage with other ways of perceiving development, and thus missing the possibility of devising more challenging alternatives

PI3Kγ is a molecular switch that controls immune suppression

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer1,2,3,4,5. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors1,2,3,4,5,6,7. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders

Bioactiviy of endosequence root repair material and bioaggregate

Aim To evaluate the bioactivity of Bioaggregate (BA), EndoSequence Root Repair Material (ERRM), and white ProRoot MTA. Methodology Sixty horizontal root sections with standardised canal spaces were divided randomly into 3 groups (n = 20) and filled with white ProRoot MTA (groups 1 and 2), BA (groups 3 and 4) or ERRM putty (groups 5 and 6). The specimens of groups 1, 3, and 5 (each of 10) were immersed in PBS for 1 week and those of groups 2, 4, and 6 (each of 10) for 2 months. After the experimental periods the specimens were processed for scanning electron microscopy (SEM) observations. Precipitation of apatite crystals on the surfaces of the cements and/or at the dentine-cement interface was evaluated and analysed elementally by energy dispersive X-ray (EDX) instrument. Results Analysis of specimens revealed various surface morphologies that were dependent on the material and immersion time in PBS. The formation of precipitates was observed on the surfaces of all materials at 1 week, which increased substantially over time. After 2 months, the surface of the cements was changed dramatically and consisted of a substantially greater amount of apatite aggregates. Interfacial layers in some areas of the dentine-cement interface were found only following 2 months of immersion. Precipitates on MTA revealed high peaks of Ca, Si, and O after 1 week of immersion; after 2 months high peaks of Ca, P, and O were present. Precipitates on BA and ERRM displayed high Ca, P, O peaks after both 1 week and 2 months. Conclusion Exposure of MTA, BA and ERRM to PBS resulted in precipitation of apatite crystalline structures that increased over time. This suggests that the tested materials are bioactive

PI3Kγ is a molecular switch that controls immune suppression.

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders