Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI2

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses

Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI2

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host byinhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison showsthatthisoverlapswiththebindingsiteonIL-33foritsreceptor,ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack thelargeloopfromCCP3arenotabletoblockIL-33-mediatedsignallingin a cell-based assay and in an in vivo female mousemodelofasthma.Thisshows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses

Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI2

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host byinhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison showsthatthisoverlapswiththebindingsiteonIL-33foritsreceptor,ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack thelargeloopfromCCP3arenotabletoblockIL-33-mediatedsignallingin a cell-based assay and in an in vivo female mousemodelofasthma.Thisshows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses

Tracking Salmonella-Specific CD4 T Cells In Vivo Reveals a Local Mucosal Response to a Disseminated Infection

AbstractA novel adoptive transfer system was used to track the fate of naive Salmonella-specific CD4 T cells in vivo. These cells showed signs of activation in the Peyer's patches as early as 3 hr after oral infection. The activated CD4 T cells then produced IL-2 and proliferated in the T cell areas of these tissues before migrating into the B cell-rich follicles. In contrast, Salmonella-specific CD4 T cells were not activated in the spleen and very few of these cells migrated to the liver, despite the presence of bacteria in both organs. These results show that the T cell response to pathogenic Salmonella infection is localized to the gut-associated lymphoid tissue and does not extend efficiently to the major sites of late infection

Setting things straight: a comparison of measures of saccade trajectory deviation

In eye movements, saccade trajectory deviation has often been used as a physiological operationalization of visual attention, distraction, or the visual system’s prioritization of different sources of information. However, there are many ways to measure saccade trajectories and to quantify their deviation. This may lead to noncomparable results and poses the problem of choosing a method that will maximize statistical power. Using data from existing studies and from our own experiments, we used principal components analysis to carry out a systematic quantification of the relationships among eight different measures of saccade trajectory deviation and their power to detect the effects of experimental manipulations, as measured by standardized effect size. We concluded that (1) the saccade deviation measure is a good default measure of saccade trajectory deviation, because it is somewhat correlated with all other measures and shows relatively high effect sizes for two well-known experimental effects; (2) more generally, measures made relative to the position of the saccade target are more powerful; and (3) measures of deviation based on the early part of the saccade are made more stable when they are based on data from an eyetracker with a high sampling rate. Our recommendations may be of use to future eye movement researchers seeking to optimize the designs of their studies

“Hang in there mama!”: The role of online parenting forums in maternal mental health

The perinatal period can be challenging and yet reluctance to disclose wellbeing concerns to health professionals is well documented. The current study sought to explore how women use online parenting forums to seek advice and support for maternal mental health concerns. Forum threads (n = 153) from a popular UK parenting website were analysed to explore postpartum mothers’ discussions about their maternal mental health. Through reflexive thematic analysis, four themes were generated: (1) Navigating the motherhood role: unprepared and overwhelmed; (2) ‘I’m struggling, but looking on here I know I’m no way alone!’; (3) Challenging feelings of failure: ‘it doesn’t make you a bad mother’; and (4) Forums facilitate help seeking. There were two main findings; first, forums may act as a potential solution to providing a supportive, reassuring community and safe space for disclosure around maternal mental health concerns. Furthermore, forums are beneficial in providing women with an honest, realistic view and expectation of motherhood, thus supporting their transition to parenthood. Consequently, forums could be utilised to inform training for healthcare professionals to understand disclosure barriers

"There are hundreds of thousands online waiting to hold your hand through difficult times”: experiences of using online parenting forums to support postpartum mental health and wellbeing.

Background and aims: Internet use in new mothers is common, with increasing numbers of women seeking support online in lieu of consulting health professionals. The current study sought to explore women’s experiences of using online parenting forums to seek advice and support for their maternal mental health. Although benefits of virtual support have previously been highlighted, little research has examined any potential harmful consequences of utilising online forum support for mental health concerns. Methods: New mothers (n=70) completed an online survey as a qualitative account of their motivations for, and experiences of, using online forums. Additionally, mothers were questioned about their experiences of healthcare professional support. Findings: Through reflexive thematic analysis, four themes were generated: (1) The value of shared experiences and empathy; (2) Forum dynamics – a double edged sword; (3) Contextual challenges and opportunities; and (4) Inconsistency of HCP support – the need for an instant solution. Findings emphasised the importance, and effectiveness, of this kind of virtual peer support that forums provide. For many, the responses indicated that forums have a great potential to foster an atmosphere of supportive and helpful feedback, creating a (self-reported) positive impact on postnatal mental health. However, the fact that some women experienced negative feedback led to feelings of motherhood failure on some occasions, and avoidance of posting through fear of negative responses. Conclusion and implications: These findings could inform future decisions made by both parenting website providers and healthcare professionals in making support for mothers more effective and accessible. These may include considerations around the integration of online and offline support services, and the potential increase in trained peer supporters working with mothers

Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development

Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS) effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo

The programming of sequences of saccades

Saccadic eye movements move the high-resolution fovea to point at regions of interest. Saccades can only be generated serially (i.e., one at a time). However, what remains unclear is the extent to which saccades are programmed in parallel (i.e., a series of such moments can be planned together) and how far ahead such planning occurs. In the current experiment, we investigate this issue with a saccade contingent preview paradigm. Participants were asked to execute saccadic eye movements in response to seven small circles presented on a screen. The extent to which participants were given prior information about target locations was varied on a trial-by-trial basis: participants were aware of the location of the next target only, the next three, five, or all seven targets. The addition of new targets to the display was made during the saccade to the next target in the sequence. The overall time taken to complete the sequence was decreased as more targets were available up to all seven targets. This was a result of a reduction in the number of saccades being executed and a reduction in their saccade latencies. Surprisingly, these results suggest that, when faced with a demand to saccade to a large number of target locations, saccade preparation about all target locations is carried out in paralle

The association between markers of tumour cell metabolism, the tumour microenvironment and outcomes in patients with colorectal cancer

Tumour cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumour microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I‐III CRC were utilised to assess tumour cell expression of MCT‐1, MCT‐2, LDH‐1 and LDH‐5 by immunohistochemistry. Expression levels were dichotomised and associations with tumour factors, the tumour microenvironment and survival analysed. Nuclear LDH‐5 associates with poor prognosis (HR 1.68 95% CI 0.99–2.84, p = 0.050) and trends toward increased tumour stroma percentage (TSP, p = 0.125). Cytoplasmic MCT‐2 also trends toward increased TSP (p = 0.081). When combined into a single score; nuclear LDH‐5 + TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27–5.35, p = 0.009), increased tumour budding (p = 0.002) and decreased stromal T‐lymphocytes (p = 0.014). Similarly, cytoplasmic MCT‐2 + TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31–4.11, p = 0.003), decreased necrosis (p = 0.039), and increased tumour budding (p = 0.004). The present study reports that the combination of TSP and nuclear LDH‐5 was significantly associated with survival, increased tumour budding, and decreased stromal T‐lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumour progression via modulation of tumour metabolism. Moreover, MCT‐2 and LDH‐5 may provide promising therapeutic targets for patients with stromal‐rich CRC