Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex.

Pathogen recognition by nucleotide-binding oligomerization domain-like receptor (NLR) results in the formation of a macromolecular protein complex (inflammasome) that drives protective inflammatory responses in the host. It is thought that the number of inflammasome complexes forming in a cell is determined by the number of NLRs being activated, with each NLR initiating its own inflammasome assembly independent of one another; however, we show here that the important foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) simultaneously activates at least two NLRs, whereas only a single inflammasome complex is formed in a macrophage. Both nucleotide-binding domain and leucine-rich repeat caspase recruitment domain 4 and nucleotide-binding domain and leucine-rich repeat pyrin domain 3 are simultaneously present in the same inflammasome, where both NLRs are required to drive IL-1β processing within the Salmonella-infected cell and to regulate the bacterial burden in mice. Superresolution imaging of Salmonella-infected macrophages revealed a macromolecular complex with an outer ring of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain and an inner ring of NLRs, with active caspase effectors containing the pro-IL-1β substrate localized internal to the ring structure. Our data reveal the spatial localization of different components of the inflammasome and how different members of the NLR family cooperate to drive robust IL-1β processing during Salmonella infection.S.M.M was supported by a Cambridge International Scholarship. T.P.M was supported by a Wellcome Trust Research Career Development Fellowship (WT085090MA). This study was supported by Biotechnology and Biological Sciences Research Council (BBSRC) grants (BB/H003916/1 and BB/K006436/1) and a BBSRC Research Development Fellowship (BB/H021930/1) awarded to C.E.B.http://www.pnas.org/content/early/2014/05/05/1402911111.abstrac

Superfluid toroidal currents in atomic condensates

The dynamics of toroidal condensates in the presence of condensate flow and dipole perturbation have been investigated. The Bogoliubov spectrum of condensate is calculated for an oblate torus using a discrete-variable representation and a spectral method to high accuracy. The transition from spheroidal to toroidal geometry of the trap displaces the energy levels into narrow bands. The lowest-order acoustic modes are quantized with the dispersion relation $\omega \sim |m| \omega_s$ with $m=0,\pm 1,\pm 2, ...$. A condensate with toroidal current $\kappa$ splits the $|m|$ co-rotating and counter-rotating pair by the amount: $\Delta E \approx 2 |m|\hbar^2 \kappa < r^{-2}>$. Radial dipole excitations are the lowest energy dissipation modes. For highly occupied condensates the nonlinearity creates an asymmetric mix of dipole circulation and nonlinear shifts in the spectrum of excitations so that the center of mass circulates around the axis of symmetry of the trap. We outline an experimental method to study these excitations.Comment: 8 pages, 8 figure

Validity of a three-variable juvenile arthritis disease activity score in children with new-onset juvenile idiopathic arthritis

&lt;p&gt;Objectives To investigate the validity and feasibility of the Juvenile Arthritis Disease Activity Score (JADAS) in the routine clinical setting for all juvenile idiopathic arthritis (JIA) disease categories and explore whether exclusion of the erythrocyte sedimentation rate (ESR) from JADAS (the ‘JADAS3’) influences correlation with single markers of disease activity.&lt;/p&gt; &lt;p&gt;Methods JADAS-71, JADAS-27 and JADAS-10 were determined at baseline for an inception cohort of children with JIA in the Childhood Arthritis Prospective Study. JADAS3-71, JADAS3-27 and JADAS3-10 were determined using an identical formula but with exclusion of ESR. Correlation of JADAS with JADAS3 and single measures of disease activity/severity were determined by category.&lt;/p&gt; &lt;p&gt;Results Of 956 eligible children, sufficient data were available to calculate JADAS-71, JADAS-27 and JADAS-10 at baseline in 352 (37%) and JADAS3 in 551 (58%). The median (IQR) JADAS-71, JADAS-27 and JADAS-10 for all 352 children was 11 (5.9–18), 10.4 (5.7–17) and 11 (5.9–17.3), respectively. Median JADAS and JADAS3 varied significantly with the category (Kruskal–Wallis p=0.0001), with the highest values in children with polyarticular disease patterns. Correlation of JADAS and JADAS3 across all categories was excellent. Correlation of JADAS71 with single markers of disease activity/severity was good to moderate, with some variation across the categories. With the exception of ESR, correlation of JADAS3-71 was similar to correlation of JADAS-71 with the same indices.&lt;/p&gt; &lt;p&gt;Conclusions This study is the first to apply JADAS to all categories of JIA in a routine clinical setting in the UK, adding further information about the feasibility and construct validity of JADAS. For the majority of categories, clinical applicability would be improved by exclusion of the ESR.&lt;/p&gt

Secular trends in reported portion size of food and beverages consumed by Irish adults

The present analysis aimed to investigate the changes in the reported portion sizes (PS) of foods and beverages commonly consumed by Irish adults (18–64 years) from the North South Ireland Food Consumption Survey (NSIFCS) (1997–2001) and the National Adult Nutrition Survey (NANS) (2008–10). Food PS, which are defined as the weight of food (g) consumed per eating occasion, were calculated for comparable foods and beverages in two nationally representative cross-sectional Irish food consumption surveys and were published in NSIFCS and NANS. Repeated measure mixed model analysis compared reported food PS at the total population level as well as subdivided by sex, age, BMI and social class. A total of thirteen commonly consumed foods were examined. The analysis demonstrated that PS significantly increased for five foods (‘white sliced bread’, ‘brown/wholemeal breads’, ‘all meat, cooked’, ‘poultry, roasted’ and ‘milk’), significantly decreased for three (‘potatoes’, ‘chips/wedges’ and ‘ham, sliced’) and did not significantly change for five foods (‘processed potato products’, ‘bacon/ham’, ‘cheese’, ‘yogurt’ and ‘butter/spreads’) between the NSIFCS and the NANS. The present study demonstrates that there was considerable variation in the trends in reported food PS over this period

Nutrition policy: developing scientific recommendations for food-based dietary guidelines for older adults living independently in Ireland

Older adults (≥65 years) are the fastest growing population group. Thus, ensuring nutritional well-being of the ‘over-65s’ to optimise health is critically important. Older adults represent a diverse population – some are fit and healthy, others are frail and many live with chronic conditions. Up to 78% of older Irish adults living independently are overweight or obese. The present paper describes how these issues were accommodated into the development of food-based dietary guidelines for older adults living independently in Ireland. Food-based dietary guidelines previously established for the general adult population served as the basis for developing more specific recommendations appropriate for older adults. Published international reports were used to update nutrient intake goals for older adults, and available Irish data on dietary intakes and nutritional status biomarkers were explored from a population-based study (the National Adult Nutrition Survey; NANS) and two longitudinal cohorts: the Trinity-Ulster and Department of Agriculture (TUDA) and the Irish Longitudinal Study on Ageing (TILDA) studies. Nutrients of public health concern were identified for further examination. While most nutrient intake goals were similar to those for the general adult population, other aspects were identified where nutritional concerns of ageing require more specific food-based dietary guidelines. These include, a more protein-dense diet using high-quality protein foods to preserve muscle mass; weight maintenance in overweight or obese older adults with no health issues and, where weight-loss is required, that lean tissue is preserved; the promotion of fortified foods, particularly as a bioavailable source of B vitamins and the need for vitamin D supplementation

Disease activity and disability in children with juvenile idiopathic arthritis one year following presentation to paediatric rheumatology. Results from the Childhood Arthritis Prospective Study

Objective. Inflammatory arthritis in childhood is variable in terms of both presentation and outcome. This analysis describes disease activity in children with juvenile idiopathic arthritis (JIA) during the first year following presentation to a paediatric rheumatologist and identifies predictors of moderate to severe disability [defined using a Childhood HAQ (CHAQ) score ⩾0.75] at 1 year

Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment

From Wiley via Jisc Publications RouterHistory: received 2021-04-29, rev-recd 2021-06-23, accepted 2021-07-15, pub-electronic 2021-07-26Article version: VoRPublication status: PublishedAbstract: Introduction: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. Aim: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. Methods: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post‐treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. Results: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). Conclusion: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia