Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of ascaris reveals a novel fold and two discrete lipid-binding sites

Parasitic nematode worms cause serious health problems in humans and other animals. They can induce allergic-type immune responses, which can be harmful but may at the same time protect against the infections. Allergens are proteins that trigger allergic reactions and these parasites produce a type that is confined to nematodes, the nematode polyprotein allergens (NPAs). These are synthesized as large precursor proteins comprising repeating units of similar amino acid sequence that are subsequently cleaved into multiple copies of the allergen protein. NPAs bind small lipids such as fatty acids and retinol (Vitamin A) and probably transport these sensitive and insoluble compounds between the tissues of the worms. Nematodes cannot synthesize these lipids, so NPAs may also be crucial for extracting nutrients from their hosts. They may also be involved in altering immune responses by controlling the lipids by which the immune and inflammatory cells communicate. We describe the molecular structure of one unit of an NPA, the well-known ABA-1 allergen of Ascaris and find its structure to be of a type not previously found for lipid-binding proteins, and we describe the unusual sites where lipids bind within this structur

Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction

Background: This study was designed to investigate the association of the 894G>T polymorphism in the eNOS gene with risk of acute myocardial infarction (AMI), extent of coronary artery disease (CAD) on coronary angiography, and in-hospital mortality after AMI. Methods: We studied 1602 consecutive patients who were enrolled in the GEMIG study. The control group was comprised by 727 individuals, who were randomly selected from the general adult population. Results: The prevalence of the Asp298 variant of eNOS was not found to be significantly and independently associated with risk of AMI (RR = 1.08, 95%CI = 0.77–1.51, P = 0.663), extent of CAD on angiography (OR = 1.18, 95%CI = 0.63–2.23, P = 0.605) and in-hospital mortality (RR = 1.08, 95%CI = 0.29–4.04, P = 0.908). Conclusion: In contrast to previous reports, homozygosity for the Asp298 variant of the 894G>T polymorphism in the eNOS gene was not found to be associated with risk of AMI, extent of CAD and in-hospital mortality after AM

Initial experience of a large, self-expanding, and fully recapturable transcatheter aortic valve: The UK & Ireland Implanters' registry.

OBJECTIVES: The UK & Ireland Implanters' registry is a multicenter registry which reports on real-world experience with novel transcatheter heart valves. BACKGROUND: The 34 mm Evolut R transcatheter aortic valve is a self-expanding and fully recapturable transcatheter aortic valve, designed to treat patients with a large aortic annulus. METHODS: Between January 2017 and April 2018, clinical, procedural and 30-day outcome data were prospectively collected from all patients receiving the 34 mm Evolut R valve across 17 participating centers in the United Kingdom and Ireland. The primary efficacy outcome was the Valve Academic Research Consortium-2(VARC-2)-defined endpoint of device success. The primary safety outcome was the VARC-2-defined composite endpoint of early safety at 30 days. RESULTS: A total of 217 patients underwent attempted implant. Mean age was 79.5 ± 8.8 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.2% ± 3.4%. Iliofemoral access was used in 91.2% of patients. Device success was 79.7%. Mean gradient was 7.0 ± 4.6 mmHg and effective orifice area 2.0 ± 0.6 cm2 . Paravalvular regurgitation was more than mild in 7.2%. A new permanent pacemaker was implanted in 15.7%. Early safety was demonstrated in 91.2%. At 30 days, all-cause mortality was 3.2%, stroke 3.7%, and major vascular complication 2.3%. CONCLUSIONS: Real-world experience of the 34 mm Evolut R transcatheter aortic valve demonstrated acceptable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation

Btk regulates macrophage polarization in response to lipopolysaccharide

Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (−\−)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(−/−) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-κB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-κB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(−/−) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(−/−) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (−/−) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation

The relationship between appetite and food preferences in British and Australian children

Background: Appetitive traits and food preferences are key determinants of children’s eating patterns but it is unclear how these behaviours relate to one another. This study explores relationships between appetitive traits and preferences for fruits and vegetables, and energy dense, nutrient poor (noncore) foods in two distinct samples of Australian and British preschool children. Methods: This study reports secondary analyses of data from families participating in the British GEMINI cohort study (n = 1044) and the control arm of the Australian NOURISH RCT (n = 167). Food preferences were assessed by parent-completed questionnaire when children were aged 3–4 years and grouped into three categories; vegetables, fruits and noncore foods. Appetitive traits; enjoyment of food, food responsiveness, satiety responsiveness, slowness in eating, and food fussiness were measured using the Children’s Eating Behaviour Questionnaire when children were 16 months (GEMINI) or 3–4 years (NOURISH). Relationships between appetitive traits and food preferences were explored using adjusted linear regression analyses that controlled for demographic and anthropometric covariates. Results: Vegetable liking was positively associated with enjoyment of food (GEMINI; β = 0.20 ± 0.03, p < 0.001, NOURISH; β = 0.43 ± 0.07, p < 0.001) and negatively related to satiety responsiveness (GEMINI; β = -0.19 ± 0.03, p < 0.001, NOURISH; β = -0.34 ± 0.08, p < 0.001), slowness in eating (GEMINI; β = -0.10 ± 0.03, p = 0.002, NOURISH; β = -0.30 ± 0.08, p < 0.001) and food fussiness (GEMINI; β = −0.30 ± 0.03, p < 0.001, NOURISH; β = -0.60 ± 0.06, p < 0.001). Fruit liking was positively associated with enjoyment of food (GEMINI; β = 0.18 ± 0.03, p < 0.001, NOURISH; β = 0.36 ± 0.08, p < 0.001), and negatively associated with satiety responsiveness (GEMINI; β = −0.13 ± 0.03, p < 0.001, NOURISH; β = −0.24 ± 0.08, p = 0.003), food fussiness (GEMINI; β = -0.26 ± 0.03, p < 0.001, NOURISH; β = −0.51 ± 0.07, p < 0.001) and slowness in eating (GEMINI only; β = -0.09 ± 0.03, p = 0.005). Food responsiveness was unrelated to liking for fruits or vegetables in either sample but was positively associated with noncore food preference (GEMINI; β = 0.10 ± 0.03, p = 0.001, NOURISH; β = 0.21 ± 0.08, p = 0.010). Conclusion: Appetitive traits linked with lower obesity risk were related to lower liking for fruits and vegetables, while food responsiveness, a trait linked with greater risk of overweight, was uniquely associated with higher liking for noncore foods

Exploring perceptions of advertising ethics: an informant-derived approach

Whilst considerable research exists on determining consumer responses to pre-determined statements within numerous ad ethics contexts, our understanding of consumer thoughts regarding ad ethics in general remains lacking. The purpose of our study therefore is to provide a first illustration of an emic and informant-based derivation of perceived ad ethics. The authors use multi-dimensional scaling as an approach enabling the emic, or locally derived deconstruction of perceived ad ethics. Given recent calls to develop our understanding of ad ethics in different cultural contexts, and in particular within the Middle East and North Africa (MENA) region, we use Lebanon—the most ethically charged advertising environment within MENA—as an illustrative context for our study. Results confirm the multi-faceted and pluralistic nature of ad ethics as comprising a number of dimensional themes already salient in the existing literature but in addition, we also find evidence for a bipolar relationship between individual themes. The specific pattern of inductively derived relationships is culturally bound. Implications of the findings are discussed, followed by limitations of the study and recommendations for further research

The perceptions of social responsibility for community resilience to flooding: the impact of past experience, age, gender and ethnicity

Community resilience to flooding depends, to a large extent, on the participation of community members to take more responsibility for enhancing their own resilience. The perception of social responsibility (SR) which is argued to be one of the antecedents influencing individual’s willingness to undertake resilient behaviours can significantly contribute to community resilience through individual and collective actions. Understanding of factors influencing the perceptions of SR of individuals within community might help with developing strategies to increase the perceptions of SR. This research explores perceptions of SR in relation to flooding for householders and local businesses and establishes their relationships with experience of flooding and demographic factors of age, gender and ethnicity. The data were obtained via a questionnaire survey of three communities in Birmingham and one community in South East London, UK, three with experience of flooding and one without. A total of 414 responses were received and used in the multiple regression analysis. The analysis identified ‘experience of flooding’, ‘age’ and ‘South Asian’ ethnic group as significant variables, suggesting that older individuals from South Asian ethnic groups with previous experience of flooding are likely to be more socially responsible than others without these attributes

The effectiveness of psychosocial interventions for anxiety in children and adolescents with autism spectrum disorder:a systematic review and meta-analysis

Anxiety is a common problem in children and adolescents with autism spectrum disorder (ASD). This meta-analysis aimed to systematically evaluate the evidence for the use of psychosocial interventions to manage anxiety in this population. Cognitive behavioural therapy (CBT) was the primary intervention modality studied. A comprehensive systematic search and study selection process was conducted. Separate statistical analyses were carried out for clinician-, parent-, and self-reported outcome measures. Sensitivity analyses were conducted by removing any outlying studies and any studies that did not use a CBT intervention. A subgroup analysis was performed to compare individual and group delivery of treatment. Ten randomised control trials involving a total of 470 participants were included. The overall SMD was d = 1.05 (95 % CI 0.45, 1.65; z = 3.45, p = 0.0006) for clinician- reported outcome measures; d = 1.00 (95%CI 0.21, 1.80; z = 2.47, p = 0.01) for parent-reported outcome measures; and d = 0.65 (95%CI -0.10, 1.07; z = 1.63, p = 0.10) for self-reported outcome measures. Clinician- and parent-reported outcome measures showed that psychosocial interventions were superior to waitlist and treatment-as-usual control conditions at post-treatment. However, the results of self-reported outcome measures failed to reach significance. The sensitivity analyses did not significantly change these results and the subgroup analysis indicated that individual treatment was more effective than group treatment. The main limitations of this review were the small number of included studies as well as the clinical and methodological variability between studies

The COGs (context, object, and goals) in multisensory processing

Our understanding of how perception operates in real-world environments has been substantially advanced by studying both multisensory processes and “top-down” control processes influencing sensory processing via activity from higher-order brain areas, such as attention, memory, and expectations. As the two topics have been traditionally studied separately, the mechanisms orchestrating real-world multisensory processing remain unclear. Past work has revealed that the observer’s goals gate the influence of many multisensory processes on brain and behavioural responses, whereas some other multisensory processes might occur independently of these goals. Consequently, other forms of top-down control beyond goal dependence are necessary to explain the full range of multisensory effects currently reported at the brain and the cognitive level. These forms of control include sensitivity to stimulus context as well as the detection of matches (or lack thereof) between a multisensory stimulus and categorical attributes of naturalistic objects (e.g. tools, animals). In this review we discuss and integrate the existing findings that demonstrate the importance of such goal-, object- and context-based top-down control over multisensory processing. We then put forward a few principles emerging from this literature review with respect to the mechanisms underlying multisensory processing and discuss their possible broader implications