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

The human FK506-binding proteins: characterization of human FKBP19

Analysis of the human repertoire of the FK506-binding protein (FKBP) family of peptidyl-prolyl cis/trans isomerases has identified an expansion of genes that code for human FKBPs in the secretory pathway. There are distinct differences in tissue distribution and expression levels of each variant. In this article we describe the characterization of human FKBP19 (Entrez Gene ID: FKBP11), an FK506-binding protein predominantly expressed in vertebrate secretory tissues. The FKBP19 sequence comprises a cleavable N-terminal signal sequence followed by a putative peptidyl-prolyl cis/trans isomerase domain with homology to FKBP12. This domain binds FK506 weakly in vitro. FKBP19 mRNA is abundant in human pancreas and other secretory tissues and high levels of FKBP19 protein are detected in the acinar cells of mouse pancreas

Khat use as risk factor for psychotic disorders: A cross-sectional and case-control study in Somalia

BACKGROUND: Little is known about the prevalence of khat-induced psychotic disorders in East African countries, where the chewing of khat leaves is common. Its main psycho-active component cathinone produces effects similar to those of amphetamine. We aimed to explore the prevalence of psychotic disorders among the general population and the association between khat use and psychotic symptoms. METHODS: In an epidemiological household assessment in the city of Hargeisa, North-West Somalia, trained local interviewers screened 4,854 randomly selected persons from among the general population for disability due to severe mental problems. The identified cases were interviewed based on a structured interview and compared to healthy matched controls. Psychotic symptoms were assessed using the items of the WHO Composite International Diagnostic Interview and quantified with the Positive and Negative Symptoms Scale. Statistical testing included Student's t-test and ANOVA. RESULTS: Local interviewers found that rates of severe disability due to mental disorders were 8.4% among males (above the age of 12) and differed according to war experiences (no war experience: 3.2%; civilian war survivors: 8.0%; ex-combatants: 15.9%). The clinical interview verified that in 83% of positive screening cases psychotic symptoms were the most prominent manifestations of psychiatric illness. On average, cases with psychotic symptoms had started to use khat earlier in life than matched controls and had been using khat 8.6 years before positive symptoms emerged. In most cases with psychotic symptoms, a pattern of binge use (> two 'bundles' per day) preceded the onset of psychotic symptoms, in contrast to controls of the same age. We found significant correlations between variables of khat consumption and clinical scales (0.35 to 0.50; p < 0.05), and between the age of onset of khat chewing and symptom onset (0.70; p <0.001). CONCLUSION: Evidence indicates a relationship between the consumption of khat and the onset of psychotic symptoms among the male population, whereby not the khat intake per se but rather early onset and excessive khat chewing seemed to be related to psychotic symptoms. The khat problem must be addressed by means other than prohibition, given the widespread use and its role in Somali culture

Evaluating the implementation and impact of a new model of care for integrating children and young people's acute mental healthcare in a paediatric setting: A protocol for a realist, mixed-methods approach

Mental health protocolCopyright information © Author(s) (or their employer(s)) 2023. Introduction: The mental health of children and young people in the UK has been declining and has continued to worsen throughout the pandemic, leading to an increase in mental health-related emergencies. In response, the Best for You programme was developed as a new service designed to integrate mental healthcare for children and young people between acute hospital and community services. The programme is comprised of four new services: a rapid assessment young people’s centre with dual-trained staff, a co-located day service offering family-based care,a digital hub, designed to integrate with the fourth element of the model, namely community support and mental health services. This evaluation protocol aims to assess the development, implementation and outcomes of the Best for You programme and develops a scalable model that could be implemented in other parts of the National Health Service (NHS). Methods and analysis: This mixed-methods realist evaluation aims to delineate the components of the system to assess their interdependent relationships within a wider context. Data collection will include interviews, participant observations, focus groups and the collection of local quantitative healthcare data. The research will be conducted across four phases. Phase 1—captures the development of the underlying programme theory. Phase 2—a process evaluation testing the programme theory. Phase 3— an outcome and economic evaluation. Phase 4—consolidation of learning from phases 1–3 to identify barriers, facilitators and wider contextual factors that have shaped implementation drawing on the Consolidated Framework for Implementation Research. Ethics and dissemination:: Ethical approval for the evaluation was received from the NHS local ethics committee. Embedded within the evaluation is a formative review to feedback and share learning with stakeholders to scale-up the programme. Findings from this study will be disseminated in peer-reviewed journals as well as presentations o be useful to service user organisations and networks.The National Institute for Health and Care Research Applied Research Collaboration Northwest London; CW+ Charity

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

From Interactive Open Learner Modelling to Intelligent Mentoring: STyLE-OLM and Beyond

STyLE-OLM (Dimitrova 2003 International Journal of Artificial Intelligence in Education, 13, 35–78) presented a framework for interactive open learner modelling which entails the development of the means by which learners can inspect, discuss and alter the learner model that has been jointly constructed by themselves and the system. This paper outlines the STyLE-OLM framework and reflects on the key challenges it addressed: (a) the design of an appropriate communication medium; this was addressed by proposing a structured language using diagrammatic presentations of conceptual graphs; (b) the management of the interaction with the learner; this was addressed by designing a framework for interactive open learner modelling dialogue utilising dialogue games; (c) the accommodation of different beliefs about the learner’s domain model; this was addressed with a mechanism for maintaining different views about the learner beliefs which adapted belief modal logic operators; and (d) the assessment of any resulting improvements in learner model accuracy and learner reflection; this was addressed in a user study with an instantiation of STyLE-OLM for diagnosing a learner’s knowledge of finance concept, as part of a larger project that developed an intelligent system to assist with learning domain terminology in a foreign language. Reviewing follow on work, we refer to projects by the authors’ students and colleagues leading to further extension and adoption of STyLE-OLM, as well as relevant approaches in open learner modelling which have cited the STyLE-OLM framework. The paper points at outstanding research challenges and outlines future a research direction to extend interactive open learner modelling towards mentor-like intelligent learning systems

A novel malaria vaccine candidate antigen expressed in Tetrahymena thermophila

Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens

The p12 Domain Is Unstructured in a Murine Leukemia Virus p12-CAN Gag Construct

The Gag polyproteins of gammaretroviruses contain a conserved p12 domain between MA and CA that plays critical roles in virus assembly, reverse transcription and nuclear integration. Here we show using nuclear magnetic resonance, that p12 is unstructured in a Moloney murine leukemia virus (MMLV) Gag fragment that includes the N-terminal domain of CA (p12-CAN). Furthermore, no long range interactions were observed between the domains, as has been previously predicted. Flexibility appears to be a common feature of Gag “late” domains required for virus release during budding. Residues near the N-terminus of CAN that form a β-hairpin in the mature CA protein are unfolded in p12-CAN, consistent with proposals that hairpin formation helps trigger capsid assembly

Mayday SeaSight: Combined Analysis of Deep Sequencing and Microarray Data

Recently emerged deep sequencing technologies offer new high-throughput methods to quantify gene expression, epigenetic modifications and DNA-protein binding. From a computational point of view, the data is very different from that produced by the already established microarray technology, providing a new perspective on the samples under study and complementing microarray gene expression data. Software offering the integrated analysis of data from different technologies is of growing importance as new data emerge in systems biology studies. Mayday is an extensible platform for visual data exploration and interactive analysis and provides many methods for dissecting complex transcriptome datasets. We present Mayday SeaSight, an extension that allows to integrate data from different platforms such as deep sequencing and microarrays. It offers methods for computing expression values from mapped reads and raw microarray data, background correction and normalization and linking microarray probes to genomic coordinates. It is now possible to use Mayday's wealth of methods to analyze sequencing data and to combine data from different technologies in one analysis