Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses

Hard ticks subvert the immune responses of their vertebrate hosts in order to feed for much longer periods than other blood-feeding ectoparasites; this may be one reason why they transmit perhaps the greatest diversity of pathogens of any arthropod vector. Tick-induced immunomodulation is mediated by salivary components, some of which neutralise elements of innate immunity or inhibit the development of adaptive immunity. As dendritic cells (DC) trigger and help to regulate adaptive immunity, they are an ideal target for immunomodulation. However, previously described immunoactive components of tick saliva are either highly promiscuous in their cellular and molecular targets or have limited effects on DC. Here we address the question of whether the largest and globally most important group of ticks (the ixodid metastriates) produce salivary molecules that specifically modulate DC activity. We used chromatography to isolate a salivary gland protein (Japanin) from Rhipicephalus appendiculatus ticks. Japanin was cloned, and recombinant protein was produced in a baculoviral expression system. We found that Japanin specifically reprogrammes DC responses to a wide variety of stimuli in vitro, radically altering their expression of co-stimulatory and co-inhibitory transmembrane molecules (measured by flow cytometry) and their secretion of pro-inflammatory, anti-inflammatory and T cell polarising cytokines (assessed by Luminex multiplex assays); it also inhibits the differentiation of DC from monocytes. Sequence alignments and enzymatic deglycosylation revealed Japanin to be a 17.7 kDa, N-glycosylated lipocalin. Using molecular cloning and database searches, we have identified a group of homologous proteins in R. appendiculatus and related species, three of which we have expressed and shown to possess DC-modulatory activity. All data were obtained using DC generated from at least four human blood donors, with rigorous statistical analysis. Our results suggest a previously unknown mechanism for parasite-induced subversion of adaptive immunity, one which may also facilitate pathogen transmission

Working toward precision medicine: Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges

Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype–phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype–phenotype relationships

DiCE: A cooperative card game for investigating multimodal accommodation

We introduce a cooperative game to elicit lexically and prosodically controlled speech material in a naturalistic and engaging setting

Characteristics and heterogeneity of schizoaffective disorder compared with unipolar depression and schizophrenia - a systematic literature review and meta-analysis

Background: Comparisons of illness characteristics between patients with schizoaffective disorder (SAD) patients and unipolar depression (UD) are rare, even though UD is one of the most important differential diagnoses of SAD. Also, the variability of illness characteristics (heterogeneity) has not been compared. We compared illness characteristics and their heterogeneity among SAD, UD, and - as another important differential diagnosis - schizophrenia (S). Methods: In order to reduce sampling bias we systematically searched for studies simultaneously comparing samples of patients with SAD, UD, and S. Using random effects and Mantel-Haenszel models we estimated and compared demographic, illness course and psychopathology parameters, using pooled standard deviations as a measurement of heterogeneity. Results: Out of 155 articles found by an earlier meta-analysis, 765 screened in Medline, 2738 screened in EMBASE, and 855 screened in PsycINFO we selected 24 studies, covering 3714 patients diagnosed according to RDC, DSM-III, DSM-IIIR, DSM-IV, or ICD-10. In almost all key characteristics, samples with schizoaffective disorders fell between unipolar depression and schizophrenia, with a tendency towards schizophrenia. On average, UD patients were significantly older at illness onset (33.0 years, SAD: 25.2, S: 23.4), more often women (59% vs. 57% vs. 39%) and more often married (53% vs. 39% vs. 27%). Their psychopathology was also less severe, as measured by BPRS, GAS, and HAMD. In demographic and clinical variables heterogeneity was roughly 5% larger in UD than in SAD, and samples of patients with schizophrenia had the lowest pooled heterogeneity. A similar picture emerged in a sensitivity analysis with coefficient of variation as the measurement of heterogeneity. Limitations: Relative to bipolar disorder there are fewer studies including unipolar patients. No studies based on DSM-5 could be included. Conclusions: Regarding unipolar affective disorder this study confirms what we have shown for bipolar disorders in earlier studies: schizoaffective disorder falls between schizophrenia and affective disorders, and there are relevant quantitative differences in key illness characteristics, which supports the validity of the schizoaffective disorder concept. Contrary to our expectations heterogeneity is not larger in SAD than in UD and not substantially higher than in S. Lower reliability of the diagnosis of SAD therefore cannot be ascribed to higher variability of illness characteristics in SAD. (C) 2015 Elsevier B.V. All rights reserved

The association of mannose-binding lectin 2 polymorphisms with outcome in very low birth weight infants.

Studies on the influence of mannose-binding lectin (MBL) deficiency on infection susceptibility in preterm infants have yielded controversial results. We investigated the association of genotype-based MBL levels with outcome in very-low-birth weight infants (VLBWI).We genotyped 3 genetic variants of MBL2 (rs1800450, rs1800451, rs5030737) in 6878 VLBWI. MBL plasma levels were categorized as normal (wild type, A/A), low (heterozygotes, A/O) or undetectable (homozygotes, O/O). Primary outcome was the effect of genotype-based MBL2 levels on blood-culture proven and clinical sepsis during primary stay in hospital. We also evaluated burden of infection within 24 months after discharge.We found no association between MBL levels and sepsis risk in the whole cohort. Infants without measurable MBL levels born between 32 0/7 to 36 6/7 weeks of gestation, however, had a higher rate of Gram-negative sepsis than infants with normal or reduced MBL levels. In a follow-up investigation at 24 months (n = 1070 infants), infants without measurable MBL levels suffered more frequently from stomatitis and urinary tract infection.In a large cohort of VLBWI MBL2 deficiency had no major impact on infection risk unless children were born between 32 0/7 and 36 6/7 weeks of gestation

The association of mannose-binding lectin 2 polymorphisms with outcome in very low birth weight infants

<div><p>Objectives</p><p>Studies on the influence of mannose-binding lectin (MBL) deficiency on infection susceptibility in preterm infants have yielded controversial results. We investigated the association of genotype-based MBL levels with outcome in very-low-birth weight infants (VLBWI).</p><p>Methods</p><p>We genotyped 3 genetic variants of MBL2 (rs1800450, rs1800451, rs5030737) in 6878 VLBWI. MBL plasma levels were categorized as normal (wild type, A/A), low (heterozygotes, A/O) or undetectable (homozygotes, O/O). Primary outcome was the effect of genotype-based MBL2 levels on blood-culture proven and clinical sepsis during primary stay in hospital. We also evaluated burden of infection within 24 months after discharge.</p><p>Results</p><p>We found no association between MBL levels and sepsis risk in the whole cohort. Infants without measurable MBL levels born between 32 0/7 to 36 6/7 weeks of gestation, however, had a higher rate of Gram-negative sepsis than infants with normal or reduced MBL levels. In a follow-up investigation at 24 months (n = 1070 infants), infants without measurable MBL levels suffered more frequently from stomatitis and urinary tract infection.</p><p>Conclusions</p><p>In a large cohort of VLBWI MBL2 deficiency had no major impact on infection risk unless children were born between 32 0/7 and 36 6/7 weeks of gestation.</p></div