Viral inhibition of bacterial phagocytosis by human macrophages: redundant role of CD36

Macrophages are essential to maintaining lung homoeostasis and recent work has demonstrated that influenza-infected lung macrophages downregulate their expression of the scavenger receptor CD36. This receptor has also been shown to be involved in phagocytosis of Streptococcus pneumoniae, a primary agent associated with pneumonia secondary to viral infection. The aim of this study was to investigate the role of CD36 in the effects of viral infection on macrophage phagocytic function. Human monocyte-derived macrophages (MDM) were exposed to H3N2 X31 influenza virus, M37 respiratory syncytial virus (RSV) or UV-irradiated virus. No infection of MDM was seen upon exposure to UV-irradiated virus but incubation with live X31 or M37 resulted in significant levels of viral detection by flow cytometry or RT-PCR respectively. Infection resulted in significantly diminished uptake of S. pneumoniae by MDM and significantly decreased expression of CD36 at both the cell surface and mRNA level. Concurrently, there was a significant increase in IFN? gene expression in response to infection and we observed a significant decrease in bacterial phagocytosis (p = 0.031) and CD36 gene expression (p = 0.031) by MDM cultured for 24 h in 50IU/ml IFN?. Knockdown of CD36 by siRNA resulted in decreased phagocytosis, but this was mimicked by transfection reagent alone. When MDM were incubated with CD36 blocking antibodies no effect on phagocytic ability was observed. These data indicate that autologous IFN? production by virally-infected cells can inhibit bacterial phagocytosis, but that decreased CD36 expression by these cells does not play a major role in this functional deficiency

Encountering Berlant part one: Concepts otherwise

In Part 1 of ‘Encountering Berlant’, we encounter the promise and provocation of Lauren Berlant's work. In 1000-word contributions, geographers and others stay with what Berlant's thought offers contemporary human geography. They amplify an encounter with their work, demonstrating how a concept, idea, or style disrupts something, opens up a new possibility, or simply invites thinking otherwise. The encounters range across the incredible body of work Berlant left us with, from the ‘national sentimentality’ trilogy through to recent work on negativity. Varying in form and tone, the encounters exemplify and enact the inexhaustible plenitude of Berlant's thought: fantasy, the case, love, impasse, feel tanks, slow death, ellipses, gesture, attrition, intimate public, ambivalence, style. Part 2 of ‘Encountering Berlant’ focuses on Berlant's most influential concept: ‘cruel optimism’. Across these heterogeneous encounters, Berlant's enduring concern with the tensions and possibilities of relationality and how to enact better forms of common life shine through. These enduring concerns and Berlant's commitment to the incoherence and overdetermination of phenomena are summarised in the Introduction, which also explores how Berlant's work has been engaged with in geography. The result is a repository of what an encounter with Berlant's thought makes possible. Short Abstract Part 1 of ‘Encountering Berlant’ explores the promise and provocation of Lauren Berlant's work. Contributors amplify an encounter with Berlant's concepts, tones, and styles, drawing out their implications for understanding relationality and how to invent and live better ways of being in common. The result is a repository of what Berlant's thinking offers geographers

Encountering Berlant part 1: Concepts otherwise

In Part 1 of ‘Encountering Berlant’, we encounter the promise and provocation of Lauren Berlant's work. In 1000-word contributions, geographers and others stay with what Berlant's thought offers contemporary human geography. They amplify an encounter with their work, demonstrating how a concept, idea, or style disrupts something, opens up a new possibility, or simply invites thinking otherwise. The encounters range across the incredible body of work Berlant left us with, from the ‘national sentimentality’ trilogy through to recent work on negativity. Varying in form and tone, the encounters exemplify and enact the inexhaustible plenitude of Berlant's thought: fantasy, the case, love, impasse, feel tanks, slow death, ellipses, gesture, attrition, intimate public, ambivalence, style. Part 2 of ‘Encountering Berlant’ focuses on Berlant's most influential concept: ‘cruel optimism’. Across these heterogeneous encounters, Berlant's enduring concern with the tensions and possibilities of relationality and how to enact better forms of common life shine through. These enduring concerns and Berlant's commitment to the incoherence and overdetermination of phenomena are summarised in the Introduction, which also explores how Berlant's work has been engaged with in geography. The result is a repository of what an encounter with Berlant's thought makes possible

Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans

BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n=390) in the cohort. Amino-acid substitutions predicted to be pathogenic were assessed by analysis of structural protein data. Immunophenotyping, immunoblotting and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype co-segregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the non-infective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%), features prior studies correlate with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B lymphocyte differentiation. Detailed assessment of B lymphocyte numbers, phenotype and function identifies the presence of a raised CD21lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells

Further development of the Children’s Mathematics Anxiety Scale UK (CMAS-UK) for ages 4–7 years

There are currently many mathematics anxiety rating scales designed typically for adult and older children populations, yet there remains a lack of assessment tools for younger children ( 0.45) and high internal consistency (α = 0.88). A single factor model of Online Mathematics Anxiety was related to the experience of an entire mathematics lesson, from first entering the classroom to completing a task. A significant negative correlation was observed between the CMAS-UK and mathematics performance scores, suggesting that children who score high for mathematics anxiety tend to score to perform less well on a mathematics task. Subsequent confirmatory factor analysis was conducted to test a range of module structures; the shortened 19-item CMAS-UK was found to have similar model indices as the 26-item model, resulting in the maintenance of the revised scale. To conclude, the 19-item CMAS-UK provides a reliable assessment of children’s mathematics anxiety and has been shown to predict mathematics performance. This research points towards the origins of mathematics anxiety occurring when number is first encountered and supports the utility of the CMAS-UK. Subsequent research in the area should consider and appropriately define an affective component that may underlie mathematics anxiety at older ages. Mathematics anxiety relates to more complex procedures that elude the experiences of younger children and may instead be the result of number-based experiences in the early years of education.N/

Complete Genomic Characterization of a Pathogenic A.II Strain of Francisella tularensis Subspecies tularensis

Francisella tularensis is the causative agent of tularemia, which is a highly lethal disease from nature and potentially from a biological weapon. This species contains four recognized subspecies including the North American endemic F. tularensis subsp. tularensis (type A), whose genetic diversity is correlated with its geographic distribution including a major population subdivision referred to as A.I and A.II. The biological significance of the A.I – A.II genetic differentiation is unknown, though there are suggestive ecological and epidemiological correlations. In order to understand the differentiation at the genomic level, we have determined the complete sequence of an A.II strain (WY96-3418) and compared it to the genome of Schu S4 from the A.I population. We find that this A.II genome is 1,898,476 bp in size with 1,820 genes, 1,303 of which code for proteins. While extensive genomic variation exists between “WY96” and Schu S4, there is only one whole gene difference. This one gene difference is a hypothetical protein of unknown function. In contrast, there are numerous SNPs (3,367), small indels (1,015), IS element differences (7) and large chromosomal rearrangements (31), including both inversions and translocations. The rearrangement borders are frequently associated with IS elements, which would facilitate intragenomic recombination events. The pathogenicity island duplicated regions (DR1 and DR2) are essentially identical in WY96 but vary relative to Schu S4 at 60 nucleotide positions. Other potential virulence-associated genes (231) varied at 559 nucleotide positions, including 357 non-synonymous changes. Molecular clock estimates for the divergence time between A.I and A.II genomes for different chromosomal regions ranged from 866 to 2131 years before present. This paper is the first complete genomic characterization of a member of the A.II clade of Francisella tularensis subsp. tularensis

A summer heat wave decreases the immunocompetence of the mesograzer, Idotea baltica

Extreme events associated with global change will impose increasing stress on coastal organisms. How strong biological interactions such as the host–parasite arms-race are modulated by environmental change is largely unknown. The immune system of invertebrates, in particular phagocytosis and phenoloxidase activity response are key defence mechanisms against parasites, yet they may be sensitive to environmental perturbations. We here simulated an extreme event that mimicked the European heat wave in 2003 to investigate the effect of environmental change on the immunocompetence of the mesograzer Idotea baltica. Unlike earlier studies, our experiment aimed at simulation of the natural situation as closely as possible by using long acclimation, a slow increase in temperature and a natural community setting including the animals’ providence with natural food sources (Zostera marina and Fucus vesiculosus). Our results demonstrate that a simulated heat wave results in decreased immunocompetence of the mesograzer Idotea baltica, in particular a drop of phagocytosis by 50%. This suggests that global change has the potential to significantly affect host–parasite interactions

Isolation and Mutagenesis of a Capsule-Like Complex (CLC) from Francisella tularensis, and Contribution of the CLC to F. tularensis Virulence in Mice

BACKGROUND: Francisella tularensis is a category-A select agent and is responsible for tularemia in humans and animals. The surface components of F. tularensis that contribute to virulence are not well characterized. An electron-dense capsule has been postulated to be present around F. tularensis based primarily on electron microscopy, but this specific antigen has not been isolated or characterized. METHODS AND FINDINGS: A capsule-like complex (CLC) was effectively extracted from the cell surface of an F. tularensis live vaccine strain (LVS) lacking O-antigen with 0.5% phenol after 10 passages in defined medium broth and growth on defined medium agar for 5 days at 32°C in 7% CO₂. The large molecular size CLC was extracted by enzyme digestion, ethanol precipitation, and ultracentrifugation, and consisted of glucose, galactose, mannose, and Proteinase K-resistant protein. Quantitative reverse transcriptase PCR showed that expression of genes in a putative polysaccharide locus in the LVS genome (FTL_1432 through FTL_1421) was upregulated when CLC expression was enhanced. Open reading frames FTL_1423 and FLT_1422, which have homology to genes encoding for glycosyl transferases, were deleted by allelic exchange, and the resulting mutant after passage in broth (LVSΔ1423/1422_P10) lacked most or all of the CLC, as determined by electron microscopy, and CLC isolation and analysis. Complementation of LVSΔ1423/1422 and subsequent passage in broth restored CLC expression. LVSΔ1423/1422_P10 was attenuated in BALB/c mice inoculated intranasally (IN) and intraperitoneally with greater than 80 times and 270 times the LVS LD₅₀, respectively. Following immunization, mice challenged IN with over 700 times the LD₅₀ of LVS remained healthy and asymptomatic. CONCLUSIONS: Our results indicated that the CLC may be a glycoprotein, FTL_1422 and -FTL_1423 were involved in CLC biosynthesis, the CLC contributed to the virulence of F. tularensis LVS, and a CLC-deficient mutant of LVS can protect mice against challenge with the parent strain

When Subterranean Termites Challenge the Rules of Fungal Epizootics

Over the past 50 years, repeated attempts have been made to develop biological control technologies for use against economically important species of subterranean termites, focusing primarily on the use of the entomopathogenic fungus Metarhizium anisopliae. However, no successful field implementation of biological control has been reported. Most previous work has been conducted under the assumption that environmental conditions within termite nests would favor the growth and dispersion of entomopathogenic agents, resulting in an epizootic. Epizootics rely on the ability of the pathogenic microorganism to self-replicate and disperse among the host population. However, our study shows that due to multilevel disease resistance mechanisms, the incidence of an epizootic within a group of termites is unlikely. By exposing groups of 50 termites in planar arenas containing sand particles treated with a range of densities of an entomopathogenic fungus, we were able to quantify behavioral patterns as a function of the death ratios resulting from the fungal exposure. The inability of the fungal pathogen M. anisopliae to complete its life cycle within a Coptotermes formosanus (Isoptera: Rhinotermitidae) group was mainly the result of cannibalism and the burial behavior of the nest mates, even when termite mortality reached up to 75%. Because a subterranean termite colony, as a superorganism, can prevent epizootics of M. anisopliae, the traditional concepts of epizootiology may not apply to this social insect when exposed to fungal pathogens, or other pathogen for which termites have evolved behavioral and physiological means of disrupting their life cycle

Encountering Berlant part 1: Concepts otherwise

In Part 1 of ‘Encountering Berlant’, we encounter the promise and provocation of Lauren Berlant's work. In 1000-word contributions, geographers and others stay with what Berlant's thought offers contemporary human geography. They amplify an encounter with their work, demonstrating how a concept, idea, or style disrupts something, opens up a new possibility, or simply invites thinking otherwise. The encounters range across the incredible body of work Berlant left us with, from the ‘national sentimentality’ trilogy through to recent work on negativity. Varying in form and tone, the encounters exemplify and enact the inexhaustible plenitude of Berlant's thought: fantasy, the case, love, impasse, feel tanks, slow death, ellipses, gesture, attrition, intimate public, ambivalence, style. Part 2 of ‘Encountering Berlant’ focuses on Berlant's most influential concept: ‘cruel optimism’. Across these heterogeneous encounters, Berlant's enduring concern with the tensions and possibilities of relationality and how to enact better forms of common life shine through. These enduring concerns and Berlant's commitment to the incoherence and overdetermination of phenomena are summarised in the Introduction, which also explores how Berlant's work has been engaged with in geography. The result is a repository of what an encounter with Berlant's thought makes possible