AK002, a Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody that Induces Antibody-Dependent Cell-Mediated Cytotoxicity against Human Eosinophils and Inhibits Mast Cell-Mediated Anaphylaxis in Mice

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and mast cells. METHODS: The affinity of AK002 for Siglec-8 and CD16 was determined by biolayer interferometry. Ex vivo activity of AK002 on human eosinophils from blood and dissociated human tissue was tested in apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. The in vivo activity of a murine precursor of AK002 (mAK002) was tested in a passive systemic anaphylaxis (PSA) humanized mouse model. RESULTS: AK002 bound selectively to mast cells, eosinophils and, at a lower level, to basophils in human blood and tissue and not to other cell types examined. AK002 induced apoptosis of interleukin-5-activated blood eosinophils and demonstrated potent ADCC activity against blood eosinophils in the presence of natural killer cells. AK002 also significantly reduced eosinophils in dissociated human lung tissue. Furthermore, mAK002 prevented PSA in humanized mice through mast cell inhibition. CONCLUSION: AK002 selectively evokes potent apoptotic and ADCC activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition

AK002, a Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody that Induces Antibody-Dependent Cell-Mediated Cytotoxicity against Human Eosinophils and Inhibits Mast Cell-Mediated Anaphylaxis in Mice.

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and mast cells. METHODS: The affinity of AK002 for Siglec-8 and CD16 was determined by biolayer interferometry. Ex vivo activity of AK002 on human eosinophils from blood and dissociated human tissue was tested in apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. The in vivo activity of a murine precursor of AK002 (mAK002) was tested in a passive systemic anaphylaxis (PSA) humanized mouse model. RESULTS: AK002 bound selectively to mast cells, eosinophils and, at a lower level, to basophils in human blood and tissue and not to other cell types examined. AK002 induced apoptosis of interleukin-5-activated blood eosinophils and demonstrated potent ADCC activity against blood eosinophils in the presence of natural killer cells. AK002 also significantly reduced eosinophils in dissociated human lung tissue. Furthermore, mAK002 prevented PSA in humanized mice through mast cell inhibition. CONCLUSION: AK002 selectively evokes potent apoptotic and ADCC activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition

How inclusive, user-centered design research can improve psychological therapies for psychosis: Development of SlowMo

Real-world implementation of psychological interventions for psychosis is poor. Barriers include therapy being insufficiently usable and useful for a diverse range of people. User-centered, inclusive design approaches could improve the usability of therapy, which may increase uptake, adherence, and effectiveness. This study aimed to optimize the usability of an existing psychological intervention, Thinking Well, which targets reasoning processes in paranoia using a basic digital interface. We conducted inclusive, user-centered design research characterized by purposive sampling of extreme users from the margins of groups, ethnographic investigation of the problem context, and iterative prototyping of solutions. The UK Design Council's double diamond method was used. This consisted of 4 phases: discover, including a case series of Thinking Well, stakeholder interviews, desk research, user profiling, system mapping, and a mood board; define, consisting of workshops to synthesize findings and generate the design brief; develop, involving concept workshops and prototype testing; and deliver, in which the final minimal viable product was storyboarded and iteratively coded. Consistent with our previous work, the Thinking Well case series showed medium to large effects on paranoia and well-being and small effects on reasoning. These were maintained at follow-up despite some participants reporting difficulties with the therapy interface. Insights from the discover phase confirmed that usability was challenged by information complexity and poor accessibility. Participants were generally positive about the potential of technology to be enjoyable, help manage paranoia, and provide tailored interpersonal support from therapists and peers, although they reported privacy and security concerns. The define phase highlighted that the therapy redesign should support monitoring, simplify information processing, enhance enjoyment and trust, promote personalization and normalization, and offer flexible interpersonal support. During the develop phase over 60 concepts were created, with 2 key concepts of thoughts visualized as bubbles and therapy as a journey selected for storyboarding. The output of the deliver phase was a minimal viable product of an innovative digital therapy, SlowMo. SlowMo works by helping people to notice their worries and fast thinking habits, and encourages them to slow down for a moment to find ways of feeling safer. A Web app supports the delivery of 8 face-to-face sessions, which are synchronized to a native mobile app. SlowMo makes use of personalization, ambient information, and visual metaphors to tailor the appeal, engagement, and memorability of therapy to a diversity of needs. Feasibility testing has been promising, and the efficacy of SlowMo therapy is now being tested in a multicentered randomized controlled trial. The study demonstrates that developments in psychological theory and techniques can be enhanced by improving the usability of the therapy interface to optimize its impact in daily life. [Abstract copyright: ©Amy Hardy, Anna Wojdecka, Jonathan West, Ed Matthews, Christopher Golby, Thomas Ward, Natalie D Lopez, Daniel Freeman, Helen Waller, Elizabeth Kuipers, Paul Bebbington, David Fowler, Richard Emsley, Graham Dunn, Philippa Garety. Originally published in JMIR Mental Health (http://mental.jmir.org), 05.12.2018.

Neural processing of criticism and positive comments from relatives in individuals with schizotypal personality traits

Objectives. High negative expressed emotion by family members towards schizophrenia patients increases the risk of subsequent relapse. The study aimed to determine whether individuals with high schizotypy (HS) and low schizotypy (LS) would differ in activation of brain areas involved in cognitive control when listening to relative criticism

It takes two: Evidence for reduced sexual conflict over parental care in a biparental canid

In biparental systems, sexual conflict over parental investment predicts that the parent providing care experiences greater reproductive costs. This inequality in parental contribution is reduced when offspring survival is dependent on biparental care. However, this idea has received little empirical attention. Here, we determined whether mothers and fathers differed in their contribution to care in a captive population of coyotes (Canis latrans). We performed parental care assays on 8 (n = 8 males, 8 females) mated pairs repeatedly over a 10-week period (i.e., 5–15 weeks of litter age) when pairs were first-time breeders (2011), and again as experienced breeders (2013). We quantified consistent individual variation (i.e., repeatability) in 8 care behaviors and examined within- and among-individual correlations to determine if behavioral plasticity within or parental personality across seasons varied by sex. Finally, we extracted hormone metabolites (i.e., cortisol and testosterone) from fecal samples collected during gestation to describe potential links between hormonal mechanisms and individual consistency in parental behaviors. Parents differed in which behaviors were repeatable: mothers demonstrated consistency in provisioning and pup-directed aggression, whereas fathers were consistent in pup checks. However, positive within-individual correlations for identical behaviors (e.g., maternal versus paternal play) suggested that the rate of change in all behaviors except provisioning was highly correlated between the sexes. Moreover, positive among-individual correlations among 50% of identical behaviors suggested that personality differences across parents were highly correlated. Lastly, negative among-individual correlations among pup-directed aggression, provisioning, and gestational testosterone in both sexes demonstrated potential links between preparental hormones and labile parental traits. We provide novel evidence that paternal contribution in a biparental species reaches near equivalent rates of their partners

Similarities and differences in the historical records of lava dome-building volcanoes: implications for understanding magmatic processes and eruption forecasting

A key question for volcanic hazard assessment is the extent to which information can be exchanged between volcanoes. This question is particularly pertinent to hazard forecasting for dome-building volcanoes, where effusive activity may persist for years to decades, and may be punctuated by periods of repose, and sudden explosive activity. Here we review historical eruptive activity of fifteen lava dome-building volcanoes over the past two centuries, with the goal of creating a hierarchy of exchangeable (i.e., similar) behaviours. Eruptive behaviour is classified using empirical observations that include patterns of SO2 flux, eruption style, and magma composition. We identify two eruptive regimes: (i) an episodic regime where eruptions are much shorter than intervening periods of repose, and degassing is temporally correlated with lava effusion; and (ii) a persistent regime where eruptions are comparable in length to periods of repose and gas emissions do not correlate with eruption rates. A corollary to these two eruptive regimes is that there are also two different types of repose: (i) inter-eruptive repose separates episodic eruptions, and is characterised by negligible gas emissions and (ii) intra-eruptive repose is observed in persistently active volcanoes, and is characterised by continuous gas emissions. We suggest that these different patterns of can be used to infer vertical connectivity within mush-dominated magmatic systems. We also note that our recognition of two different types of repose raises questions about traditional definitions of historical volcanism as a point process. This is important, because the ontology of eruptive activity (that is, the definition of volcanic activity in time) influences both analysis of volcanic data and, by extension, interpretations of magmatic processes. Our analysis suggests that one identifying exchangeable traits or behaviours provides a starting point for developing robust ontologies of volcanic activity. Moreover, by linking eruptive regimes to conceptual models of magmatic processes, we illustrate a path towards developing a conceptual framework not only for comparing data between different volcanoes but also for improving forecasts of eruptive activity