Catalytic dehydrocoupling of Amine-Boranes Using Cationic Zirconium(IV)-Phosphine Frustrated Lewis Pairs

A series of novel, intramolecular Zr­(IV)/P frustrated Lewis pairs (FLPs) based on cationic zirconocene fragments with a variety of ancillary cyclopentadienyl and 2-phosphinoaryloxide (−O­(C₆H₄)­PR₂, R = ^tBu and 3,5-CF₃-(C₆H₃)) ligands are reported and their activity as catalysts for the dehydrocoupling of dimethylamine–borane (Me₂NH·BH₃) assessed. The FLP system [(C₉H₇)₂ZrO­(C₆H₄)­P^tBu₂]­[B­(C₆F₅)₄] is shown to give unprecedented turnover frequencies (TOF) for a catalyst based on a group 4 metal (TOF ≥ 600 h^–1), while also proving to be the most efficient FLP catalyst reported to date. The mechanism of this reaction has been probed using analogous intermolecular Zr­(IV)/P FLPs, permitting deconvolution of the reactions taking place at both the Lewis acidic and basic sites. Elucidation of this mechanism revealed an interesting cooperative two-cycle process where one cycle is FLP mediated and the other, a redistribution of a linear diborazane intermediate, relies solely on the presence of a Zr­(IV) Lewis acid

Knowledge and attitudes towards dementia in adolescent students

Background: Improving people’s knowledge, perceptions and attitudes of dementia is important in the formation of dementia-friendly communities. However, at present, there is very little evidence from adolescents, who are already the junior members of such communities and will be carers in their own rights in the future. Our aim was to evaluate adolescents’ knowledge and attitudes of dementia. Methods: Four-hundred and fifty adolescents, aged 15–18 years, from schools in Sussex (UK) were invited to complete a series of questions that assessed their dementia knowledge and attitudes. Results: A total of 359 adolescent students completed the questionnaire. Out of 15 questions on dementia knowledge, participants were on average able to answer less than half correctly (M = 6.65, standard deviation = 2.34). Responses to the attitudes questionnaire showed that adolescent students had both positive and negative attitudes toward dementia. Discussion: There is scope for adolescents attending school to improve their dementia knowledge and attitudes. More effort is needed to embed initial dementia understanding in the school curriculum which will improve awareness about dementia at an earlier age and will enhance dementia-friendly communities

Self Assessment in Insects: Honeybee Queens Know Their Own Strength

Contests mediate access to reproductive opportunities in almost all species of animals. An important aspect of the evolution of contests is the reduction of the costs incurred during intra-specific encounters to a minimum. However, escalated fights are commonly lethal in some species like the honeybee, Apis mellifera. By experimentally reducing honeybee queens' fighting abilities, we demonstrate that they refrain from engaging in lethal contests that typically characterize their reproductive dominance behavior and coexist peacefully within a colony. This suggests that weak queens exploit an alternative reproductive strategy and provides an explanation for rare occurrences of queen cohabitation in nature. Our results further indicate that self-assessment, but not mutual assessment of fighting ability occurs prior to and during the agonistic encounters

Informing evaluation of a smartphone application for people with acquired brain injury: a stakeholder engagement study

Background Brain in Hand is a smartphone application (app) that allows users to create structured diaries with problems and solutions, attach reminders, record task completion and has a symptom monitoring system. Brain in Hand was designed to support people with psychological problems, and encourage behaviour monitoring and change. The aim of this paper is to describe the process of exploring the barriers and enablers for the uptake and use of Brain in Hand in clinical practice, identify potential adaptations of the app for use with people with acquired brain injury (ABI), and determine whether the behaviour change wheel can be used as a model for engagement. Methods We identified stakeholders: ABI survivors and carers, National Health Service and private healthcare professionals, and engaged with them via focus groups, conference presentations, small group discussions, and through questionnaires. The results were evaluated using the behaviour change wheel and descriptive statistics of questionnaire responses. Results We engaged with 20 ABI survivors, 5 carers, 25 professionals, 41 questionnaires were completed by stakeholders. Comments made during group discussions were supported by questionnaire results. Enablers included smartphone competency (capability), personalisation of app (opportunity), and identifying perceived need (motivation). Barriers included a physical and cognitive inability to use smartphone (capability), potential cost and reliability of technology (opportunity), and no desire to use technology or change from existing strategies (motivation). The stakeholders identified potential uses and changes to the app, which were not easily mapped onto the behaviour change wheel, e.g. monitoring fatigue levels, method of logging task completion, and editing the diary on their smartphone. Conclusions The study identified that both ABI survivors and therapists could see a use for Brain in Hand, but wanted users to be able to personalise it themselves to address individual user needs, e.g. monitoring activity levels. The behaviour change wheel is a useful tool when designing and evaluating engagement activities as it addresses most aspects of implementation, however additional categories may be needed to explore the specific features of assistive technology interventions, e.g. technical functions

Staphylococcus aureus α-Hemolysin Activates the NLRP3-Inflammasome in Human and Mouse Monocytic Cells

Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) causes severe necrotizing infections of the skin, soft tissues, and lungs. Staphylococcal α-hemolysin is an essential virulence factor in mouse models of CA-MRSA necrotizing pneumonia. S. aureus α-hemolysin has long been known to induce inflammatory signaling and cell death in host organisms, however the mechanism underlying these signaling events were not well understood. Using highly purified recombinant α-hemolysin, we now demonstrate that α-hemolysin activates the Nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 protein (NLRP3)-inflammasome, a host inflammatory signaling complex involved in responses to pathogens and endogenous danger signals. Non-cytolytic mutant α-hemolysin molecules fail to elicit NLRP3-inflammasome signaling, demonstrating that the responses are not due to non-specific activation of this innate immune signaling system by bacterially derived proteins. In monocyte-derived cells from humans and mice, inflammasome assembly in response to α-hemolysin results in activation of the cysteine proteinase, caspase-1. We also show that inflammasome activation by α-hemolysin works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1β and IL-18. Additionally, α-hemolysin induces cell death in these cells through an NLRP3-dependent program of cellular necrosis, resulting in the release of endogenous pro-inflammatory molecules, like the chromatin-associated protein, High-mobility group box 1 (HMGB1). These studies link the activity of a major S. aureus virulence factor to a specific host signaling pathway. The cellular events linked to inflammasome activity have clear relevance to the disease processes associated with CA-MRSA including tissue necrosis and inflammation

Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial.

BACKGROUND: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. METHODS: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. RESULTS: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4 + T cell (Treg), effector T cell (Teff) CD4 + and CD8 + subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later.  NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69 + and Ki-67 + effector memory Teffs were followed by the emergence of memory CD8 + Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. CONCLUSIONS: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection

Cryopyrin-Associated Periodic Syndrome: An Update on Diagnosis and Treatment Response

Cryopyrin-associated periodic syndrome (CAPS) is a rare hereditary inflammatory disorder encompassing a continuum of three phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease. Distinguishing features include cutaneous, neurological, ophthalmologic, and rheumatologic manifestations. CAPS results from a gain-of-function mutation of the NLRP3 gene coding for cryopyrin, which forms intracellular protein complexes known as inflammasomes. Defects of the inflammasomes lead to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS. Diagnosis is often delayed and requires a thorough review of clinical symptoms. Remarkable advances in our understanding of the genetics and the molecular pathway that is responsible for the clinical phenotype of CAPS has led to the development of effective treatments. It also has become clear that the NLRP3 inflammasome plays a critical role in innate immune defense and therefore has wider implications for other inflammatory disease states

P2 purinergic receptor modulation of cytokine production

Cytokines serve important functions in controlling host immunity. Cells involved in the synthesis of these polypeptide mediators have evolved highly regulated processes to ensure that production is carefully balanced. In inflammatory and immune disorders, however, mis-regulation of the production and/or activity of cytokines is recognized as a major contributor to the disease process, and therapeutics that target individual cytokines are providing very effective treatment options in the clinic. Leukocytes are the principle producers of a number of key cytokines, and these cells also express numerous members of the purinergic P2 receptor family. Studies in several cellular systems have provided evidence that P2 receptor modulation can affect cytokine production, and mechanistic features of this regulation have emerged. This review highlights three separate examples corresponding to (1) P2Y6 receptor mediated impact on interleukin (IL)-8 production, (2) P2Y11 receptor-mediated affects on IL-12/23 output, and (3) P2X7 receptor mediated IL-1β posttranslational processing. These examples demonstrate important roles of purinergic receptors in the modulation of cytokine production. Extension of these cellular observations to in vivo situations may lead to new therapeutic strategies for treating cytokine-mediated diseases

Group size and individual 'personality' influence emergence times in hermit crabs

Many animals benefit from aggregating due to the anti-predator effects associated with living in groups. Hermit crabs are known to form groups, or ‘clusters’, which may occur at sites of high shell availability. Clustering may also have anti-predator benefits, if individuals in larger clusters able to spend less time engaging in defensive behaviours such as hiding in their shells. Here, we test the hypothesis that crabs in larger clusters will emerge faster from their shells after an elicited startle response in the European hermit crab (Pagurus bernhardus). We found that individuals were generally consistent in their emergence times across group sizes (displaying ‘personality’ in relation to emergence time), but that group size influenced emergence time in P. bernhardus. In contrast to the hypothesis, crabs in larger clusters had longer emergence times relative to their own emergence times in smaller clusters. Suggested explanations for this effect include intra-specific competition for the gastropod shells that hermit crabs inhabit, as well as the possible release of chemical cues by crabs in larger clusters