Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection.

To restrict infection by Legionella pneumophila, mouse macrophages require Naip5, a member of the nucleotide-binding oligomerization domain leucine-rich repeat family of pattern recognition receptors, which detect cytoplasmic microbial products. We report that mouse macrophages restricted L. pneumophila replication and initiated a proinflammatory program of cell death when flagellin contaminated their cytosol. Nuclear condensation, membrane permeability, and interleukin-1beta secretion were triggered by type IV secretion-competent bacteria that encode flagellin. The macrophage response to L. pneumophila was independent of Toll-like receptor signaling but correlated with Naip5 function and required caspase 1 activity. The L. pneumophila type IV secretion system provided only pore-forming activity because listeriolysin O of Listeria monocytogenes could substitute for its contribution. Flagellin monomers appeared to trigger the macrophage response from perforated phagosomes: once heated to disassemble filaments, flagellin triggered cell death but native flagellar preparations did not. Flagellin made L. pneumophila vulnerable to innate immune mechanisms because Naip5+ macrophages restricted the growth of virulent microbes, but flagellin mutants replicated freely. Likewise, after intratracheal inoculation of Naip5+ mice, the yield of L. pneumophila in the lungs declined, whereas the burden of flagellin mutants increased. Accordingly, macrophages respond to cytosolic flagellin by a mechanism that requires Naip5 and caspase 1 to restrict bacterial replication and release proinflammatory cytokines that control L. pneumophila infection

Integration of speech and gesture in aphasia

BACKGROUND: Information from speech and gesture is often integrated to comprehend a message. This integration process requires the appropriate allocation of cognitive resources to both the gesture and speech modalities. People with aphasia are likely to find integration of gesture and speech difficult. This is due to a reduction in cognitive resources, a difficulty with resource allocation or a combination of the two. Despite it being likely that people who have aphasia will have difficulty with integration, empirical evidence describing this difficulty is limited. Such a difficulty was found in a single case study by Cocks et al. in 2009, and is replicated here with a greater number of participants. AIMS: To determine whether individuals with aphasia have difficulties understanding messages in which they have to integrate speech and gesture. METHODS & PROCEDURES: Thirty-one participants with aphasia (PWA) and 30 control participants watched videos of an actor communicating a message in three different conditions: verbal only, gesture only, and verbal and gesture message combined. The message related to an action in which the name of the action (e.g., 'eat') was provided verbally and the manner of the action (e.g., hands in a position as though eating a burger) was provided gesturally. Participants then selected a picture that 'best matched' the message conveyed from a choice of four pictures which represented a gesture match only (G match), a verbal match only (V match), an integrated verbal-gesture match (Target) and an unrelated foil (UR). To determine the gain that participants obtained from integrating gesture and speech, a measure of multimodal gain (MMG) was calculated. OUTCOMES & RESULTS: The PWA were less able to integrate gesture and speech than the control participants and had significantly lower MMG scores. When the PWA had difficulty integrating, they more frequently selected the verbal match. CONCLUSIONS & IMPLICATIONS: The findings suggest that people with aphasia can have difficulty integrating speech and gesture in order to obtain meaning. Therefore, when encouraging communication partners to use gesture alongside language when communicating with people with aphasia, education regarding the types of gestures that would facilitate understanding is recommended

Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor

BACKGROUND AND PURPOSE: Thermostabilization by mutagenesis is one method which has facilitated the determination of high-resolution structures of the adenosine A(2A) receptor (A(2A)R). Sets of mutations were identified, which both thermostabilized the receptor and resulted in preferential agonist (Rag23 mutant) or antagonist (Rant5 and Rant21) binding forms as assessed by radioligand binding analysis. While the ligand-binding profiles of these mutants are known, the effects these mutations have on receptor activation and downstream signalling are less well characterized. EXPERIMENTAL APPROACH: Here we have investigated the effects of the thermostabilizing mutations on receptor activation using a yeast cell growth assay. The assay employs an engineered Saccharomyces cerevisiae, MMY24, which couples receptor activation to cell growth. KEY RESULTS: Analysis of the receptor activation profile revealed that the wild-type (WT) A(2A)R had considerable constitutive activity. In contrast, the Rag23, Rant5 and Rant21 thermostabilized mutants all exhibited no constitutive activity. While the preferentially antagonist-binding mutants Rant5 and Rant21 showed a complete lack of agonist-induced activity, the Rag23 mutant showed high levels of agonist-induced receptor activity. Further analysis using a mutant intermediate between Rag23 and WT indicated that the loss of constitutive activity observed in the agonist responsive mutants was not due to reduced G-protein coupling. CONCLUSIONS AND IMPLICATIONS: The loss of constitutive activity may be an important feature of these thermostabilized GPCRs. In addition, the constitutively active and agonist-induced active conformations of the A(2A)R are distinct

Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor

In this note we present an explicit realization of the affine vertex algebra V^cri(gl(1|1)) inside of the tensor product F ⊗ M where F is a fermionic verex algebra and M is a commutative vertex algebra. This immediately gives an alternative description of the center of V^cri(gl(1|1)) as a subalgebra M_0 of M. We reconstruct the Molev-Mukhin formula for the Hilbert-Poincare series of the center of V^cri(gl(1|1)). Moreover, we construct a family of irreducible Vcri(gl(1|1))-modules realized on F and parameterized by χ+, χ- ∈ C((z)). We propose a generalization of V^cri(gl(1|1)) as a critical level version of the super W_{1+∞} vertex algebra

Prediabetes and the risk of type 2 diabetes: investigating the roles of depressive and anxiety symptoms in the Lifelines Cohort Study

Background Depression and anxiety may increase the risk of progressing from prediabetes to type 2 diabetes. The present study examined the interactions between prediabetes status and elevated depressive and anxiety symptoms with the risk of type 2 diabetes. Methods Participants (N=72,428) were adults aged 40 years and above without diabetes at baseline from the Lifelines Cohort Study (58% female; mean age=51.4 years). The Mini-International Neuropsychiatric Interview screened for elevated symptoms of major depressive disorder and generalized anxiety disorder. Glycated hemoglobin A1c (HbA1c) levels determined prediabetes status at baseline (2007-2013), and HbA1c and self-reported diabetes diagnoses determined diabetes status at follow-up (2014-2017). Groups were formed for elevated depressive and anxiety symptoms, respectively, and prediabetes status at baseline (elevated depressive/anxiety symptoms with prediabetes, elevated depressive/anxiety symptoms alone, and prediabetes alone), and compared to a reference group (no prediabetes or anxiety/depression) on the likelihood of developing diabetes during the follow-up period. Findings N=1,300 (1.8%) participants developed diabetes. While prediabetes alone was associated with incident diabetes (OR=5.94; 95% CI=5.10-6.90, p<.001), the group with combined prediabetes and depressive symptoms had the highest likelihood of developing diabetes over follow-up (OR=8.29; 95% CI=5.58-12.32, p<.001). Similar results were found for prediabetes and anxiety symptoms (OR=6.57; 95% CI=4.62-9.33, p<.001), compared to prediabetes alone (OR=6.09; 95% CI=5.23-7.11, p<.001), though with a smaller effect. The interaction between depressive symptoms and prediabetes was synergistic in age-and-sex adjusted analyses. Conclusion Individuals with elevated depressive, and to some extent anxiety, symptoms in combination with prediabetes may represent a high-risk subgroup for type 2 diabetes

Introduction to Mentalization-Based Approaches for Parents, Children, Youths, and Families

Family members mentalize when they try to understand each other's behavior on the basis of intentional mental states. This article aims to introduce and briefly describe how the concept of mentalization can provide a useful framework for clinicians to understand psychopathology of children, youths, and families. The authors further outline how mentalization-based techniques and interventions can be applied to build epistemic trust and to reestablish mentalizing in families by presenting clinical vignettes of initial sessions from various clinical settings in the United Kingdom and Germany. The article concludes with a brief summary about the current evidence for mentalization-based interventions with children, adolescents, and families and provides an outlook for future clinical and research work

Identification and Estimation of Differentiated Products Models using Cost Data

We propose a new methodology for estimating the demand and cost functions of differentiated products models when demand and cost data are available. The method deals with the endogeneity of prices to demand shocks and the endogeneity of outputs to cost shocks, by using variation in market size that does not need to be exogenous, and cost data. We establish nonparametric identification, consistency and asymptotic normality of our estimator. Using Monte-Carlo experiments, we show our method works well in contexts where instruments are correlated with demand and cost shocks, and where commonly-used instrumental variables estimators are biased and numerically unstable

Bouncing Neutrons and the Neutron Centrifuge

The recent observation of the quantum state of the neutron bouncing freely under gravity allows some novel experiments. A method of purifying the ground state is given, and possible applications to the measurement of the electric dipole moment of the neutron and the short distance behaviour of gravity are discussed.Comment: 7 pages, 7 figure

Alternative splicing and protein diversity: plants versus animals

Plants, unlike animals, exhibit a very high degree of plasticity in their growth and development and employ diverse strategies to cope with the variations during diurnal cycles and stressful conditions. Plants and animals, despite their remarkable morphological and physiological differences, share many basic cellular processes and regulatory mechanisms. Alternative splicing (AS) is one such gene regulatory mechanism that modulates gene expression in multiple ways. It is now well established that AS is prevalent in all multicellular eukaryotes including plants and humans. Emerging evidence indicates that in plants, as in animals, transcription and splicing are coupled. Here, we reviewed recent evidence in support of co-transcriptional splicing in plants and highlighted similarities and differences between plants and humans. An unsettled question in the field of AS is the extent to which splice isoforms contribute to protein diversity. To take a critical look at this question, we presented a comprehensive summary of the current status of research in this area in both plants and humans, discussed limitations with the currently used approaches and suggested improvements to current methods and alternative approaches. We end with a discussion on the potential role of epigenetic modifications and chromatin state in splicing memory in plants primed with stresses