Involvement of the glutamate receptor AtGLR3.3 in plant defense signaling and resistance to Hyaloperonospora arabidopsidis

Like their animal counterparts, plant glutamate receptor‐like (GLR) homologs are intimately associated with Ca²⁺ influx through plasma membrane and participate in various physiological processes. In pathogen‐associated molecular patterns (PAMP)‐/elicitor‐mediated resistance, Ca²⁺ fluxes are necessary for activating downstream signaling events related to plant defense. In this study, oligogalacturonides (OGs), which are endogenous elicitors derived from cell wall degradation, were used to investigate the role of Arabidopsis GLRs in defense signaling. Pharmacological investigations indicated that GLRs are partly involved in free cytosolic [Ca²⁺] ([Ca²⁺]_cyt) variations, nitric oxide (NO) production, reactive oxygen species (ROS) production and expression of defense‐related genes by OGs. In addition, wild‐type Col‐0 plants treated with the glutamate‐receptor antagonist 6,7‐dinitriquinoxaline‐2,3‐dione (DNQX) had a compromised resistance to Botrytis cinerea and Hyaloperonospora arabidopsidis. Moreover, we provide genetic evidence that AtGLR3.3 is a key component of resistance against H. arabidopsidis. In addition, some OGs‐triggered immune events such as defense gene expression, NO and ROS production are also to different extents dependent on AtGLR3.3. Taken together, these data provide evidence for the involvement of GLRs in elicitor/pathogen‐mediated plant defense signaling pathways in Arabidopsis thaliana.     

Design,synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.     

Anoctamin 1 dysregulation alters bronchial epithelial repair in cystic fibrosis

Cystic fibrosis (CF) airway epithelium is constantly subjected to injury events due to chronic infection and inflammation. Moreover, abnormalities in CF airway epithelium repair have been described and contribute to the lung function decline seen in CF patients. In the last past years, it has been proposed that anoctamin 1 (ANO1), a Ca^2 +-activated Cl^? channel, might offset the CFTR deficiency but this protein has not been characterized in CF airways. Interestingly, recent evidence indicates a role for ANO1 in cell proliferation and tumor growth. Our aims were to study non-CF and CF bronchial epithelial repair and to determine whether ANO1 is involved in airway epithelial repair. Here, we showed, with human bronchial epithelial cell lines and primary cells, that both cell proliferation and migration during epithelial repair are delayed in CF compared to non-CF cells. We then demonstrated that ANO1 Cl^? channel activity was significantly decreased in CF versus non-CF cells. To explain this decreased Cl^? channel activity in CF context, we compared ANO1 expression in non-CF vs. CF bronchial epithelial cell lines and primary cells, in lung explants from wild-type vs. F508del mice and non-CF vs. CF patients. In all these models, ANO1 expression was markedly lower in CF compared to non-CF. Finally, we established that ANO1 inhibition or overexpression was associated respectively with decreases and increases in cell proliferation and migration. In summary, our study demonstrates involvement of ANO1 decreased activity and expression in abnormal CF airway epithelial repair and suggests that ANO1 correction may improve this process.     

CrypticIBDcheck: an R package for checking cryptic relatedness in nominally unrelated individuals

Background

In population association studies, standard methods of statistical inference assume that study subjects are independent samples. In genetic association studies, it is therefore of interest to diagnose undocumented close relationships in nominally unrelated study samples.

Results

We describe the R package CrypticIBDcheck to identify pairs of closely-related subjects based on genetic marker data from single-nucleotide polymorphisms (SNPs). The package is able to accommodate SNPs in linkage disequibrium (LD), without the need to thin the markers so that they are approximately independent in the population. Sample pairs are identified by superposing their estimated identity-by-descent (IBD) coefficients on plots of IBD coefficients for pairs of simulated subjects from one of several common close relationships.

Conclusions

The methods implemented in CrypticIBDcheck are particularly relevant to candidate-gene association studies, in which dependent SNPs cluster in a relatively small number of genes spread throughout the genome. The accommodation of LD allows the use of all available genetic data, a desirable property when working with a modest number of dependent SNPs within candidate genes. CrypticIBDcheck is available from the Comprehensive R Archive Network (CRAN).

     

Internet marketing directed at children on food and restaurant websites in two policy environments

Objective:

Food and beverage marketing has been associated with childhood obesity yet little research has examined the influence of advertising policy on children's exposure to food/beverage marketing on the Internet. The purpose of this study was to assess the influence of Quebec's Consumer Protection Act and the self‐regulatory Canadian Children's Food and Beverage Advertising Initiative (CAI) on food manufacturer and restaurant websites in Canada.

Design and Methods:

A content analysis of 147 French and English language food and restaurant websites was undertaken. The presence of child‐directed content was assessed and an analysis of marketing features, games and activities, child protection features, and the promotion of healthy lifestyle messages was then examined on those sites with child‐directed content.

Results:

There were statistically no fewer French language websites (n = 22) with child‐directed content compared to English language websites (n = 27). There were no statistically significant differences in the number of the various marketing features, or in the average number of marketing features between the English and French websites. There were no fewer CAI websites (n = 14) with child‐directed content compared to non‐CAI websites (n = 13). The CAI sites had more healthy lifestyle messages and child protection features compared to the non‐CAI sites.

Conclusion:

Systematic surveillance of the Consumer Protection Act in Quebec is recommended. In the rest of Canada, the CAI needs to be significantly expanded or replaced by regulatory measures to adequately protect children from the marketing of foods/beverages high in fat, sugar, and sodium on the Internet.     

A Shared Neural Substrate for Mentalizing and the Affective Component of Sentence Comprehension

Using event-related fMRI in a sample of 42 healthy participants, we compared the cerebral activity maps obtained when classifying spoken sentences based on the mental content of the main character (belief, deception or empathy) or on the emotional tonality of the sentence (happiness, anger or sadness). To control for the effects of different syntactic constructions (such as embedded clauses in belief sentences), we subtracted from each map the BOLD activations obtained during plausibility judgments on structurally matching sentences, devoid of emotions or ToM. The obtained theory of mind (ToM) and emotional speech comprehension networks overlapped in the bilateral temporo-parietal junction, posterior cingulate cortex, right anterior temporal lobe, dorsomedial prefrontal cortex and in the left inferior frontal sulcus. These regions form a ToM network, which contributes to the emotional component of spoken sentence comprehension. Compared with the ToM task, in which the sentences were enounced on a neutral tone, the emotional sentence classification task, in which the sentences were play-acted, was associated with a greater activity in the bilateral superior temporal sulcus, in line with the presence of emotional prosody. Besides, the ventromedial prefrontal cortex was more active during emotional than ToM sentence processing. This region may link mental state representations with verbal and prosodic emotional cues. Compared with emotional sentence classification, ToM was associated with greater activity in the caudate nucleus, paracingulate cortex, and superior frontal and parietal regions, in line with behavioral data showing that ToM sentence comprehension was a more demanding task.     

Neonatal environment exerts a sustained influence on the development of the intestinal microbiota and metabolic phenotype

The postnatal environment, including factors such as weaning and acquisition of the gut microbiota, has been causally linked to the development of later immunological diseases such as allergy and autoimmunity, and has also been associated with a predisposition to metabolic disorders. We show that the very early-life environment influences the development of both the gut microbiota and host metabolic phenotype in a porcine model of human infants. Farm piglets were nursed by their mothers for 1 day, before removal to highly controlled, individual isolators where they received formula milk until weaning at 21 days. The experiment was repeated, to create two batches, which differed only in minor environmental fluctuations during the first day. At day 1 after birth, metabolic profiling of serum by ¹H nuclear magnetic resonance spectroscopy demonstrated significant, systemic, inter-batch variation which persisted until weaning. However, the urinary metabolic profiles demonstrated that significant inter-batch effects on 3-hydroxyisovalerate, trimethylamine-N-oxide and mannitol persisted beyond weaning to at least 35 days. Batch effects were linked to significant differences in the composition of colonic microbiota at 35 days, determined by 16 S pyrosequencing. Different weaning diets modulated both the microbiota and metabolic phenotype independently of the persistent batch effects. We demonstrate that the environment during the first day of life influences development of the microbiota and metabolic phenotype and thus should be taken into account when interrogating experimental outcomes. In addition, we suggest that intervention at this early time could provide ‘metabolic rescue'' for at-risk infants who have undergone aberrant patterns of initial intestinal colonisation.     

The Incidence Patterns Model to Estimate the Distribution of New HIV Infections in Sub-Saharan Africa: Development and Validation of a Mathematical Model

BackgroundProgrammatic planning in HIV requires estimates of the distribution of new HIV infections according to identifiable characteristics of individuals. In sub-Saharan Africa, robust routine data sources and historical epidemiological observations are available to inform and validate such estimates.ConclusionsIt is possible to reliably predict the distribution of new HIV infections acquired using data routinely available in many countries in the sub-Saharan African region with a single relatively simple mathematical model. This tool would complement more specific analyses to guide resource allocation, data collection, and programme planning.