NLR diversity, helpers and integrated domains: making sense of the NLR IDentity.

Plant innate immunity relies on genetically predetermined repertoires of immune receptors to detect pathogens and trigger an effective immune response. A large proportion of these receptors are from the Nucletoide Binding Leucine Rich Repeat (NLR) gene family. As plants live longer than most pathogens, maintaining diversity of NLRs and deploying efficient 'pathogen traps' is necessary to withstand the evolutionary battle. In this review, we summarize the sources of diversity in NLR plant immune receptors giving an overview of genomic, regulatory as well as functional studies, including the latest concepts of NLR helpers and NLRs with integrated domains.

Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism.

Several common alleles in the oxytocin receptor gene (OXTR) are associated with altered brain function in reward circuitry in neurotypical adults and may increase risk for autism spectrum disorders (ASD). Yet, it is currently unknown how variation in the OXTR relates to brain functioning in individuals with ASD, and, critically, whether neural endophenotypes vary as a function of aggregate genetic risk. Here, for we believe the first time, we use a multi-locus approach to examine how genetic variation across several OXTR single-nucleotide polymorphisms (SNPs) affect functional connectivity of the brain's reward network. Using data from 41 children with ASD and 41 neurotypical children, we examined functional connectivity of the nucleus accumbens (NAcc) - a hub of the reward network - focusing on how connectivity varies with OXTR risk-allele dosage. Youth with ASD showed reduced NAcc connectivity with other areas in the reward circuit as a function of increased OXTR risk-allele dosage, as well as a positive association between risk-allele dosage and symptom severity, whereas neurotypical youth showed increased NAcc connectivity with frontal brain regions involved in mentalizing. In addition, we found that increased NAcc-frontal cortex connectivity in typically developing youth was related to better scores on a standardized measure of social functioning. Our results indicate that cumulative genetic variation on the OXTR impacts reward system connectivity in both youth with ASD and neurotypical controls. By showing differential genetic effects on neuroendophenotypes, these pathways elucidate mechanisms of vulnerability versus resilience in carriers of disease-associated risk alleles.

Effector recognition and activation of the Arabidopsis thaliana NLR innate immune receptors.

Plant immunity to coevolved pathogens relies on the perception of pathogenic effectors by nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins-sophisticated intracellular receptors that have both perception and signaling roles in activating defenses. Given the conserved domain architecture of NLRs, a structural biology perspective is particularly relevant to understanding mechanisms of their activation. Here, we summarize our recent findings on the Arabidopsis resistance protein RPP1, a member of the TIR-NBS-LRR family of plant NLRs that specifically recognizes the cognate effector protein ATR1. To study the basis of RPP1 activation, we have taken advantage of a series of RPP1 and ATR1 alleles that differentially condition resistance. In planta association between the LRR domain of RPP1 and ATR1 only occurs in a resistance-activating combination of alleles, suggesting that a direct interaction between RPP1 and ATR1 protein leads to activation of the NLR (Krasileva et al. 2010). Given critical amino acid residues' locations on the solved ATR1 crystal structure, and variable amino acid residues on the predicted LRR structure of RPP1, we hypothesize that specific "hotspots" of the horseshoe-like LRR fold mediate binding to the ATR1 ligand and that polymorphisms mapping to these surfaces condition differences in allelic recognition specificity. We present docking models of a possible co-complex between RPP1 and ATR1, and we propose that ATR1 binding relieves autoinhibition of RPP1 resistance signaling. This is consistent with current models of activation for both TIR- and CC-type plant NLRs, where conformational changes could lead to NLR oligomerization, nucleotide binding, translocation, and other critical downstream events in triggering immunity.