Multiple functional self-association interfaces in plant TIR domains

The self-association of Toll/interleukin-1 receptor/resistance protein (TIR) domains has been implicated in signaling in plant and animal immunity receptors. Structure-based studies identified different TIR-domain dimerization interfaces required for signaling of the plant nucleotide-binding oligomerization domain-like receptors (NLRs) L6 from flax and disease resistance protein RPS4 from Arabidopsis. Here we show that the crystal structure of the TIR domain from the Arabidopsis NLR suppressor of npr1-1, constitutive 1 (SNC1) contains both an L6-like interface involving helices alpha D and alpha E (DE interface) and an RPS4-like interface involving helices alpha A and alpha E (AE interface). Mutations in either the AE- or DE-interface region disrupt cell-death signaling activity of SNC1, L6, and RPS4 TIR domains and full-length L6 and RPS4. Self-association of L6 and RPS4 TIR domains is affected by mutations in either region, whereas only AE-interface mutations affect SNC1 TIR-domain self-association. We further show two similar interfaces in the crystal structure of the TIR domain from the Arabidopsis NLR recognition of Peronospora parasitica 1 (RPP1). These data demonstrate that both the AE and DE self-association interfaces are simultaneously required for self-association and cell-death signaling in diverse plant NLRs.11139Ysciescopu

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

G.H. Mead: theorist of the social act

There have been many readings of Mead's work, and this paper proposes yet another: Mead, theorist of the social act. It is argued that Mead's core theory of the social act has been neglected, and that without this theory, the concept of taking the attitude of the other is inexplicable and the contemporary relevance of the concept of the significant symbol is obfuscated. The paper traces the development of the social act out of Dewey's theory of the act. According to Mead, Dewey's theory does not sufficiently account for consciousness. Grappling with this problematic leads Mead to several key ideas, which culminate in his theory of the social act. The social act and taking the attitude of the other are then illustrated by the analysis of a game of football. The interpretation presented has two novel aspects: first, symbolisation arises not simply through self taking the attitude of the other, but through the pairing of this attitude with the complementary attitude in self; second, self is able to take the attitude of the other to the extent that self has in actuality or in imagination previously been in the social position of the other. From this standpoint the key issue is how the attitude of self and other become integrated. New directions for empirical research, aimed at advancing this question are outlined. Finally, the paper shows how the social act can contribute to our contemporary concerns about the nature of the symbolic