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TIR domains are NAD-degrading enzymes that function during immune signaling in prokaryotes, plants, and animals. In plants, most TIR domains are incorporated into intracellular immune receptors termed TNLs. In Arabidopsis, TIR-derived small molecules bind and activate EDS1 heterodimers, which in turn activate RNLs, a class of cation channel–forming immune receptors. RNL activation drives cytoplasmic Ca 2+ influx, transcriptional reprogramming, pathogen resistance, and host cell death. We screened for mutants that suppress an RNL activation mimic allele and identified a TNL, SADR1. Despite being required for the function of an autoactivated RNL, SADR1 is not required for defense signaling triggered by other tested TNLs. SADR1 is required for defense signaling initiated by some transmembrane pattern recognition receptors and contributes to the unbridled spread of cell death in lesion simulating disease 1 . Together with RNLs, SADR1 regulates defense gene expression at infection site borders, likely in a non-cell autonomous manner. RNL mutants that cannot sustain this pattern of gene expression are unable to prevent disease spread beyond localized infection sites, suggesting that this pattern corresponds to a pathogen containment mechanism. SADR1 potentiates RNL-driven immune signaling not only through the activation of EDS1 but also partially independently of EDS1. We studied EDS1-independent TIR function using nicotinamide, an NADase inhibitor. Nicotinamide decreased defense induction from transmembrane pattern recognition receptors and decreased calcium influx, pathogen growth restriction, and host cell death following intracellular immune receptor activation. We demonstrate that TIR domains can potentiate calcium influx and defense and are thus broadly required for Arabidopsis immunity.

Summary Background In early 2020, the response to the SARS-CoV-2 pandemic focused on non-pharmaceutical interventions, some of which aimed to reduce transmission by changing mixing patterns between people. Aggregated location data from mobile phones are an important source of real-time information about human mobility on a population level, but the degree to which these mobility metrics capture the relevant contact patterns of individuals at risk of transmitting SARS-CoV-2 is not clear. In this study we describe changes in the relationship between mobile phone data and SARS-CoV-2 transmission in the USA. Methods In this population-based study, we collected epidemiological data on COVID-19 cases and deaths, as well as human mobility metrics collated by advertisement technology that was derived from global positioning systems, from 1396 counties across the USA that had at least 100 laboratory-confirmed cases of COVID-19. We grouped these counties into six ordinal categories, defined by the National Center for Health Statistics (NCHS) and graded from urban to rural, and quantified the changes in COVID-19 transmission using estimates of the effective reproduction number (Rt) between Jan 22 and July 9, 2020, to investigate the relationship between aggregated mobility metrics and epidemic trajectory. For each county, we model the time series of Rt values with mobility proxies. Findings We show that the reproduction number is most strongly associated with mobility proxies for change in the travel into counties (0·757 [95% CI 0·689 to 0·857]), but this relationship primarily holds for counties in the three most urban categories as defined by the NCHS. This relationship weakens considerably after the initial 15 weeks of the epidemic (0·442 [−0·492 to −0·392]), consistent with the emergence of more complex local policies and behaviours, including masking. Interpretation Our study shows that the integration of mobility metrics into retrospective modelling efforts can be useful in identifying links between these metrics and Rt. Importantly, we highlight potential issues in the data generation process for transmission indicators derived from mobile phone data, representativeness, and equity of access, which must be addressed to improve the interpretability of these data in public health. Funding There was no funding source for this study.

Calcium signaling for host cell death In response to microbial pathogens, some plants kill off their own cells to limit further spread of infection. The Toll/Interleukin-1 receptor/Resistance class of nucleotide-binding leucine-rich repeat receptors (known as TNLs) function in plants as immune receptors. These TNLs work together with a dedicated set of helper proteins. Jacob et al. reveal the structure of one of these helpers known as NRG1 (N REQUIREMENT GENE 1). The structure resembles a known animal cation channel. The authors demonstrate that helper NLRs directly control calcium ion influx to initiate host cell death, providing a mechanism for TNL outputs. Science , abg7917, this issue p. 420

We are very grateful to all commenters for their stimulating remarks, questions, as well as useful pointers to the literature which span a wide range of statistical methods over decades of research...

Some plant NLR immune receptors are encoded in head-to-head pairs that function together. Alleles of the NLR pair CHS3/CSA1 form three clades. The clade 1 sensor CHS3 contains an integrated domain (ID) with homology to regulatory domains, which is lacking in clades 2 and 3. We defined two regulatory modes for CHS3/CSA1 pairs. One is likely mediated by effector binding to the clade 1 ID of CHS3 and the other relies on CHS3/CSA1 pairs from all clades detecting effector modification of an associated pattern recognition receptor. We suggest that an ancestral Arabidopsis CHS3/CSA1 pair gained a second recognition specificity and regulatory mechanism through ID acquisition, while retaining its original specificity as a ‘Guard’ against perturbation of pattern recognition receptor targeting by a pathogen effector. This likely comes with a cost, since both ID and non-ID alleles of the pair persist in diverse Arabidopsis populations through balancing selection.SummaryWe dissect a novel case where two regulatory modes emerged across three clades of the co-evolved CHS3/CSA1 plant immune receptor pairs, which features recruitment of an integrated domain (ID) into the clade 1 CHS3 alleles. Pre- and post-ID integration alleles maintain functionality; balancing selection maintains both in the Arabidopsis pan-genome.

We investigated whether communicative cues help observers to make sense of human interaction. We recorded EEG from an observer monitoring two individuals who were occasionally communicating with each other via either mutual eye contact and/or pointing gestures, and then jointly attending to the same object or attending to different objects that were placed on a table in front of them. The analyses were focussed on the processing of the interaction outcome (i.e. presence or absence of joint attention) and showed that its interpretation is a two-stage process, as reflected in the N300 and the N400 potentials. The N300 amplitude was reduced when the two individuals shared their focus of attention, which indicates the operation of a cognitive process that involves the relatively fast identification and evaluation of actor–object relationships. On the other hand, the N400 was insensitive to the sharing or distribution of the two individuals’ attentional focus. Interestingly, the N400 was reduced when the interaction outcome was preceded either by mutual eye contact or by a perceived pointing gesture. This shows that observation of communication “opens up” the mind to a wider range of action possibilities and thereby helps to interpret unusual outcomes of social interactions.

Résumé Jules Vuillemin était un philosophe érudit et savant ; il entretenait avec la philosophie analytique de son temps une relation étroite, mais rendue énigmatique par sa fidélité au principe de l’inséparabilité entre la philosophie et l’histoire de la philosophie hérité de l’historien de la philosophie, Martial Gueroult. La question principale que je me pose ici est de savoir quelle était l’attitude exacte de Vuillemin à l’égard de la triple controverse entre Quine et Carnap provoquée par les critiques dirigées par Quine contre la tripartition de Carnap entre les propositions analytiques (de la logique et des mathématiques), les propositions synthétiques (des sciences expérimentales) et les choix ontologiques purement pragmatiques. Tout en souscrivant à la tripartition carnapienne, Vuillemin réprouvait l’idée positiviste de l’irrésolubilité des controverses ontologiques et défendait, au nom de la liberté de la raison spéculative, l’idée de la pluralité des solutions.

Summary Markov chain Monte Carlo (MCMC) methods provide consistent approximations of integrals as the number of iterations goes to ∞. MCMC estimators are generally biased after any fixed number of iterations. We propose to remove this bias by using couplings of Markov chains together with a telescopic sum argument of Glynn and Rhee. The resulting unbiased estimators can be computed independently in parallel. We discuss practical couplings for popular MCMC algorithms. We establish the theoretical validity of the estimators proposed and study their efficiency relative to the underlying MCMC algorithms. Finally, we illustrate the performance and limitations of the method on toy examples, on an Ising model around its critical temperature, on a high dimensional variable-selection problem, and on an approximation of the cut distribution arising in Bayesian inference for models made of multiple modules.

Non-cognitive gadgets are fancy tools shaped to meet specific, local needs. Cecilia Heyes defines cognitive gadgets as dedicated psychological mechanisms (e.g. cooking and sporting expertise) created through social interactions and culturally, not genetically, inherited by humans. She has boldly proposed that many human cognitive mechanisms (including imitation, numeracy, literacy, language and mindreading) are gadgets. If true, these claims would have far-reaching implications for our scientific understanding of human social cognition. Here we assess Heyes’s cognitive gadget approach as it applies to mindreading. We do not think that the evidence supports Heyes’s thought-provoking thesis that human children are taught to read minds the way they are taught to read words. We highlight a potential circularity lurking behind this analogy, and we explain why we are unpersuaded by Heyes’s anti-mentalistic proposal for handling data inconsistent with the gadget view, which others take to be evidence for mindreading in human infancy. We conclude that while human minds may well be filled with gadgets, mindreading is unlikely to be one of them.

Some plant NLR immune receptors are encoded in head-to-head "sensor-executor" pairs that function together. Alleles of the NLR pair CHS3/CSA1 form three clades. The clade 1 sensor CHS3 contains an integrated domain (ID) with homology to regulatory domains, which is lacking in clades 2 and 3. In this study, we defined two cell-death regulatory modes for CHS3/CSA1 pairs. One is mediated by ID domain on clade 1 CHS3, and the other relies on CHS3/CSA1 pairs from all clades detecting perturbation of an associated pattern-recognition receptor (PRR) co-receptor. Our data support the hypothesis that an ancestral Arabidopsis CHS3/CSA1 pair gained a second recognition specificity and regulatory mechanism through ID acquisition while retaining its original specificity as a "guard" against PRR co-receptor perturbation. This likely comes with a cost, since both ID and non-ID alleles of the pair persist in diverse Arabidopsis populations through balancing selection.

Statistical inference can be performed by minimizing, over the parameter space, the Wasserstein distance between model distributions and the empirical distribution of the data. We study asymptotic properties of such minimum Wasserstein distance estimators, complementing results derived by Bassetti, Bodini and Regazzini in 2006. In particular, our results cover the misspecified setting, in which the data-generating process is not assumed to be part of the family of distributions described by the model. Our results are motivated by recent applications of minimum Wasserstein estimators to complex generative models. We discuss some difficulties arising in the approximation of these estimators and illustrate their behavior in several numerical experiments. Two of our examples are taken from the literature on approximate Bayesian computation and have likelihood functions that are not analytically tractable. Two other examples involve misspecified models., Comment: 29 pages (+18 pages of appendices), 6 figures. To appear in Information and Inference: A Journal of the IMA. A previous version of this paper contained work on approximate Bayesian computation with the Wasserstein distance, which can now be found at arxiv:1905.03747

In a (2018) paper published in Psychological Review, Tyler Burge has offered a unified non-mentalistic account of a wide range of social cognitive developmental findings. His proposal is that far from attributing mental states (e.g. beliefs), young children attribute to humans the same kind of internal generic states of sensory registration that biologists attribute to e.g. snails and ticks. Burge’s proposal deserves close attention: it is especially challenging because it departs from both the mentalistic and all the non-mentalistic accounts of the data so far. Moreover Burge has been one of the leading philosophers of mind of the past 40 years and some of his writings on the objectivity of perception display a deep understanding of the relevance of science for sharpening our understanding of the mind. After taking a close look at the developmental evidence, in particular at false-belief studies, I argue that Burge’s (Psychological Review, 125(3), 409–434, 2018) account faces severe obstacles. To give one telling example: if young children can only attribute to others sensory registrations, then it is hard to explain the evidence showing that they respond differently to an agent’s ignorance and to her false belief.

1.AbstractUnderstanding the relatedness of individuals within or between populations is a common goal in biology. Increasingly, relatedness features in genetic epidemiology studies of pathogens. These studies are relatively new compared to those in humans and other organisms, but are important for designing interventions and understanding pathogen transmission. Only recently have researchers begun to routinely apply relatedness to apicomplexan eukaryotic malaria parasites, and to date have used a range of different approaches on an ad hoc basis. It remains unclear how to compare different studies, therefore, and which measures to use. Here, we systematically compare measures based on identity-by-state and identity-by-descent using a globally diverse data set of malaria parasites,Plasmodium falciparumandPlasmodium vivax, and provide marker requirements for estimates based on identity-by-descent. We formally show that the informativeness of polyallelic markers for relatedness inference is maximised when alleles are equifrequent. Estimates based on identity-by-state are sensitive to allele frequencies, which vary across populations and by experimental design. For portability across studies, we thus recommend estimates based on identity-by-descent. To generate reliable estimates, we recommend approximately 200 biallelic or 100 polyallelic markers. Confidence intervals illuminate inference across studies based on different sets of markers. These marker requirements, unlike many thus far reported, are immediately applicable to haploid malaria parasites and other haploid eukaryotes. This is the first attempt to provide rigorous analysis of the reliability of, and requirements for, relatedness inference in malaria genetic epidemiology, and will provide a basis for statistically informed prospective study design and surveillance strategies.

Summary We propose a method for parallelization of Hamiltonian Monte Carlo estimators. Our approach involves constructing a pair of Hamiltonian Monte Carlo chains that are coupled in such a way that they meet exactly after some random number of iterations. These chains can then be combined so that the resulting estimators are unbiased. This allows us to produce independent replicates in parallel and average them to obtain estimators that are consistent in the limit of the number of replicates, rather than in the usual limit of the number of Markov chain iterations. We investigate the scalability of our coupling in high dimensions on a toy example. The choice of algorithmic parameters and the efficiency of our proposed approach are then illustrated on a logistic regression with 300 covariates and a log-Gaussian Cox point processes model with low- to fine-grained discretizations.

A growing number of generative statistical models do not permit the numerical evaluation of their likelihood functions. Approximate Bayesian computation (ABC) has become a popular approach to overcome this issue, in which one simulates synthetic data sets given parameters and compares summaries of these data sets with the corresponding observed values. We propose to avoid the use of summaries and the ensuing loss of information by instead using the Wasserstein distance between the empirical distributions of the observed and synthetic data. This generalizes the well-known approach of using order statistics within ABC to arbitrary dimensions. We describe how recently developed approximations of the Wasserstein distance allow the method to scale to realistic data sizes, and propose a new distance based on the Hilbert space-filling curve. We provide a theoretical study of the proposed method, describing consistency as the threshold goes to zero while the observations are kept fixed, and concentration properties as the number of observations grows. Various extensions to time series data are discussed. The approach is illustrated on various examples, including univariate and multivariate g-and-k distributions, a toggle switch model from systems biology, a queueing model, and a L\'evy-driven stochastic volatility model., Comment: 42 pages, 10 figures. Supplementary materials can be found on the first author's webpage. Portions of this work previously appeared as arXiv:1701.05146

Global efforts to prevent the spread of the SARS-COV-2 pandemic in early 2020 focused on non-pharmaceutical interventions like social distancing; policies that aim to reduce transmission by changing mixing patterns between people. As countries have implemented these interventions, aggregated location data from mobile phones have become an important source of real-time information about human mobility and behavioral changes on a population level. Human activity measured using mobile phones reflects the aggregate behavior of a subset of people, and although metrics of mobility are related to contact patterns between people that spread the coronavirus, they do not provide a direct measure. In this study, we use results from a nowcasting approach from 1,396 counties across the US between January 22nd, 2020 and July 9th, 2020 to determine the effective reproductive number (R(t)) along an urban/rural gradient. For each county, we compare the time series of R(t) values with mobility proxies from mobile phone data from Camber Systems, an aggregator of mobility data from various providers in the United States. We show that the reproduction number is most strongly associated with mobility proxies for change in the travel into counties compared to baseline, but that the relationship weakens considerably after the initial 15 weeks of the epidemic, consistent with the emergence of a more complex ecosystem of local policies and behaviors including masking. Importantly, we highlight potential issues in the data generation process, representativeness and equity of access which must be addressed to allow for general use of these data in public health.

Background: The stepped wedge cluster randomised trial is an increasingly common trial design. The design can be useful for informing real-world clinical decision-making, including decisions about the effectiveness of interventions in particular subgroups. However, there is little existing guidance about how to perform subgroup analyses in the stepped wedge design. We aim to determine the prevalence of subgroup analyses and describe statistical methods used to perform them in stepped wedge cluster randomised trials.Methods: We will conduct a systematic review following the methodology recommended in the Cochrane Handbook for Systematic Reviews of Interventions. We report this protocol according to the PRISMA-P checklist. The protocol has been registered in the Open Science Framework. We will search for terms related to ‘stepped wedge’. Sources will be PubMed, Embase, PsycINFO, Web of Science, CINAHL, Cochrane Library, and Current Controlled Trials Register up to 16 October 2020. Studies will be eligible if they are written in English, involve human participants and are primary or secondary reports of planned or completed stepped wedge cluster randomised trials. Two reviewers will first screen the titles and abstracts, then full texts, to select studies that should be included in the review. Disagreements will be solved by consensus through discussion with a third reviewer. We will extract data related to study characteristics including presence or absence of subgroup analyses, characteristics of subgroup variables examined, statistical methods used to perform subgroup analyses, and adherence to the most consistently recommendations suggested for subgroup analyses in general including in clinical trials. We will perform a qualitative synthesis of the extracted data.Discussion: This protocol offers a reproducible and transparent procedure for a systematic review of the literature. It will provide a portrait of the frequency and types of subgroup analyses performed in stepped wedge cluster randomised trials. These results will inform the development of recommendations for subgroup analyses in such trials.Systematic review registration: This protocol has been registered on Open Science Framework, Registration ID: https://osf.io/2kwrz.