Lin Liu, Yuqi Qiu, Loki Natarajan, Karen Messer.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1370--1396.

Abstract:
It is common to encounter missing data among the potential predictor variables in the setting of model selection. For example, in a recent study we attempted to improve the US guidelines for risk stratification after screening colonoscopy ( Cancer Causes Control 27 (2016) 1175–1185), with the aim to help reduce both overuse and underuse of follow-on surveillance colonoscopy. The goal was to incorporate selected additional informative variables into a neoplasia risk-prediction model, going beyond the three currently established risk factors, using a large dataset pooled from seven different prospective studies in North America. Unfortunately, not all candidate variables were collected in all studies, so that one or more important potential predictors were missing on over half of the subjects. Thus, while variable selection was a main focus of the study, it was necessary to address the substantial amount of missing data. Multiple imputation can effectively address missing data, and there are also good approaches to incorporate the variable selection process into model-based confidence intervals. However, there is not consensus on appropriate methods of inference which address both issues simultaneously. Our goal here is to study the properties of model-based confidence intervals in the setting of imputation for missing data followed by variable selection. We use both simulation and theory to compare three approaches to such post-imputation-selection inference: a multiple-imputation approach based on Rubin’s Rules for variance estimation ( Comput. Statist. Data Anal. 71 (2014) 758–770); a single imputation-selection followed by bootstrap percentile confidence intervals; and a new bootstrap model-averaging approach presented here, following Efron ( J. Amer. Statist. Assoc. 109 (2014) 991–1007). We investigate relative strengths and weaknesses of each method. The “Rubin’s Rules” multiple imputation estimator can have severe undercoverage, and is not recommended. The imputation-selection estimator with bootstrap percentile confidence intervals works well. The bootstrap-model-averaged estimator, with the “Efron’s Rules” estimated variance, may be preferred if the true effect sizes are moderate. We apply these results to the colorectal neoplasia risk-prediction problem which motivated the present work.

Peter Bank, Yan Dolinsky.

Source: Bernoulli, Volume 26, Number 3, 2176--2201.

Abstract:
We prove a scaling limit theorem for the super-replication cost of options in a Cox–Ross–Rubinstein binomial model with transient price impact. The correct scaling turns out to keep the market depth parameter constant while resilience over fixed periods of time grows in inverse proportion with the duration between trading times. For vanilla options, the scaling limit is found to coincide with the one obtained by PDE-methods in ( Math. Finance 22 (2012) 250–276) for models with purely temporary price impact. These models are a special case of our framework and so our probabilistic scaling limit argument allows one to expand the scope of the scaling limit result to path-dependent options.

Javier Cárcamo, Antonio Cuevas, Luis-Alberto Rodríguez.

Source: Bernoulli, Volume 26, Number 3, 2143--2175.

Abstract:
We show that various functionals related to the supremum of a real function defined on an arbitrary set or a measure space are Hadamard directionally differentiable. We specifically consider the supremum norm, the supremum, the infimum, and the amplitude of a function. The (usually non-linear) derivatives of these maps adopt simple expressions under suitable assumptions on the underlying space. As an application, we improve and extend to the multidimensional case the results in Raghavachari ( Ann. Statist. 1 (1973) 67–73) regarding the limiting distributions of Kolmogorov–Smirnov type statistics under the alternative hypothesis. Similar results are obtained for analogous statistics associated with copulas. We additionally solve an open problem about the Berk–Jones statistic proposed by Jager and Wellner (In A Festschrift for Herman Rubin (2004) 319–331 IMS). Finally, the asymptotic distribution of maximum mean discrepancies over Donsker classes of functions is derived.

Akio Fujiwara, Koichi Yamagata.

Source: Bernoulli, Volume 26, Number 3, 2105--2142.

Abstract:
We herein develop a theory of contiguity in the quantum domain based upon a novel quantum analogue of the Lebesgue decomposition. The theory thus formulated is pertinent to the weak quantum local asymptotic normality introduced in the previous paper [Yamagata, Fujiwara, and Gill, Ann. Statist. 41 (2013) 2197–2217], yielding substantial enlargement of the scope of quantum statistics.

Ulrike Mayer, Henryk Zähle, Zhou Zhou.

Source: Bernoulli, Volume 26, Number 3, 1891--1911.

Abstract:
We derive a functional weak limit theorem for a local empirical process of a wide class of piece-wise locally stationary (PLS) time series. The latter result is applied to derive the asymptotics of weighted empirical quantiles and weighted V-statistics of non-stationary time series. The class of admissible underlying time series is illustrated by means of PLS linear processes and PLS ARCH processes.

Holger Sambale, Arthur Sinulis.

Source: Bernoulli, Volume 26, Number 3, 1863--1890.

Abstract:
We derive sufficient conditions for a probability measure on a finite product space (a spin system ) to satisfy a (modified) logarithmic Sobolev inequality. We establish these conditions for various examples, such as the (vertex-weighted) exponential random graph model, the random coloring and the hard-core model with fugacity. This leads to two separate branches of applications. The first branch is given by mixing time estimates of the Glauber dynamics. The proofs do not rely on coupling arguments, but instead use functional inequalities. As a byproduct, this also yields exponential decay of the relative entropy along the Glauber semigroup. Secondly, we investigate the concentration of measure phenomenon (particularly of higher order) for these spin systems. We show the effect of better concentration properties by centering not around the mean, but around a stochastic term in the exponential random graph model. From there, one can deduce a central limit theorem for the number of triangles from the CLT of the edge count. In the Erdős–Rényi model the first-order approximation leads to a quantification and a proof of a central limit theorem for subgraph counts.

Sébastien Gadat, Sébastien Gerchinovitz, Clément Marteau.

Source: Bernoulli, Volume 26, Number 3, 1797--1831.

Abstract:
We consider the binary supervised classification problem with the Gaussian functional model introduced in ( Math. Methods Statist. 22 (2013) 213–225). Taking advantage of the Gaussian structure, we design a natural plug-in classifier and derive a family of upper bounds on its worst-case excess risk over Sobolev spaces. These bounds are parametrized by a separation distance quantifying the difficulty of the problem, and are proved to be optimal (up to logarithmic factors) through matching minimax lower bounds. Using the recent works of (In Advances in Neural Information Processing Systems (2014) 3437–3445 Curran Associates) and ( Ann. Statist. 44 (2016) 982–1009), we also derive a logarithmic lower bound showing that the popular $k$-nearest neighbors classifier is far from optimality in this specific functional setting.

Stanislav Minsker, Xiaohan Wei.

Source: Bernoulli, Volume 26, Number 1, 694--727.

Abstract:
Let $Y$ be a $d$-dimensional random vector with unknown mean $mu $ and covariance matrix $Sigma $. This paper is motivated by the problem of designing an estimator of $Sigma $ that admits exponential deviation bounds in the operator norm under minimal assumptions on the underlying distribution, such as existence of only 4th moments of the coordinates of $Y$. To address this problem, we propose robust modifications of the operator-valued U-statistics, obtain non-asymptotic guarantees for their performance, and demonstrate the implications of these results to the covariance estimation problem under various structural assumptions.

Mingjie Liang, René L. Schilling, Jian Wang.

Source: Bernoulli, Volume 26, Number 1, 664--693.

Abstract:
We present a general method to construct couplings of stochastic differential equations driven by Lévy noise in terms of coupling operators. This approach covers both coupling by reflection and refined basic coupling which are often discussed in the literature. As applications, we prove regularity results for the transition semigroups and obtain successful couplings for the solutions to stochastic differential equations driven by additive Lévy noise.

Nicolas Privault, Grzegorz Serafin.

Source: Bernoulli, Volume 26, Number 1, 587--615.

Abstract:
We derive normal approximation bounds in the Kolmogorov distance for sums of discrete multiple integrals and weighted $U$-statistics made of independent Bernoulli random variables. Such bounds are applied to normal approximation for the renormalized subgraph counts in the Erdős–Rényi random graph. This approach completely solves a long-standing conjecture in the general setting of arbitrary graph counting, while recovering recent results obtained for triangles and improving other bounds in the Wasserstein distance.

Eric Beutner, Laurent Bordes, Laurent Doyen.

Source: Bernoulli, Volume 26, Number 1, 557--586.

Abstract:
Virtual age models are very useful to analyse recurrent events. Among the strengths of these models is their ability to account for treatment (or intervention) effects after an event occurrence. Despite their flexibility for modeling recurrent events, the number of applications is limited. This seems to be a result of the fact that in the semiparametric setting all the existing results assume the virtual age function that describes the treatment (or intervention) effects to be known. This shortcoming can be overcome by considering semiparametric virtual age models with parametrically specified virtual age functions. Yet, fitting such a model is a difficult task. Indeed, it has recently been shown that for these models the standard profile likelihood method fails to lead to consistent estimators. Here we show that consistent estimators can be constructed by smoothing the profile log-likelihood function appropriately. We show that our general result can be applied to most of the relevant virtual age models of the literature. Our approach shows that empirical process techniques may be a worthwhile alternative to martingale methods for studying asymptotic properties of these inference methods. A simulation study is provided to illustrate our consistency results together with an application to real data.

Xiucai Ding.

Source: Bernoulli, Volume 26, Number 1, 387--417.

Abstract:
We consider the recovery of a low rank $M imes N$ matrix $S$ from its noisy observation $ ilde{S}$ in the high dimensional framework when $M$ is comparable to $N$. We propose two efficient estimators for $S$ under two different regimes. Our analysis relies on the local asymptotics of the eigenstructure of large dimensional rectangular matrices with finite rank perturbation. We derive the convergent limits and rates for the singular values and vectors for such matrices.

Fangzheng Xie, Yanxun Xu.

Source: Bayesian Analysis, Volume 15, Number 1, 159--186.

Abstract:
We propose a kernel mixture of polynomials prior for Bayesian nonparametric regression. The regression function is modeled by local averages of polynomials with kernel mixture weights. We obtain the minimax-optimal contraction rate of the full posterior distribution up to a logarithmic factor by estimating metric entropies of certain function classes. Under the assumption that the degree of the polynomials is larger than the unknown smoothness level of the true function, the posterior contraction behavior can adapt to this smoothness level provided an upper bound is known. We also provide a frequentist sieve maximum likelihood estimator with a near-optimal convergence rate. We further investigate the application of the kernel mixture of polynomials to partial linear models and obtain both the near-optimal rate of contraction for the nonparametric component and the Bernstein-von Mises limit (i.e., asymptotic normality) of the parametric component. The proposed method is illustrated with numerical examples and shows superior performance in terms of computational efficiency, accuracy, and uncertainty quantification compared to the local polynomial regression, DiceKriging, and the robust Gaussian stochastic process.

Lizhen Lin, Niu Mu, Pokman Cheung, David Dunson.

Source: Bayesian Analysis, Volume 14, Number 3, 907--926.

Abstract:
Gaussian processes (GPs) are very widely used for modeling of unknown functions or surfaces in applications ranging from regression to classification to spatial processes. Although there is an increasingly vast literature on applications, methods, theory and algorithms related to GPs, the overwhelming majority of this literature focuses on the case in which the input domain corresponds to a Euclidean space. However, particularly in recent years with the increasing collection of complex data, it is commonly the case that the input domain does not have such a simple form. For example, it is common for the inputs to be restricted to a non-Euclidean manifold, a case which forms the motivation for this article. In particular, we propose a general extrinsic framework for GP modeling on manifolds, which relies on embedding of the manifold into a Euclidean space and then constructing extrinsic kernels for GPs on their images. These extrinsic Gaussian processes (eGPs) are used as prior distributions for unknown functions in Bayesian inferences. Our approach is simple and general, and we show that the eGPs inherit fine theoretical properties from GP models in Euclidean spaces. We consider applications of our models to regression and classification problems with predictors lying in a large class of manifolds, including spheres, planar shape spaces, a space of positive definite matrices, and Grassmannians. Our models can be readily used by practitioners in biological sciences for various regression and classification problems, such as disease diagnosis or detection. Our work is also likely to have impact in spatial statistics when spatial locations are on the sphere or other geometric spaces.

Daniela Pauger, Helga Wagner.

Source: Bayesian Analysis, Volume 14, Number 2, 341--369.

Abstract:
We propose a Bayesian approach to obtain a sparse representation of the effect of a categorical predictor in regression type models. As this effect is captured by a group of level effects, sparsity cannot only be achieved by excluding single irrelevant level effects or the whole group of effects associated to this predictor but also by fusing levels which have essentially the same effect on the response. To achieve this goal, we propose a prior which allows for almost perfect as well as almost zero dependence between level effects a priori. This prior can alternatively be obtained by specifying spike and slab prior distributions on all effect differences associated to this categorical predictor. We show how restricted fusion can be implemented and develop an efficient MCMC (Markov chain Monte Carlo) method for posterior computation. The performance of the proposed method is investigated on simulated data and we illustrate its application on real data from EU-SILC (European Union Statistics on Income and Living Conditions).

Peter D. Hoff

Source: Bayesian Anal., Volume 6, Number 2, 179--196.

Abstract:
Modern datasets are often in the form of matrices or arrays, potentially having correlations along each set of data indices. For example, data involving repeated measurements of several variables over time may exhibit temporal correlation as well as correlation among the variables. A possible model for matrix-valued data is the class of matrix normal distributions, which is parametrized by two covariance matrices, one for each index set of the data. In this article we discuss an extension of the matrix normal model to accommodate multidimensional data arrays, or tensors. We show how a particular array-matrix product can be used to generate the class of array normal distributions having separable covariance structure. We derive some properties of these covariance structures and the corresponding array normal distributions, and show how the array-matrix product can be used to define a semi-conjugate prior distribution and calculate the corresponding posterior distribution. We illustrate the methodology in an analysis of multivariate longitudinal network data which take the form of a four-way array.

Ruosi Guo, Chunming Zhang, Zhengjun Zhang.

Source: Statistical Science, Volume 35, Number 1, 145--157.

Abstract:
In many scientific disciplines, finding hidden influential factors behind observational data is essential but challenging. The majority of existing approaches, such as the independent component analysis (${mathrm{ICA}}$), rely on linear transformation, that is, true signals are linear combinations of hidden components. Motivated from analyzing nonlinear temporal signals in neuroscience, genetics, and finance, this paper proposes the “maximum independent component analysis” (${mathrm{MaxICA}}$), based on max-linear combinations of components. In contrast to existing methods, ${mathrm{MaxICA}}$ benefits from focusing on significant major components while filtering out ignorable components. A major tool for parameter learning of ${mathrm{MaxICA}}$ is an augmented genetic algorithm, consisting of three schemes for the elite weighted sum selection, randomly combined crossover, and dynamic mutation. Extensive empirical evaluations demonstrate the effectiveness of ${mathrm{MaxICA}}$ in either extracting max-linearly combined essential sources in many applications or supplying a better approximation for nonlinearly combined source signals, such as $mathrm{EEG}$ recordings analyzed in this paper.

Gregorio Quintana-Ortí, Amelia Simó.

Source: Statistical Science, Volume 34, Number 2, 236--252.

Abstract:
This paper is focused on kernel regression when the response variable is the shape of a 3D object represented by a configuration matrix of landmarks. Regression methods on this shape space are not trivial because this space has a complex finite-dimensional Riemannian manifold structure (non-Euclidean). Papers about it are scarce in the literature, the majority of them are restricted to the case of a single explanatory variable, and many of them are based on the approximated tangent space. In this paper, there are several methodological innovations. The first one is the adaptation of the general method for kernel regression analysis in manifold-valued data to the three-dimensional case of Kendall’s shape space. The second one is its generalization to the multivariate case and the addressing of the curse-of-dimensionality problem. Finally, we propose bootstrap confidence intervals for prediction. A simulation study is carried out to check the goodness of the procedure, and a comparison with a current approach is performed. Then, it is applied to a 3D database obtained from an anthropometric survey of the Spanish child population with a potential application to online sales of children’s wear.

Jasper Akerboom
Oct 3, 2012; 32:13819-13840
Cellular

WD Knowles
Nov 1, 1981; 1:1236-1241
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Brian Zingg
Apr 15, 2020; 40:3250-3267
Systems/Circuits

KM Harris
Jul 1, 1992; 12:2685-2705
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Jasper Akerboom
Oct 3, 2012; 32:13819-13840
Cellular

P Seguela
Feb 1, 1993; 13:596-604
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Guo-qiang Bi
Dec 15, 1998; 18:10464-10472
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Italian translation of the BIS press release about the BIS Quarterly Review, December 2017

Italian translation of the BIS press release about the BIS Quarterly Review, March 2018

Italian translation of the BIS press release about the BIS Quarterly Review, September 2018

Italian translation of the BIS press release about the BIS Quarterly Review, March 2019

French translation of the Basel Committee is publishing "Sound Practices: implications of fintech developments for banks and bank supervisors", February 2018.

French translation of "Pillar 3 disclosure requirements - updated framework", December 2018

02020-02-09: Yucatan Peninsula

Based on remarks by Mr Luiz Awazu Pereira da Silva, Deputy General Manager of the BIS, with Jon Frost and Leonardo Gambacorta at the Santander International Banking Conference on "Banking on trust: Building confidence in the future", Madrid, 5 November 2019.

Human ventral temporal cortex (VTC) is critical for visual recognition. It is thought that this ability is supported by large-scale patterns of activity across VTC that contain information about visual categories. However, it is unknown how category representations in VTC are organized at the submillimeter scale and across cortical depths. To fill this gap in knowledge, we measured BOLD responses in medial and lateral VTC to images spanning 10 categories from five domains (written characters, bodies, faces, places, and objects) at an ultra-high spatial resolution of 0.8 mm using 7 Tesla fMRI in both male and female participants. Representations in lateral VTC were organized most strongly at the general level of domains (e.g., places), whereas medial VTC was also organized at the level of specific categories (e.g., corridors and houses within the domain of places). In both lateral and medial VTC, domain-level and category-level structure decreased with cortical depth, and downsampling our data to standard resolution (2.4 mm) did not reverse differences in representations between lateral and medial VTC. The functional diversity of representations across VTC partitions may allow downstream regions to read out information in a flexible manner according to task demands. These results bridge an important gap between electrophysiological recordings in single neurons at the micron scale in nonhuman primates and standard-resolution fMRI in humans by elucidating distributed responses at the submillimeter scale with ultra-high-resolution fMRI in humans.

SIGNIFICANCE STATEMENT Visual recognition is a fundamental ability supported by human ventral temporal cortex (VTC). However, the nature of fine-scale, submillimeter distributed representations in VTC is unknown. Using ultra-high-resolution fMRI of human VTC, we found differential distributed visual representations across lateral and medial VTC. Domain representations (e.g., faces, bodies, places, characters) were most salient in lateral VTC, whereas category representations (e.g., corridors/houses within the domain of places) were equally salient in medial VTC. These results bridge an important gap between electrophysiological recordings in single neurons at a micron scale and fMRI measurements at a millimeter scale.

Revealing the organization and function of neural circuits is greatly facilitated by viral tools that spread transsynaptically. Adeno-associated virus (AAV) exhibits anterograde transneuronal transport, however, the synaptic specificity of this spread and its broad application within a diverse set of circuits remains to be explored. Here, using anatomic, functional, and molecular approaches, we provide evidence for the preferential transport of AAV1 to postsynaptically connected neurons and reveal its spread is strongly dependent on synaptic transmitter release. In addition to glutamatergic pathways, AAV1 also spreads through GABAergic synapses to both excitatory and inhibitory cell types. We observed little or no transport, however, through neuromodulatory projections (e.g., serotonergic, cholinergic, and noradrenergic). In addition, we found that AAV1 can be transported through long-distance descending projections from various brain regions to effectively transduce spinal cord neurons. Combined with newly designed intersectional and sparse labeling strategies, AAV1 can be applied within a wide variety of pathways to categorize neurons according to their input sources, morphology, and molecular identities. These properties make AAV1 a promising anterograde transsynaptic tool for establishing a comprehensive cell-atlas of the brain, although its capacity for retrograde transport currently limits its use to unidirectional circuits.

SIGNIFICANCE STATEMENT The discovery of anterograde transneuronal spread of AAV1 generates great promise for its application as a unique tool for manipulating input-defined cell populations and mapping their outputs. However, several outstanding questions remain for anterograde transsynaptic approaches in the field: (1) whether AAV1 spreads exclusively or specifically to synaptically connected neurons, and (2) how broad its application could be in various types of neural circuits in the brain. This study provides several lines of evidence in terms of anatomy, functional innervation, and underlying mechanisms, to strongly support that AAV1 anterograde transneuronal spread is highly synapse specific. In addition, several potentially important applications of transsynaptic AAV1 in probing neural circuits are described.

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.

SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

Autism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, reflected in exaggerated and variable responses to sensory stimuli. Attentional engagement is known to be regulated by the locus ceruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether, under different attentional task demands, individuals with ASD exhibit a different profile of LC activity compared with typically developing controls. Males and females with ASD and age- and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses, an established correlate for LC activity, were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared with controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed specifically in response to task-relevant events, providing confirmation that the group differences most likely were specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.

SIGNIFICANCE STATEMENT Individuals with autism spectrum disorder (ASD) exhibit atypical attentional behaviors, including altered sensory responses and atypical fixedness, but the neural mechanism underlying these behaviors remains elusive. One candidate mechanism is atypical locus ceruleus (LC) activity, as the LC plays a critical role in attentional modulation. Specifically, LC activity is involved in regulating the trade-off between environmental exploration and focused attention. This study shows that, under tightly controlled conditions, task-evoked pupil responses, an LC activity proxy, are lower in individuals with ASD than in controls, but only in the presence of task-irrelevant stimuli. This suggests that individuals with ASD evince atypical modulation of LC activity in accordance with changes in attentional demands, offering a mechanistic account for attentional atypicalities in ASD.

MECP2 gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene–circuit–behavior analyses including MECP2 coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5 MECP2 overexpressed monkeys (Macaca fascicularis; 3 females) and 20 wild-type monkeys (Macaca fascicularis; 11 females). Whole-genome expression analysis revealed MECP2 coexpressed genes significantly enriched in GABA-related signaling pathways, whereby reduced β-synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile, MECP2-induced hyperconnectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 patients with autism and 72 healthy controls of 1112 subjects using functional connectivity patterns, and identified dysconnectivity profiles similar to those in monkeys. By establishing a circuit-based construct link between genetically defined models and stratified patients, these results pave new avenues to deconstruct clinical heterogeneity and advance accurate diagnosis in psychiatric disorders.

SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a complex disorder with co-occurring symptoms caused by multiple genetic variations and brain circuit abnormalities. To dissect the gene–circuit–behavior causal chain underlying ASD, animal models are established by manipulating causative genes such as MECP2. However, it is unknown whether such models have captured any circuit-level pathology in ASD patients, as demonstrated by human brain imaging studies. Here, we use transgenic macaques to examine the causal effect of MECP2 overexpression on gene coexpression, brain circuits, and behaviors. For the first time, we demonstrate that the circuit abnormalities linked to MECP2 and autism-like traits in the monkeys can be mapped to a homogeneous ASD subgroup, thereby offering a new strategy to deconstruct clinical heterogeneity in ASD.

Eradicating hunger must be accompanied by strenuous efforts to end malnutrition and its devastating effects. That was a pivotal message at the launch of FAO’s key publication The State of Food and Agriculture, which this year focuses on Food systems for better nutrition. “FAO’s message is that we must strive for nothing less than the eradication of hunger and malnutrition,” said Director-General [...]

Global food security largely depends on smallholder family farms where in many regions of the world women play a crucial role as both producers and providers of food. Studies show that when women and other rural poor have better access to resources, the benefits are far-reaching. Families are healthier, more children attend school, agricultural productivity improves, incomes increase, and rural communities [...]

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