Takashi Owada, Omer Bobrowski.

Source: Bernoulli, Volume 26, Number 3, 2275--2310.

Abstract:
In this paper, we study the persistent homology associated with topological crackle generated by distributions with an unbounded support. Persistent homology is a topological and algebraic structure that tracks the creation and destruction of topological cycles (generalizations of loops or holes) in different dimensions. Topological crackle is a term that refers to topological cycles generated by random points far away from the bulk of other points, when the support is unbounded. We establish weak convergence results for persistence diagrams – a point process representation for persistent homology, where each topological cycle is represented by its $({mathit{birth},mathit{death}})$ coordinates. In this work, we treat persistence diagrams as random closed sets, so that the resulting weak convergence is defined in terms of the Fell topology. Using this framework, we show that the limiting persistence diagrams can be divided into two parts. The first part is a deterministic limit containing a densely-growing number of persistence pairs with a shorter lifespan. The second part is a two-dimensional Poisson process, representing persistence pairs with a longer lifespan.

Galatia Cleanthous, Athanasios G. Georgiadis, Gerard Kerkyacharian, Pencho Petrushev, Dominique Picard.

Source: Bernoulli, Volume 26, Number 3, 1832--1862.

Abstract:
We consider the problem of estimating the density of observations taking values in classical or nonclassical spaces such as manifolds and more general metric spaces. Our setting is quite general but also sufficiently rich in allowing the development of smooth functional calculus with well localized spectral kernels, Besov regularity spaces, and wavelet type systems. Kernel and both linear and nonlinear wavelet density estimators are introduced and studied. Convergence rates for these estimators are established and discussed.

Pavel Chigansky, Marina Kleptsyna, Dmytro Marushkevych.

Source: Bernoulli, Volume 26, Number 3, 1706--1726.

Abstract:
Spectral decomposition of the covariance operator is one of the main building blocks in the theory and applications of Gaussian processes. Unfortunately, it is notoriously hard to derive in a closed form. In this paper, we consider the eigenproblem for Gaussian bridges. Given a base process, its bridge is obtained by conditioning the trajectories to start and terminate at the given points. What can be said about the spectrum of a bridge, given the spectrum of its base process? We show how this question can be answered asymptotically for a family of processes, including the fractional Brownian motion.

Emanuele Dolera, Stefano Favaro.

Source: Bernoulli, Volume 26, Number 2, 1294--1322.

Abstract:
Given a sequence ${X_{n}}_{ngeq 1}$ of exchangeable Bernoulli random variables, the celebrated de Finetti representation theorem states that $frac{1}{n}sum_{i=1}^{n}X_{i}stackrel{a.s.}{longrightarrow }Y$ for a suitable random variable $Y:Omega ightarrow [0,1]$ satisfying $mathsf{P}[X_{1}=x_{1},dots ,X_{n}=x_{n}|Y]=Y^{sum_{i=1}^{n}x_{i}}(1-Y)^{n-sum_{i=1}^{n}x_{i}}$. In this paper, we study the rate of convergence in law of $frac{1}{n}sum_{i=1}^{n}X_{i}$ to $Y$ under the Kolmogorov distance. After showing that a rate of the type of $1/n^{alpha }$ can be obtained for any index $alpha in (0,1]$, we find a sufficient condition on the distribution of $Y$ for the achievement of the optimal rate of convergence, that is $1/n$. Besides extending and strengthening recent results under the weaker Wasserstein distance, our main result weakens the regularity hypotheses on $Y$ in the context of the Hausdorff moment problem.

Yating Liu, Gilles Pagès.

Source: Bernoulli, Volume 26, Number 2, 1171--1204.

Abstract:
We establish conditions to characterize probability measures by their $L^{p}$-quantization error functions in both $mathbb{R}^{d}$ and Hilbert settings. This characterization is two-fold: static (identity of two distributions) and dynamic (convergence for the $L^{p}$-Wasserstein distance). We first propose a criterion on the quantization level $N$, valid for any norm on $mathbb{R}^{d}$ and any order $p$ based on a geometrical approach involving the Voronoï diagram. Then, we prove that in the $L^{2}$-case on a (separable) Hilbert space, the condition on the level $N$ can be reduced to $N=2$, which is optimal. More quantization based characterization cases in dimension 1 and a discussion of the completeness of a distance defined by the quantization error function can be found at the end of this paper.

Sumit Mukherjee.

Source: Bernoulli, Volume 26, Number 2, 1016--1043.

Abstract:
A sufficient criterion for “non-degeneracy” is given for Exponential Random Graph Models on sparse graphs with sufficient statistics which are functions of the degree sequence. This criterion explains why statistics such as alternating $k$-star are non-degenerate, whereas subgraph counts are degenerate. It is further shown that this criterion is “almost” tight. Existence of consistent estimates is then proved for non-degenerate Exponential Random Graph Models.

Jie Yen Fan, Kais Hamza, Peter Jagers, Fima Klebaner.

Source: Bernoulli, Volume 26, Number 2, 893--926.

Abstract:
We consider a family of general branching processes with reproduction parameters depending on the age of the individual as well as the population age structure and a parameter $K$, which may represent the carrying capacity. These processes are Markovian in the age structure. In a previous paper ( Proc. Steklov Inst. Math. 282 (2013) 90–105), the Law of Large Numbers as $K o infty $ was derived. Here we prove the central limit theorem, namely the weak convergence of the fluctuation processes in an appropriate Skorokhod space. We also show that the limit is driven by a stochastic partial differential equation.

Jing Lei.

Source: Bernoulli, Volume 26, Number 1, 767--798.

Abstract:
We provide upper bounds of the expected Wasserstein distance between a probability measure and its empirical version, generalizing recent results for finite dimensional Euclidean spaces and bounded functional spaces. Such a generalization can cover Euclidean spaces with large dimensionality, with the optimal dependence on the dimensionality. Our method also covers the important case of Gaussian processes in separable Hilbert spaces, with rate-optimal upper bounds for functional data distributions whose coordinates decay geometrically or polynomially. Moreover, our bounds of the expected value can be combined with mean-concentration results to yield improved exponential tail probability bounds for the Wasserstein error of empirical measures under Bernstein-type or log Sobolev-type conditions.

Elena Issoglio, Francesco Russo.

Source: Bernoulli, Volume 26, Number 1, 728--766.

Abstract:
In this paper, we investigate BSDEs where the driver contains a distributional term (in the sense of generalised functions) and derive general Feynman–Kac formulae related to these BSDEs. We introduce an integral operator to give sense to the equation and then we show the existence of a strong solution employing results on a related PDE. Due to the irregularity of the driver, the $Y$-component of a couple $(Y,Z)$ solving the BSDE is not necessarily a semimartingale but a weak Dirichlet process.

Tobias Zwingmann, Hajo Holzmann.

Source: Bernoulli, Volume 26, Number 1, 323--351.

Abstract:
We show weak convergence of quantile and expectile processes to Gaussian limit processes in the space of bounded functions endowed with an appropriate semimetric which is based on the concepts of epi- and hypo- convergence as introduced in A. Bücher, J. Segers and S. Volgushev (2014), ‘ When Uniform Weak Convergence Fails: Empirical Processes for Dependence Functions and Residuals via Epi- and Hypographs ’, Annals of Statistics 42 . We impose assumptions for which it is known that weak convergence with respect to the supremum norm generally fails to hold. For quantiles, we consider stationary observations, where the marginal distribution function is assumed to be strictly increasing and continuous except for finitely many points and to admit strictly positive – possibly infinite – left- and right-sided derivatives. For expectiles, we focus on independent and identically distributed (i.i.d.) observations. Only a finite second moment and continuity at the boundary points but no further smoothness properties of the distribution function are required. We also show consistency of the bootstrap for this mode of convergence in the i.i.d. case for quantiles and expectiles.

Kay Bogerd, Rui M. Castro, Remco van der Hofstad.

Source: Bernoulli, Volume 26, Number 1, 253--285.

Abstract:
We study the asymptotic behavior of the clique number in rank-1 inhomogeneous random graphs, where edge probabilities between vertices are roughly proportional to the product of their vertex weights. We show that the clique number is concentrated on at most two consecutive integers, for which we provide an expression. Interestingly, the order of the clique number is primarily determined by the overall edge density, with the inhomogeneity only affecting multiplicative constants or adding at most a $log log (n)$ multiplicative factor. For sparse enough graphs the clique number is always bounded and the effect of inhomogeneity completely vanishes.

Genetic genealogy -- Handbooks, manuals, etc.

Germans -- South Australia.

Rungie (Family)

Reaction and analysis from Fox News contributor Byron York and former Florida Attorney General Pam Bondi.

Rajarshi Guhaniyogi, Abel Rodriguez.

Source: Bayesian Analysis, Volume 15, Number 2, 477--503.

Abstract:
This article proposes a framework based on shared, time varying stochastic latent factor models for modeling relational data in which network and node-attributes co-evolve over time. Our proposed framework is flexible enough to handle both categorical and continuous attributes, allows us to estimate the dimension of the latent social space, and automatically yields Bayesian hypothesis tests for the association between network structure and nodal attributes. Additionally, the model is easy to compute and readily yields inference and prediction for missing link between nodes. We employ our model framework to study co-evolution of international relations between 22 countries and the country specific indicators over a period of 11 years.

Jarno Vanhatalo, Marcelo Hartmann, Lari Veneranta.

Source: Bayesian Analysis, Volume 15, Number 2, 415--447.

Abstract:
Species distribution models (SDM) are a key tool in ecology, conservation and management of natural resources. Two key components of the state-of-the-art SDMs are the description for species distribution response along environmental covariates and the spatial random effect that captures deviations from the distribution patterns explained by environmental covariates. Joint species distribution models (JSDMs) additionally include interspecific correlations which have been shown to improve their descriptive and predictive performance compared to single species models. However, current JSDMs are restricted to hierarchical generalized linear modeling framework. Their limitation is that parametric models have trouble in explaining changes in abundance due, for example, highly non-linear physical tolerance limits which is particularly important when predicting species distribution in new areas or under scenarios of environmental change. On the other hand, semi-parametric response functions have been shown to improve the predictive performance of SDMs in these tasks in single species models. Here, we propose JSDMs where the responses to environmental covariates are modeled with additive multivariate Gaussian processes coded as linear models of coregionalization. These allow inference for wide range of functional forms and interspecific correlations between the responses. We propose also an efficient approach for inference with Laplace approximation and parameterization of the interspecific covariance matrices on the Euclidean space. We demonstrate the benefits of our model with two small scale examples and one real world case study. We use cross-validation to compare the proposed model to analogous semi-parametric single species models and parametric single and joint species models in interpolation and extrapolation tasks. The proposed model outperforms the alternative models in all cases. We also show that the proposed model can be seen as an extension of the current state-of-the-art JSDMs to semi-parametric models.

Khanh N. Dinh, Roman Jaksik, Marek Kimmel, Amaury Lambert, Simon Tavaré.

Source: Statistical Science, Volume 35, Number 1, 129--144.

Abstract:
Recent years have seen considerable work on inference about cancer evolution from mutations identified in cancer samples. Much of the modeling work has been based on classical models of population genetics, generalized to accommodate time-varying cell population size. Reverse-time, genealogical views of such models, commonly known as coalescents, have been used to infer aspects of the past of growing populations. Another approach is to use branching processes, the simplest scenario being the classical linear birth-death process. Inference from evolutionary models of DNA often exploits summary statistics of the sequence data, a common one being the so-called Site Frequency Spectrum (SFS). In a bulk tumor sequencing experiment, we can estimate for each site at which a novel somatic point mutation has arisen, the proportion of cells that carry that mutation. These numbers are then grouped into collections of sites which have similar mutant fractions. We examine how the SFS based on birth-death processes differs from those based on the coalescent model. This may stem from the different sampling mechanisms in the two approaches. However, we also show that despite this, they are quantitatively comparable for the range of parameters typical for tumor cell populations. We also present a model of tumor evolution with selective sweeps, and demonstrate how it may help in understanding the history of a tumor as well as the influence of data pre-processing. We illustrate the theory with applications to several examples from The Cancer Genome Atlas tumors.

Zhixiang Lin, Mahdi Zamanighomi, Timothy Daley, Shining Ma, Wing Hung Wong.

Source: Statistical Science, Volume 35, Number 1, 2--13.

Abstract:
Unsupervised methods, including clustering methods, are essential to the analysis of single-cell genomic data. Model-based clustering methods are under-explored in the area of single-cell genomics, and have the advantage of quantifying the uncertainty of the clustering result. Here we develop a model-based approach for the integrative analysis of single-cell chromatin accessibility and gene expression data. We show that combining these two types of data, we can achieve a better separation of the underlying cell types. An efficient Markov chain Monte Carlo algorithm is also developed.

Qingyuan Zhao, Jingshu Wang, Wes Spiller, Jack Bowden, Dylan S. Small.

Source: Statistical Science, Volume 34, Number 2, 317--333.

Abstract:
Instrumental variable analysis is a widely used method to estimate causal effects in the presence of unmeasured confounding. When the instruments, exposure and outcome are not measured in the same sample, Angrist and Krueger ( J. Amer. Statist. Assoc. 87 (1992) 328–336) suggested to use two-sample instrumental variable (TSIV) estimators that use sample moments from an instrument-exposure sample and an instrument-outcome sample. However, this method is biased if the two samples are from heterogeneous populations so that the distributions of the instruments are different. In linear structural equation models, we derive a new class of TSIV estimators that are robust to heterogeneous samples under the key assumption that the structural relations in the two samples are the same. The widely used two-sample two-stage least squares estimator belongs to this class. It is generally not asymptotically efficient, although we find that it performs similarly to the optimal TSIV estimator in most practical situations. We then attempt to relax the linearity assumption. We find that, unlike one-sample analyses, the TSIV estimator is not robust to misspecified exposure model. Additionally, to nonparametrically identify the magnitude of the causal effect, the noise in the exposure must have the same distributions in the two samples. However, this assumption is in general untestable because the exposure is not observed in one sample. Nonetheless, we may still identify the sign of the causal effect in the absence of homogeneity of the noise.

Víctor Elvira, Luca Martino, David Luengo, Mónica F. Bugallo.

Source: Statistical Science, Volume 34, Number 1, 129--155.

Abstract:
Importance sampling (IS) methods are broadly used to approximate posterior distributions or their moments. In the standard IS approach, samples are drawn from a single proposal distribution and weighted adequately. However, since the performance in IS depends on the mismatch between the targeted and the proposal distributions, several proposal densities are often employed for the generation of samples. Under this multiple importance sampling (MIS) scenario, extensive literature has addressed the selection and adaptation of the proposal distributions, interpreting the sampling and weighting steps in different ways. In this paper, we establish a novel general framework with sampling and weighting procedures when more than one proposal is available. The new framework encompasses most relevant MIS schemes in the literature, and novel valid schemes appear naturally. All the MIS schemes are compared and ranked in terms of the variance of the associated estimators. Finally, we provide illustrative examples revealing that, even with a good choice of the proposal densities, a careful interpretation of the sampling and weighting procedures can make a significant difference in the performance of the method.

Jennifer L. Zamanian
May 2, 2012; 32:6391-6410
Neurobiology of Disease

Irune Diaz-Aparicio
Feb 12, 2020; 40:1453-1482
Development Plasticity Repair

Amanda Avona
May 29, 2019; 39:4323-4331
Systems/Circuits

Sandra Manninen
Jun 21, 2017; 37:6125-6131
BehavioralSystemsCognitive

CJ Pike
Apr 1, 1993; 13:1676-1687
Articles

Chris Englund
Jan 5, 2005; 25:247-251
BRIEF COMMUNICATION

Zhengui Xia
Sep 1, 1996; 16:5425-5436
Articles

HG Kuhn
Mar 15, 1996; 16:2027-2033
Articles

Lennart Mucke
Jun 1, 2000; 20:4050-4058
Cellular

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

French translation of "Frequently asked questions on market risk capital requirements" by the Basel Committee, March 2018.

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

French translation of BIS Papers No 99 - Central banks and debt: emerging risks to the effectiveness of monetary policy in Africa?, October 2018.

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

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

Does your customer relationship management strategy have what it takes to reach Generation Y? It's estimated that by 2021, an additional $394 billion in revenue could be gained from artificial intelligence adoption in CRM activities in the U.S. As companies grow and technology evolves at a faster-than-ever pace, collecting, storing and providing data is becoming a bigger and bigger task.

Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive. We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons in mice. Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons. Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but absent in NPY/AgRP neurons. To study the role of Prdm12 in vivo, we developed and characterized a floxed Prdm12 allele. Selective ablation of Prdm12 in embryonic POMC neurons led to significantly reduced Pomc expression as well as early-onset obesity in mice of either sex that recapitulates symptoms of human POMC deficiency. Interestingly, however, specific deletion of Prdm12 in adult POMC neurons showed that it is no longer required for Pomc expression or energy balance. Collectively, these findings establish a critical role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis. Finally, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the hypothalamus whose neurodevelopment remains poorly studied.

SIGNIFICANCE STATEMENT POMC and NPY/AgRP neurons are derived from the same hypothalamic progenitors but have opposing effects on food intake. We profiled the transcriptomes of genetically labeled POMC and NPY/AgRP neurons in the developing mouse hypothalamus to decipher the transcriptional codes behind the versus orexigenic neuron identity. Our analyses revealed 29 transcription regulators that are selectively enriched in one of the two populations. We generated new mouse genetic models to selective ablate one of POMC-neuron enriched transcription factors Prdm12 in developing and adult POMC neurons. Our studies establish a previously unrecognized role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis.

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [¹¹C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[¹¹C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.

SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[¹¹C]ABP688 and [¹¹C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

To determine whether Cav1.2 voltage-gated Ca²⁺ channels contribute to astrocyte activation, we generated an inducible conditional knock-out mouse in which the Cav1.2 α subunit was deleted in GFAP-positive astrocytes. This astrocytic Cav1.2 knock-out mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP-positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of proinflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knock-out mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca²⁺ channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the cuprizone treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca²⁺ channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and that attenuation of astrocytic voltage-gated Ca²⁺ influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.

SIGNIFICANCE STATEMENT Reducing voltage-gated Ca²⁺ influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination.

The tuberal hypothalamus is comprised of the dorsomedial, ventromedial, and arcuate nuclei, as well as parts of the lateral hypothalamic area, and it governs a wide range of physiologies. During neurogenesis, tuberal hypothalamic neurons are thought to be born in a dorsal-to-ventral and outside-in pattern, although the accuracy of this description has been questioned over the years. Moreover, the intrinsic factors that control the timing of neurogenesis in this region are poorly characterized. Proneural genes, including Achate-scute-like 1 (Ascl1) and Neurogenin 3 (Neurog3) are widely expressed in hypothalamic progenitors and contribute to lineage commitment and subtype-specific neuronal identifies, but the potential role of Neurogenin 2 (Neurog2) remains unexplored. Birthdating in male and female mice showed that tuberal hypothalamic neurogenesis begins as early as E9.5 in the lateral hypothalamic and arcuate and rapidly expands to dorsomedial and ventromedial neurons by E10.5, peaking throughout the region by E11.5. We confirmed an outside-in trend, except for neurons born at E9.5, and uncovered a rostrocaudal progression but did not confirm a dorsal-ventral patterning to tuberal hypothalamic neuronal birth. In the absence of Neurog2, neurogenesis stalls, with a significant reduction in early-born BrdU⁺ cells but no change at later time points. Further, the loss of Ascl1 yielded a similar delay in neuronal birth, suggesting that Ascl1 cannot rescue the loss of Neurog2 and that these proneural genes act independently in the tuberal hypothalamus. Together, our findings show that Neurog2 functions as a classical proneural gene to regulate the temporal progression of tuberal hypothalamic neurogenesis.

SIGNIFICANCE STATEMENT Here, we investigated the general timing and pattern of neurogenesis within the tuberal hypothalamus. Our results confirmed an outside-in trend of neurogenesis and uncovered a rostrocaudal progression. We also showed that Neurog2 acts as a classical proneural gene and is responsible for regulating the birth of early-born neurons within the ventromedial hypothalamus, acting independently of Ascl1. In addition, we revealed a role for Neurog2 in cell fate specification and differentiation of ventromedial -specific neurons. Last, Neurog2 does not have cross-inhibitory effects on Neurog1, Neurog3, and Ascl1. These findings are the first to reveal a role for Neurog2 in hypothalamic development.

Dopaminergic neurons innervate extensive areas of the brain and release dopamine (DA) onto a wide range of target neurons. However, DA release is also precisely regulated. In Drosophila melanogaster brain explant preparations, DA is released specifically onto α3/α'3 compartments of mushroom body (MB) neurons that have been coincidentally activated by cholinergic and glutamatergic inputs. The mechanism for this precise release has been unclear. Here we found that coincidentally activated MB neurons generate carbon monoxide (CO), which functions as a retrograde signal evoking local DA release from presynaptic terminals. CO production depends on activity of heme oxygenase in postsynaptic MB neurons, and CO-evoked DA release requires Ca²⁺ efflux through ryanodine receptors in DA terminals. CO is only produced in MB areas receiving coincident activation, and removal of CO using scavengers blocks DA release. We propose that DA neurons use two distinct modes of transmission to produce global and local DA signaling.

SIGNIFICANCE STATEMENT Dopamine (DA) is needed for various higher brain functions, including memory formation. However, DA neurons form extensive synaptic connections, while memory formation requires highly specific and localized DA release. Here we identify a mechanism through which DA release from presynaptic terminals is controlled by postsynaptic activity. Postsynaptic neurons activated by cholinergic and glutamatergic inputs generate carbon monoxide, which acts as a retrograde messenger inducing presynaptic DA release. Released DA is required for memory-associated plasticity. Our work identifies a novel mechanism that restricts DA release to the specific postsynaptic sites that require DA during memory formation.

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.

As FAO launches dedicated webpages on post-2015, here are seven things to know about the process and how FAO is playing its part. 7 - Post-2015 development agenda - The name refers to the process through which Member States agree on a new global development framework to succeed the Millennium Development Goals (MDGs), eight goals that followed the UN Millennium Declaration [...]

Biodiversity for food and agriculture is among the earth’s most important resources. Biodiversity is indispensable: be it the insects that pollinate plants, the microscopic bacteria used for making cheese, the diverse livestock breeds used to make a living in harsh environments, the thousands species of fish, and other aquatic species in our lakes, rivers and oceans, or the thousands of [...]

Climate change is what most of us perceive as the top global threat, and the dangers it poses affect present and future generations alike.  How global warming is threatening the planet has been a theme in children’s books for all ages for some time.   How everyone, especially today’s youth, can make a difference to the future of the world [...]

Constituting only 5 percent of the world population, indigenous peoples nevertheless are vital stewards of the environment. Traditional indigenous territories encompass 22 percent of the world’s land surface, but 80 percent of the planet’s biodiversity.  A third of global forests, crucial for curbing gas emissions, are primarily managed by indigenous peoples, families, smallholders and local communities. Indigenous foods are also particularly [...]

Disasters, like an earthquake or a violent coup d’état, can strike suddenly, or like droughts and floods, develop slowly. Emergencies are devastating for people everywhere, but for those whose livelihoods or food needs depend entirely on agriculture and natural resources, these disasters can often be overwhelming. FAO addresses emergencies in a variety of ways from early warning and preparedness to [...]

How the beloved figure has become a lightning rod in a heated environmental debate