Chengchun Shi, Rui Song, Wenbin Lu.

Source: The Annals of Statistics, Volume 47, Number 4, 2348--2377.

Abstract:
Precision medicine is an emerging medical paradigm that focuses on finding the most effective treatment strategy tailored for individual patients. In the literature, most of the existing works focused on estimating the optimal treatment regime. However, there has been less attention devoted to hypothesis testing regarding the optimal treatment regime. In this paper, we first introduce the notion of conditional qualitative treatment effects (CQTE) of a set of variables given another set of variables and provide a class of equivalent representations for the null hypothesis of no CQTE. The proposed definition of CQTE does not assume any parametric form for the optimal treatment rule and plays an important role for assessing the incremental value of a set of new variables in optimal treatment decision making conditional on an existing set of prescriptive variables. We then propose novel testing procedures for no CQTE based on kernel estimation of the conditional contrast functions. We show that our test statistics have asymptotically correct size and nonnegligible power against some nonstandard local alternatives. The empirical performance of the proposed tests are evaluated by simulations and an application to an AIDS data set.

Benedikt Bauer, Michael Kohler.

Source: The Annals of Statistics, Volume 47, Number 4, 2261--2285.

Abstract:
Assuming that a smoothness condition and a suitable restriction on the structure of the regression function hold, it is shown that least squares estimates based on multilayer feedforward neural networks are able to circumvent the curse of dimensionality in nonparametric regression. The proof is based on new approximation results concerning multilayer feedforward neural networks with bounded weights and a bounded number of hidden neurons. The estimates are compared with various other approaches by using simulated data.

Ability to work with each other. In the loosely coupled environment of a service-oriented architecture, separate resources don't need to know the details of how they each work, but they need to have enough common ground to reliably exchange messages without error or misunderstanding. Standardized specifications go a long way towards creating this common ground, but differences in implementation may still lead to breakdowns in communication. Interoperability is when services can interact with each other without encountering such problems.

Yicheng Li, Adrian E. Raftery.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 381--408.

Abstract:
Smoking is one of the leading preventable threats to human health and a major risk factor for lung cancer, upper aerodigestive cancer and chronic obstructive pulmonary disease. Estimating and forecasting the smoking attributable fraction (SAF) of mortality can yield insights into smoking epidemics and also provide a basis for more accurate mortality and life expectancy projection. Peto et al. ( Lancet 339 (1992) 1268–1278) proposed a method to estimate the SAF using the lung cancer mortality rate as an indicator of exposure to smoking in the population of interest. Here, we use the same method to estimate the all-age SAF (ASAF) for both genders for over 60 countries. We document a strong and cross-nationally consistent pattern of the evolution of the SAF over time. We use this as the basis for a new Bayesian hierarchical model to project future male and female ASAF from over 60 countries simultaneously. This gives forecasts as well as predictive distributions that can be used to find uncertainty intervals for any quantity of interest. We assess the model using out-of-sample predictive validation and find that it provides good forecasts and well-calibrated forecast intervals, comparing favorably with other methods.

Armin Schwartzman, Andrew J. Schork, Rong Zablocki, Wesley K. Thompson.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2509--2538.

Abstract:
Analysis of genome-wide association studies (GWAS) is characterized by a large number of univariate regressions where a quantitative trait is regressed on hundreds of thousands to millions of single-nucleotide polymorphism (SNP) allele counts, one at a time. This article proposes an estimator of the SNP heritability of the trait, defined here as the fraction of the variance of the trait explained by the SNPs in the study. The proposed GWAS heritability (GWASH) estimator is easy to compute, highly interpretable and is consistent as the number of SNPs and the sample size increase. More importantly, it can be computed from summary statistics typically reported in GWAS, not requiring access to the original data. The estimator takes full account of the linkage disequilibrium (LD) or correlation between the SNPs in the study through moments of the LD matrix, estimable from auxiliary datasets. Unlike other proposed estimators in the literature, we establish the theoretical properties of the GWASH estimator and obtain analytical estimates of the precision, allowing for power and sample size calculations for SNP heritability estimates and forming a firm foundation for future methodological development.

Jose Ameijeiras-Alonso, Akli Benali, Rosa M. Crujeiras, Alberto Rodríguez-Casal, José M. C. Pereira.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2120--2139.

Abstract:
Understanding the role of vegetation fires in the Earth system is an important environmental problem. Although fire occurrence is influenced by natural factors, human activity related to land use and management has altered the temporal patterns of fire in several regions of the world. Hence, for a better insight into fires regimes it is of special interest to analyze where human activity has altered fire seasonality. For doing so, multimodality tests are a useful tool for determining the number of annual fire peaks. The periodicity of fires and their complex distributional features motivate the use of nonparametric circular statistics. The unsatisfactory performance of previous circular nonparametric proposals for testing multimodality justifies the introduction of a new approach, considering an adapted version of the excess mass statistic, jointly with a bootstrap calibration algorithm. A systematic application of the test on the Russia–Kazakhstan area is presented in order to determine how many fire peaks can be identified in this region. A False Discovery Rate correction, accounting for the spatial dependence of the data, is also required.

Ying Chen, J. S. Marron, Jiejie Zhang.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1590--1616.

Abstract:
Electricity prices are high dimensional, serially dependent and have seasonal variations. We propose a Warping Functional AutoRegressive (WFAR) model that simultaneously accounts for the cross time-dependence and seasonal variations of the large dimensional data. In particular, electricity price curves are obtained by smoothing over the $24$ discrete hourly prices on each day. In the functional domain, seasonal phase variations are separated from level amplitude changes in a warping process with the Fisher–Rao distance metric, and the aligned (season-adjusted) electricity price curves are modeled in the functional autoregression framework. In a real application, the WFAR model provides superior out-of-sample forecast accuracy in both a normal functioning market, Nord Pool, and an extreme situation, the California market. The forecast performance as well as the relative accuracy improvement are stable for different markets and different time periods.

Pavel Zorin-Kranich.

Source: Bernoulli, Volume 26, Number 3, 2311--2318.

Abstract:
We prove an estimate for weighted $p$th moments of the pathwise $r$-variation of a martingale in terms of the $A_{p}$ characteristic of the weight. The novelty of the proof is that we avoid real interpolation techniques.

Anton Thalmaier, James Thompson.

Source: Bernoulli, Volume 26, Number 3, 2202--2225.

Abstract:
In this article, we derive moment estimates, exponential integrability, concentration inequalities and exit times estimates for canonical diffusions firstly on sub-Riemannian limits of Riemannian foliations and secondly in the nonsmooth setting of $operatorname{RCD}^{*}(K,N)$ spaces. In each case, the necessary ingredients are Itô’s formula and a comparison theorem for the Laplacian, for which we refer to the recent literature. As an application, we derive pointwise Carmona-type estimates on eigenfunctions of Schrödinger operators.

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.

Marie Ernst, Gesine Reinert, Yvik Swan.

Source: Bernoulli, Volume 26, Number 3, 2051--2081.

Abstract:
We propose probabilistic representations for inverse Stein operators (i.e., solutions to Stein equations) under general conditions; in particular, we deduce new simple expressions for the Stein kernel. These representations allow to deduce uniform and nonuniform Stein factors (i.e., bounds on solutions to Stein equations) and lead to new covariance identities expressing the covariance between arbitrary functionals of an arbitrary univariate target in terms of a weighted covariance of the derivatives of the functionals. Our weights are explicit, easily computable in most cases and expressed in terms of objects familiar within the context of Stein’s method. Applications of the Cauchy–Schwarz inequality to these weighted covariance identities lead to sharp upper and lower covariance bounds and, in particular, weighted Poincaré inequalities. Many examples are given and, in particular, classical variance bounds due to Klaassen, Brascamp and Lieb or Otto and Menz are corollaries. Connections with more recent literature are also detailed.

Adam Osękowski.

Source: Bernoulli, Volume 26, Number 3, 1912--1926.

Abstract:
Let $X=(X_{t})_{tgeq 0}in H^{1}$ and $Y=(Y_{t})_{tgeq 0}in{mathrm{BMO}} $ be arbitrary continuous-path martingales. The paper contains the proof of the inequality egin{equation*}mathbb{E}int _{0}^{infty }iglvert dlangle X,Y angle_{t}igrvert leq sqrt{2}Vert XVert _{H^{1}}Vert YVert _{mathrm{BMO}_{2}},end{equation*} and the constant $sqrt{2}$ is shown to be the best possible. The proof rests on the construction of a certain special function, enjoying appropriate size and concavity conditions.

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.

Kamran Kalbasi, Thomas Mountford.

Source: Bernoulli, Volume 26, Number 2, 1504--1534.

Abstract:
In this paper, we study the local times of vector-valued Gaussian fields that are ‘diagonally operator-self-similar’ and whose increments are stationary. Denoting the local time of such a Gaussian field around the spatial origin and over the temporal unit hypercube by $Z$, we show that there exists $lambdain(0,1)$ such that under some quite weak conditions, $lim_{n ightarrow+infty}frac{sqrt[n]{mathbb{E}(Z^{n})}}{n^{lambda}}$ and $lim_{x ightarrow+infty}frac{-logmathbb{P}(Z>x)}{x^{frac{1}{lambda}}}$ both exist and are strictly positive (possibly $+infty$). Moreover, we show that if the underlying Gaussian field is ‘strongly locally nondeterministic’, the above limits will be finite as well. These results are then applied to establish similar statements for the intersection local times of diagonally operator-self-similar Gaussian fields with stationary increments.

Giovanni Conforti, Luigia Ripani.

Source: Bernoulli, Volume 26, Number 2, 1431--1452.

Abstract:
In this article, we study generalization of the classical Talagrand transport-entropy inequality in which the Wasserstein distance is replaced by the entropic transportation cost. This class of inequalities has been introduced in the recent work ( Probab. Theory Related Fields 174 (2019) 1–47), in connection with the study of Schrödinger bridges. We provide several equivalent characterizations in terms of reverse hypercontractivity for the heat semigroup, contractivity of the Hamilton–Jacobi–Bellman semigroup and dimension-free concentration of measure. Properties such as tensorization and relations to other functional inequalities are also investigated. In particular, we show that the inequalities studied in this article are implied by a Logarithmic Sobolev inequality and imply Talagrand inequality.

Wensheng Wang, Zhonggen Su, Yimin Xiao.

Source: Bernoulli, Volume 26, Number 2, 1410--1430.

Abstract:
We establish the exact moduli of non-differentiability of Gaussian random fields with stationary increments. As an application of the result, we prove that the uniform Hölder condition for the maximum local times of Gaussian random fields with stationary increments obtained in Xiao (1997) is optimal. These results are applicable to fractional Riesz–Bessel processes and stationary Gaussian random fields in the Matérn and Cauchy classes.

Pasha Tkachov.

Source: Bernoulli, Volume 26, Number 2, 1354--1380.

Abstract:
The aim of this paper is to prove stability of traveling waves for integro-differential equations connected with branching Markov processes. In other words, the limiting law of the left-most particle of a (time-continuous) branching Markov process with a Lévy non-branching part is demonstrated. The key idea is to approximate the branching Markov process by a branching random walk and apply the result of Aïdékon [ Ann. Probab. 41 (2013) 1362–1426] on the limiting law of the latter one.

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.

The Round Rock Independent School District in Texas is looking for a digital curriculum and blended learning program. Baltimore is looking for a comprehensive high school literacy program.

The post Austin-Area District Looks for Digital/Blended Learning Program; Baltimore Seeks High School Literacy Program appeared first on Market Brief.

The military is preparing to deploy to the region to try to stop illegal logging and mining.

Ioannis Ntzoufras, Claudia Tarantola, Monia Lupparelli.

Source: Bayesian Analysis, Volume 14, Number 3, 797--823.

Abstract:
We introduce a novel Bayesian approach for quantitative learning for graphical log-linear marginal models. These models belong to curved exponential families that are difficult to handle from a Bayesian perspective. The likelihood cannot be analytically expressed as a function of the marginal log-linear interactions, but only in terms of cell counts or probabilities. Posterior distributions cannot be directly obtained, and Markov Chain Monte Carlo (MCMC) methods are needed. Finally, a well-defined model requires parameter values that lead to compatible marginal probabilities. Hence, any MCMC should account for this important restriction. We construct a fully automatic and efficient MCMC strategy for quantitative learning for such models that handles these problems. While the prior is expressed in terms of the marginal log-linear interactions, we build an MCMC algorithm that employs a proposal on the probability parameter space. The corresponding proposal on the marginal log-linear interactions is obtained via parameter transformation. We exploit a conditional conjugate setup to build an efficient proposal on probability parameters. The proposed methodology is illustrated by a simulation study and a real dataset.

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.

Iain M. Johnstone.

Source: Statistical Science, Volume 34, Number 4, 657--668.

Abstract:
Many papers in the early part of Brown’s career focused on the admissibility or otherwise of estimators of a vector parameter. He established that inadmissibility of invariant estimators in three and higher dimensions is a general phenomenon, and found deep and beautiful connections between admissibility and other areas of mathematics. This review touches on several of his major contributions, with a focus on his celebrated 1971 paper connecting admissibility, recurrence and elliptic partial differential equations.

Eitan Greenshtein, Ya’acov Ritov.

Source: Statistical Science, Volume 34, Number 2, 224--228.

Abstract:
We present some personal reflections on empirical Bayes/ compound decision (EB/CD) theory following Efron (2019). In particular, we consider the role of exchangeability in the EB/CD theory and how it can be achieved when there are covariates. We also discuss the interpretation of EB/CD confidence interval, the theoretical efficiency of the CD procedure, and the impact of sparsity assumptions.

They’re already going out of stock.

Fatma Deniz
Sep 25, 2019; 39:7722-7736
BehavioralSystemsCognitive

Svetlana Mastitskaya
Apr 8, 2020; 40:3052-3062
Systems/Circuits

Sebastian Onasch
Apr 15, 2020; 40:3186-3202
Systems/Circuits

Randy L. Buckner
Feb 11, 2009; 29:1860-1873
Neurobiology of Disease

Peter Klivenyi
Jan 1, 2000; 20:1-7
Cellular

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, December 2018

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

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

Speech by Mr Claudio Borio, Head of the Monetary and Economic Department of the BIS, at the OECD-G20 High Level Policy Seminar, Paris, 11 September 2019.

Exiting low inflation traps by "consensus": nominal wages and price stability - Speech by Luiz A Pereira da Silva and Benoît Mojon, based on the keynote speech at the Eighth High-level Policy Dialogue between the Eurosystem and Latin American Central Banks, Cartagena de Indias, Colombia, 28-29 November 2019.

Maintenance of cardiorespiratory homeostasis depends on autonomic reflexes controlled by neuronal circuits of the brainstem. The neurophysiology and neuroanatomy of these reflex pathways are well understood, however, the mechanisms and functional significance of autonomic circuit modulation by glial cells remain largely unknown. In the experiments conducted in male laboratory rats we show that astrocytes of the nucleus of the solitary tract (NTS), the brain area that receives and integrates sensory information from the heart and blood vessels, respond to incoming afferent inputs with [Ca²⁺]_i elevations. Astroglial [Ca²⁺]_i responses are triggered by transmitters released by vagal afferents, glutamate acting at AMPA receptors and 5-HT acting at 5-HT_2A receptors. In conscious freely behaving animals blockade of Ca²⁺-dependent vesicular release mechanisms in NTS astrocytes by virally driven expression of a dominant-negative SNARE protein (dnSNARE) increased baroreflex sensitivity by 70% (p < 0.001). This effect of compromised astroglial function was specific to the NTS as expression of dnSNARE in astrocytes of the ventrolateral brainstem had no effect. ATP is considered the principle gliotransmitter and is released by vesicular mechanisms blocked by dnSNARE expression. Consistent with this hypothesis, in anesthetized rats, pharmacological activation of P2Y₁ purinoceptors in the NTS decreased baroreflex gain by 40% (p = 0.031), whereas blockade of P2Y₁ receptors increased baroreflex gain by 57% (p = 0.018). These results suggest that glutamate and 5-HT, released by NTS afferent terminals, trigger Ca²⁺-dependent astroglial release of ATP to modulate baroreflex sensitivity via P2Y₁ receptors. These data add to the growing body of evidence supporting an active role of astrocytes in brain information processing.

SIGNIFICANCE STATEMENT Cardiorespiratory reflexes maintain autonomic balance and ensure cardiovascular health. Impaired baroreflex may contribute to the development of cardiovascular disease and serves as a robust predictor of cardiovascular and all-cause mortality. The data obtained in this study suggest that astrocytes are integral components of the brainstem mechanisms that process afferent information and modulate baroreflex sensitivity via the release of ATP. Any condition associated with higher levels of "ambient" ATP in the NTS would be expected to decrease baroreflex gain by the mechanism described here. As ATP is the primary signaling molecule of glial cells (astrocytes, microglia), responding to metabolic stress and inflammatory stimuli, our study suggests a plausible mechanism of how the central component of the baroreflex is affected in pathological conditions.

Neurons and circuits each with a distinct balance of intrinsic and synaptic conductances can generate similar behavior but sometimes respond very differently to perturbation. Examining a large family of circuit models with non-identical neurons and synapses underlying rhythmic behavior, we analyzed the circuits' response to modifications in single and multiple intrinsic conductances in the individual neurons. To summarize these changes over the entire range of perturbed parameters, we quantified circuit output by defining a global stability measure. Using this measure, we identified specific subsets of conductances that when perturbed generate similar behavior in diverse individuals of the population. Our unbiased clustering analysis enabled us to quantify circuit stability when simultaneously perturbing multiple conductances as a nonlinear combination of single conductance perturbations. This revealed surprising conductance combinations that can predict the response to specific perturbations, even when the remaining intrinsic and synaptic conductances are unknown. Therefore, our approach can expose hidden variability in the balance of intrinsic and synaptic conductances of the same neurons across different versions of the same circuit solely from the circuit response to perturbations. Developed for a specific family of model circuits, our quantitative approach to characterizing high-dimensional degenerate systems provides a conceptual and analytic framework to guide future theoretical and experimental studies on degeneracy and robustness.

SIGNIFICANCE STATEMENT Neural circuits can generate nearly identical behavior despite neuronal and synaptic parameters varying several-fold between individual instantiations. Yet, when these parameters are perturbed through channel deletions and mutations or environmental disturbances, seemingly identical circuits can respond very differently. What distinguishes inconsequential perturbations that barely alter circuit behavior from disruptive perturbations that drastically disturb circuit output remains unclear. Focusing on a family of rhythmic circuits, we propose a computational approach to reveal hidden variability in the intrinsic and synaptic conductances in seemingly identical circuits based solely on circuit output to different perturbations. We uncover specific conductance combinations that work similarly to maintain stability and predict the effect of changing multiple conductances simultaneously, which often results from neuromodulation or injury.

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.

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.

SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Last, we use cortical cultures derived from Dcx KO mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.

SIGNIFICANCE STATEMENT Nestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.

Cash transfer programmes – regular money payments to poor households - aim to reduce poverty, promote sustainable livelihoods and increase production in the developing world. During the past decade, an increasing number of governments in sub-Saharan Africa have launched cash transfer programmes that target the most vulnerable groups, including subsistence farmers, people with disabilities and HIV/AIDS, as well as families [...]

Peste des petits ruminants (PPR) or sheep and goat plague is a highly contagious animal disease affecting small ruminants. An estimated 300 million families who rely on small ruminants, such as sheep and goats, as a source of food and income are at risk of losing their livelihoods and may be forced to migrate, particularly in areas where food insecurity, other resource shortages [...]

Eradicating world hunger can only be achieved if food is safe, nutritious and of good quality. Eating unsafe food increases the chances of contracting diseases and can be, in some cases, deadly. Unsafe food can also lead to rejections causing food to be wasted, which then impacts on food security. One thing is certain: there can be no food security [...]

Oceans cover 70 percent of our planet. But did you know that 40 percent of the earth’s surface is covered by what is known as our common oceans?