ses Bayesian Functional Forecasting with Locally-Autoregressive Dependent Processes By projecteuclid.org Published On :: Thu, 19 Dec 2019 22:10 EST Guillaume Kon Kam King, Antonio Canale, Matteo Ruggiero. Source: Bayesian Analysis, Volume 14, Number 4, 1121--1141.Abstract: Motivated by the problem of forecasting demand and offer curves, we introduce a class of nonparametric dynamic models with locally-autoregressive behaviour, and provide a full inferential strategy for forecasting time series of piecewise-constant non-decreasing functions over arbitrary time horizons. The model is induced by a non Markovian system of interacting particles whose evolution is governed by a resampling step and a drift mechanism. The former is based on a global interaction and accounts for the volatility of the functional time series, while the latter is determined by a neighbourhood-based interaction with the past curves and accounts for local trend behaviours, separating these from pure noise. We discuss the implementation of the model for functional forecasting by combining a population Monte Carlo and a semi-automatic learning approach to approximate Bayesian computation which require limited tuning. We validate the inference method with a simulation study, and carry out predictive inference on a real dataset on the Italian natural gas market. Full Article
ses Extrinsic Gaussian Processes for Regression and Classification on Manifolds By projecteuclid.org Published On :: Tue, 11 Jun 2019 04:00 EDT 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. Full Article
ses Modeling Population Structure Under Hierarchical Dirichlet Processes By projecteuclid.org Published On :: Wed, 13 Mar 2019 22:00 EDT Lloyd T. Elliott, Maria De Iorio, Stefano Favaro, Kaustubh Adhikari, Yee Whye Teh. Source: Bayesian Analysis, Volume 14, Number 2, 313--339.Abstract: We propose a Bayesian nonparametric model to infer population admixture, extending the hierarchical Dirichlet process to allow for correlation between loci due to linkage disequilibrium. Given multilocus genotype data from a sample of individuals, the proposed model allows inferring and classifying individuals as unadmixed or admixed, inferring the number of subpopulations ancestral to an admixed population and the population of origin of chromosomal regions. Our model does not assume any specific mutation process, and can be applied to most of the commonly used genetic markers. We present a Markov chain Monte Carlo (MCMC) algorithm to perform posterior inference from the model and we discuss some methods to summarize the MCMC output for the analysis of population admixture. Finally, we demonstrate the performance of the proposed model in a real application, using genetic data from the ectodysplasin-A receptor (EDAR) gene, which is considered to be ancestry-informative due to well-known variations in allele frequency as well as phenotypic effects across ancestry. The structure analysis of this dataset leads to the identification of a rare haplotype in Europeans. We also conduct a simulated experiment and show that our algorithm outperforms parametric methods. Full Article
ses Assessing the Causal Effect of Binary Interventions from Observational Panel Data with Few Treated Units By projecteuclid.org Published On :: Fri, 11 Oct 2019 04:03 EDT Pantelis Samartsidis, Shaun R. Seaman, Anne M. Presanis, Matthew Hickman, Daniela De Angelis. Source: Statistical Science, Volume 34, Number 3, 486--503.Abstract: Researchers are often challenged with assessing the impact of an intervention on an outcome of interest in situations where the intervention is nonrandomised, the intervention is only applied to one or few units, the intervention is binary, and outcome measurements are available at multiple time points. In this paper, we review existing methods for causal inference in these situations. We detail the assumptions underlying each method, emphasize connections between the different approaches and provide guidelines regarding their practical implementation. Several open problems are identified thus highlighting the need for future research. Full Article
ses Lasso Meets Horseshoe: A Survey By projecteuclid.org Published On :: Fri, 11 Oct 2019 04:03 EDT Anindya Bhadra, Jyotishka Datta, Nicholas G. Polson, Brandon Willard. Source: Statistical Science, Volume 34, Number 3, 405--427.Abstract: The goal of this paper is to contrast and survey the major advances in two of the most commonly used high-dimensional techniques, namely, the Lasso and horseshoe regularization. Lasso is a gold standard for predictor selection while horseshoe is a state-of-the-art Bayesian estimator for sparse signals. Lasso is fast and scalable and uses convex optimization whilst the horseshoe is nonconvex. Our novel perspective focuses on three aspects: (i) theoretical optimality in high-dimensional inference for the Gaussian sparse model and beyond, (ii) efficiency and scalability of computation and (iii) methodological development and performance. Full Article
ses Two-Sample Instrumental Variable Analyses Using Heterogeneous Samples By projecteuclid.org Published On :: Thu, 18 Jul 2019 22:01 EDT 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. Full Article
ses Gaussian Integrals and Rice Series in Crossing Distributions—to Compute the Distribution of Maxima and Other Features of Gaussian Processes By projecteuclid.org Published On :: Fri, 12 Apr 2019 04:00 EDT Georg Lindgren. Source: Statistical Science, Volume 34, Number 1, 100--128.Abstract: We describe and compare how methods based on the classical Rice’s formula for the expected number, and higher moments, of level crossings by a Gaussian process stand up to contemporary numerical methods to accurately deal with crossing related characteristics of the sample paths. We illustrate the relative merits in accuracy and computing time of the Rice moment methods and the exact numerical method, developed since the late 1990s, on three groups of distribution problems, the maximum over a finite interval and the waiting time to first crossing, the length of excursions over a level, and the joint period/amplitude of oscillations. We also treat the notoriously difficult problem of dependence between successive zero crossing distances. The exact solution has been known since at least 2000, but it has remained largely unnoticed outside the ocean science community. Extensive simulation studies illustrate the accuracy of the numerical methods. As a historical introduction an attempt is made to illustrate the relation between Rice’s original formulation and arguments and the exact numerical methods. Full Article
ses Editor’s Pick: Gifts for Your Tech-Obsessed Friend By www.health.com Published On :: Tue, 26 Nov 2019 12:49:30 -0500 A guide to the tech gadgets even your hard-to-shop-for friends and family members will love. Full Article
ses Sleep Deprivation Biases the Neural Mechanisms Underlying Economic Preferences By www.jneurosci.org Published On :: 2011-03-09 Vinod VenkatramanMar 9, 2011; 31:3712-3718BehavioralSystemsCognitive Full Article
ses Dural Calcitonin Gene-Related Peptide Produces Female-Specific Responses in Rodent Migraine Models By www.jneurosci.org Published On :: 2019-05-29 Amanda AvonaMay 29, 2019; 39:4323-4331Systems/Circuits Full Article
ses Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation [published erratum appears in J Neurosci 1992 Aug;1 By www.jneurosci.org Published On :: 1992-07-01 KM HarrisJul 1, 1992; 12:2685-2705Articles Full Article
ses Experience-Dependent Plasticity of Binocular Responses in the Primary Visual Cortex of the Mouse By www.jneurosci.org Published On :: 1996-05-15 Joshua A. GordonMay 15, 1996; 16:3274-3286Articles Full Article
ses A computational analysis of the relationship between neuronal and behavioral responses to visual motion By www.jneurosci.org Published On :: 1996-02-15 MN ShadlenFeb 15, 1996; 16:1486-1510Articles Full Article
ses Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases By www.jneurosci.org Published On :: 1996-04-01 M NiethammerApr 1, 1996; 16:2157-2163Articles Full Article
ses Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease By www.jneurosci.org Published On :: 2009-02-11 Randy L. BucknerFeb 11, 2009; 29:1860-1873Neurobiology of Disease Full Article
ses Quantitative Ultrastructural Analysis of Hippocampal Excitatory Synapses By www.jneurosci.org Published On :: 1997-08-01 Thomas SchikorskiAug 1, 1997; 17:5858-5867Articles Full Article
ses Wintrust Financial Corporation to Make Loans to Approximately 8,900 Small Businesses Through the Paycheck Protection Program By www.snl.com Published On :: Fri, 17 Apr 2020 22:27:00 GMT To view more press releases, please visit http://www.snl.com/irweblinkx/news.aspx?iid=1024452. Full Article
ses Microsoft Covers All the Bases With Impressive Surface Lineup By www.technewsworld.com Published On :: 2020-05-07T09:43:07-07:00 Microsoft has introduced a slew of new products, including the Surface Go 2, the Surface Book 3, Surface Headphones 2 and Surface Earbuds. Both the Surface Go 2 and the Surface Book 3 come in consumer and corporate versions. "The two products are very different," noted Rob Enderle, principal analyst at the Enderle Group. "The Go 2 is a high-value product -- the Surface Book 3 high innovation." Full Article
ses Keith Olbermann: If the Tea Party wins, America loses By www.msnbc.msn.com Published On :: Full Article
ses Comparative Transcriptomic Analyses of Developing Melanocortin Neurons Reveal New Regulators for the Anorexigenic Neuron Identity By www.jneurosci.org Published On :: 2020-04-15T09:30:18-07:00 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. Full Article
ses Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model By www.jneurosci.org Published On :: 2020-04-22T09:29:41-07:00 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. Full Article
ses Nitric Oxide Signaling Strengthens Inhibitory Synapses of Cerebellar Molecular Layer Interneurons through a GABARAP-Dependent Mechanism By www.jneurosci.org Published On :: 2020-04-22T09:29:41-07:00 Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABAA receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca2+ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABAARs synapses through a GABA receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway. SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca2+-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABAA receptor synapses via Ca2+/calmodulin-dependent protein kinase II. Although Ca2+ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated. Full Article
ses Ependymal Vps35 Promotes Ependymal Cell Differentiation and Survival, Suppresses Microglial Activation, and Prevents Neonatal Hydrocephalus By www.jneurosci.org Published On :: 2020-05-06T09:30:22-07:00 Hydrocephalus is a pathologic condition associated with various brain diseases, including Alzheimer's disease (AD). Dysfunctional ependymal cells (EpCs) are believed to contribute to the development of hydrocephalus. It is thus of interest to investigate EpCs' development and function. Here, we report that vacuolar protein sorting-associated protein 35 (VPS35) is critical for EpC differentiation, ciliogenesis, and survival, and thus preventing neonatal hydrocephalus. VPS35 is abundantly expressed in EpCs. Mice with conditional knock-out (cKO) of Vps35 in embryonic (Vps35GFAP-Cre and Vps35Emx1-Cre) or postnatal (Vps35Foxj1-CreER) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35GFAP-Cre and Vps35Foxj1-CreER mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35GFAP-Cre and Vps35Foxj1-CreER neonatal pups exhibit increased cell proliferation and death largely in a region close to LV-EpCs. Many microglia close to the mutant LV-EpC region become activated. Depletion of the microglia by PLX3397, an antagonist of colony-stimulating factor 1 receptor (CSF1R), restores LV-EpCs and diminishes the pathology of neonatal hydrocephalus in Vps35Foxj1-CreER mice. Taken together, these observations suggest unrecognized functions of Vps35 in EpC differentiation, ciliogenesis, and survival in neonatal LV, and reveal pathologic roles of locally activated microglia in EpC homeostasis and hydrocephalus development. SIGNIFICANCE STATEMENT This study reports critical functions of vacuolar protein sorting-associated protein 35 (VPS35) not only in promoting ependymal cell (EpC) differentiation, ciliogenesis, and survival, but also in preventing local microglial activation. The dysfunctional EpCs and activated microglia are likely to induce hydrocephalus. Full Article
ses Uncharacteristic Task-Evoked Pupillary Responses Implicate Atypical Locus Ceruleus Activity in Autism By www.jneurosci.org Published On :: 2020-05-06T09:30:22-07:00 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. Full Article
ses MECP2 Duplication Causes Aberrant GABA Pathways, Circuits and Behaviors in Transgenic Monkeys: Neural Mappings to Patients with Autism By www.jneurosci.org Published On :: 2020-05-06T09:30:22-07:00 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. Full Article
ses Calcineurin Inhibition Causes {alpha}2{delta}-1-Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity By www.jneurosci.org Published On :: 2020-05-06T09:30:22-07:00 Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2-1–GluN1 complexes in the spinal cord and the level of α2-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2-1 with gabapentin or disrupting the α2-1–NMDAR interaction with α2-1Tat peptide completely reversed the effects of FK506. In α2-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS. SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2-1 and NMDARs and their synaptic trafficking in the spinal cord. α2-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2-1 or disrupting α2-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition. Full Article
ses M-Current Inhibition in Hippocampal Excitatory Neurons Triggers Intrinsic and Synaptic Homeostatic Responses at Different Temporal Scales By www.jneurosci.org Published On :: 2020-05-06T09:30:22-07:00 Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1–4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Nav1.6 and Kv7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (~2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate. SIGNIFICANCE STATEMENT Persistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate. Full Article
ses Asia-Pacific campaign targets reduced food losses By www.fao.org Published On :: Thu, 29 Aug 2013 00:00:00 GMT FAO and its partners have launched an initiative aimed at cutting food waste across the Asia-Pacific region. Save Food Asia-Pacific Campaign targets losses both straight after harvest and between the market and people’s plates. FAO estimates that reducing global food waste by just one quarter would be sufficient to feed the 870 million people suffering from chronic hunger in the world. [...] Full Article
ses Quiz – do you have a taste for pulses? By www.fao.org Published On :: Tue, 10 Nov 2015 00:00:00 GMT Pulses have been consumed for at least 10 000 years and are among the most extensively used foods in the world. They provide protein and fibre, and are a great source of vitamins and minerals, such as iron, zinc and magnesium. You probably already eat more pulses than you realize but can you put your finger on these facts on pulses? [...] Full Article
ses Let the countdown to the International Year of Pulses begin! By www.fao.org Published On :: Wed, 06 Jan 2016 00:00:00 GMT 10: EtymologyThe word pulse originates directly from the Latin puls meaning "thick gruel, porridge, mush.” 9: Pulses vs legumes, what’s the difference?The term "legume" refers to the plants whose fruit is enclosed in a pod. Pulses are a subgroup of the legume family, but the term “pulse” refers only to the dried seed. Dried beans, lentils and peas are the most commonly known and consumed types [...] Full Article
ses Recommended: 7 free e-learning courses to bookmark By www.fao.org Published On :: Thu, 03 Mar 2016 00:00:00 GMT E-learning was quite the buzzword a couple of decades ago – then when the internet started in earnest it became even more so. Today e-learning is mainstreamed in many organization, including FAO with more than 400 000 learners taking advantage of FAO’s offerings. FAO’s e-learning center offers free interactive courses – in English, French and Spanish - on topics ranging [...] Full Article
ses Spotlight: How do pulses contribute to a sustainable world? By www.fao.org Published On :: Wed, 27 Apr 2016 00:00:00 GMT Pulses are being celebrated in 2016 all over the world since they are nutritious, suited for use in a variety of dishes, easy on the budget and good for the health of the soil. From food security and nutrition to ensuring biodiversity and mitigating the effects of climate change, pulses contribute to sustainable development. Here is how. 1. Nutritional benefits of pulses Pulses [...] Full Article
ses Nature's nutritious seeds: 10 reasons why you should opt for pulses By www.fao.org Published On :: Wed, 28 Sep 2016 00:00:00 GMT We see them each and every day: at the grocery store, the farmer’s market and as side orders served with your favourite dish. In many countries, they are part of the cultural heritage and are consumed on a regular basis. In other parts of the world, they hardly garner a mention except when served as soup on a cold winter’s [...] Full Article
ses Wrapping up the International Year of Pulses By www.fao.org Published On :: Wed, 15 Feb 2017 00:00:00 GMT In 2016 we celebrated the International Year of Pulses and it is obvious why. Pulses are good for you, beneficial to farmers' livelihoods and have a positive impact on the environment. It is clear that even though dried beans, lentils and peas have been around for centuries, they will play a fundamental role in our sustainable future. Even though #IYP2016 has [...] Full Article
ses On the ground before, during and after crises By www.fao.org Published On :: Mon, 05 Feb 2018 00:00:00 GMT Hassan Al-Hassan, a Syrian farmer known to locals as Abu Hasan, remembers how difficult it had been in the past few years in the village of al-Rabeha in the southern governorate of Homs. “Due to lack of water, we could hardly produce anything,” said Abu Hasan. FAO is helping to restore access to water for over 40 000 families – about [...] Full Article
ses How to get kids to eat pulses By www.fao.org Published On :: Thu, 16 Aug 2018 00:00:00 GMT Pulses are highly versatile ingredients to cook with—as either a main meal or a side dish, they are the perfect complement to even the boldest of flavours. But just like any new type of food, convincing the pickiest eaters in the family to try these nutritious beans, peas and lentils can sometimes prove difficult. Full Article
ses FAO releases COVID-19 Q&As to help government policymakers By www.fao.org Published On :: Thu, 02 Apr 2020 00:00:00 GMT As the novel coronavirus disease COVID-19 continues to spread, questions have been raised about the potential impact on food supply and availability and on livelihoods around the globe. FAO Full Article
ses Council opposes elimination of Ocean Rangers: City sets meeting with linemen, union rep By www.ketchikandailynews.com Published On :: Full Article
ses Where Predators Are Scarce, Mongooses May Transmit More Disease By www.smithsonianmag.com Published On :: Tue, 17 Mar 2020 21:44:01 +0000 New research hints at how different environments impact animal behavior and the spread of infection Full Article
ses Notre-Dame Restoration Pauses Amid France's Two-Week Lockdown By www.smithsonianmag.com Published On :: Thu, 19 Mar 2020 16:04:16 +0000 Lead decontamination policies enacted in August are now in conflict with measures to prevent spread of COVID-19 Full Article
ses The Museum of Modern Art Now Offers Free Online Classes By www.smithsonianmag.com Published On :: Tue, 14 Apr 2020 18:12:23 +0000 The nine classes span contemporary art, fashion and photography Full Article
ses Unwind With These Free, Museum-Led Meditation and Mindfulness Sessions By www.smithsonianmag.com Published On :: Wed, 22 Apr 2020 13:59:20 +0000 The Rubin Museum of Art and the Smithsonian's National Museum of Asian Art offer an array of relaxing experiences Full Article
ses Despite Their Differences, Dogs and Horses Find Common Ground in Play By www.smithsonianmag.com Published On :: Fri, 24 Apr 2020 14:52:27 +0000 Canine-equid pairs can mimic each other’s facial expressions during play, which has never been seen between animals of different species Full Article
ses Plan proposes $18.7M in funds for AMHS: Alaska House subcommittee advances plan to restore minimal service By www.ketchikandailynews.com Published On :: Full Article
ses Smithsonian Scientists Discover Six New Coronaviruses in Bats in Myanmar By www.smithsonianmag.com Published On :: Mon, 13 Apr 2020 13:00:00 +0000 The new viruses are not harmful to humans or closely related to SARS-CoV-2, the coronavirus that causes COVID-19 Full Article
ses New Virtual Exhibition Showcases the Healing Power of Art By www.smithsonianmag.com Published On :: Thu, 30 Apr 2020 14:28:12 +0000 “Care Package” showcases Asian American and Pacific Islander artists, writers and scholars as sources of solace during the Covid-19 pandemic Full Article
ses Six Online Courses About Europe to Take Before You Can Safely Travel There Again By www.smithsonianmag.com Published On :: Mon, 27 Apr 2020 18:09:59 +0000 Sheltering in place doesn’t mean you can’t study up for your next European adventure Full Article
ses Inflated power bills another hit to businesses dealing with COVID closures By www.cbc.ca Published On :: Fri, 8 May 2020 05:00:00 EDT Some New Brunswick business owners already facing a cash crunch because of COVID-19 have received an unwelcome shock from NB Power: electricity bills that don’t take into account how little energy they’ve been consuming. Full Article News/Canada/New Brunswick