The causes and consequences explicit in verbs

Interpretation of a pronoun in one clause can be systematically affected by the verb in the previous clause. Compare Archibald angered Bartholomew because he … (he = Archibald) with Archibald criticised Bartholomew because he … (he = Bartholomew). While it is clear that meaning plays a critical role, it is unclear whether that meaning is directly encoded in the verb or, alternatively, inferred from world knowledge. We report evidence favouring the former account. We elicited pronoun biases for 502 verbs from seven Levin verb classes in two discourse contexts (implicit causality and implicit consequentiality), showing that in both contexts, verb class reliably predicts pronoun bias. These results confirm and extend recent findings about implicit causality and represent the first such study for implicit consequentiality. We discuss these findings in the context of recent work in semantics, and also develop a new, probabilistic generative account of pronoun interpretation.National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award Grant 5F32HD072748)National Science Foundation (U.S.). Graduate Research Fellowshi

Fragment Grammars: Exploring Computation and Reuse in Language

Language relies on a division of labor between stored units and structure building operations which combine the stored units into larger structures. This division of labor leads to a tradeoff: more structure-building means less need to store while more storage means less need to compute structure. We develop a hierarchical Bayesian model called fragment grammar to explore the optimum balance between structure-building and reuse. The model is developed in the context of stochastic functional programming (SFP) and in particular using a probabilistic variant of Lisp known as the Church programming language (Goodman, Mansinghka, Roy, Bonawitz, & Tenenbaum, 2008). We show how to formalize several probabilistic models of language structure using Church, and how fragment grammar generalizes one of them---adaptor grammars (Johnson, Griffiths, & Goldwater, 2007). We conclude with experimental data with adults and preliminary evaluations of the model on natural language corpus data

Compositional Policy Priors

This paper describes a probabilistic framework for incorporating structured inductive biases into reinforcement learning. These inductive biases arise from policy priors, probability distributions over optimal policies. Borrowing recent ideas from computational linguistics and Bayesian nonparametrics, we define several families of policy priors that express compositional, abstract structure in a domain. Compositionality is expressed using probabilistic context-free grammars, enabling a compact representation of hierarchically organized sub-tasks. Useful sequences of sub-tasks can be cached and reused by extending the grammars nonparametrically using Fragment Grammars. We present Monte Carlo methods for performing inference, and show how structured policy priors lead to substantially faster learning in complex domains compared to methods without inductive biases.This work was supported by AFOSR FA9550-07-1-0075 and ONR N00014-07-1-0937. SJG was supported by a Graduate Research Fellowship from the NSF

Linking Meaning to Language: Linguistic Universals and Variation

To use natural language, speakers must map the participants in events or states in the world onto grammatical roles. There remains considerable disagreement about the nature of these so-called linking rules (Levin & Rappaport Hovav, 2005). In order to probe the nature of linking rules, we investigate verbs of psychological state, which demonstrate complex linking patterns both within and between languages. We find that the typical duration of the psychological state guides the application of linking rules to novel verbs in both English and Japanese, consistent with a universal constraint. Nonetheless, there are marked differences in the baseline preferences for the individual linking rules across the two languages. We discuss these findings both in terms of theories of exceptionless linking rules and accounts on which linking rules are governed by probabilistic biases as well as cross-linguistic variation.Psycholog

Does impaired O-2 delivery during exercise accentuate central and peripheral fatigue in patients with coexistent COPD-CHF?

Impairment in oxygen (O-2) delivery to the central nervous system (brain) and skeletal locomotor muscle during exercise has been associated with central and peripheral neuromuscular fatigue in healthy humans. From a clinical perspective, impaired tissue O-2 transport is a key pathophysiological mechanism shared by cardiopulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). in addition to arterial hypoxemic conditions in COPD, there is growing evidence that cerebral and muscle blood flow and oxygenation can be reduced during exercise in both isolated COPD and CHF. Compromised cardiac output due to impaired cardiopulmonary function/interactions and blood flow redistribution to the overloaded respiratory muscles (i.e., up arrow work of breathing) may underpin these abnormalities. Unfortunately, COPD and CHF coexist in almost a third of elderly patients making these mechanisms potentially more relevant to exercise intolerance. in this context, it remains unknown whether decreased O-2 delivery accentuates neuromuscular manifestations of central and peripheral fatigue in coexistent COPD-CHF If this holds true, it is conceivable that delivering a low-density gas mixture (heliox) through non-invasive positive pressure ventilation could ameliorate cardiopulmonary function/interactions and reduce the work of breathing during exercise in these patients. the major consequence would be increased O-2 delivery to the brain and active muscles with potential benefits to exercise capacity (i.e.,,central and peripheral neuromuscular fatigue, respectively). We therefore hypothesize that patients with coexistent COPD-CHF stop exercising prematurely due to impaired central motor drive and muscle contractility as the cardiorespiratory system fails to deliver sufficient O-2 to simultaneously attend the metabolic demands of the brain and the active limb muscles.Universidade Federal de São Paulo, Dept Med, Pulm Funct & Clin Exercise Physiol Unit SEFICE, Resp Div,Sch Med,UNIFESP, São Paulo, BrazilQueens Univ, Dept Med, Lab Clin Exercise Physiol, Div Resp & Crit Care Med, Kingston, ON K7L 3N6, CanadaQueens Univ, Dept Med, Resp Invest Unit, Div Resp & Crit Care Med, Kingston, ON K7L 3N6, CanadaGrenoble Alpes Univ, Lab HP2, Grenoble, FranceUniversidade Federal de São Paulo, Dept Med, Pulm Funct & Clin Exercise Physiol Unit SEFICE, Resp Div,Sch Med,UNIFESP, São Paulo, BrazilWeb of Scienc

Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties.

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events