Mentalizing and motivation neural function during social interactions in autism spectrum disorders

AbstractAutism Spectrum Disorders (ASDs) are characterized by core deficits in social functions. Two theories have been suggested to explain these deficits: mind-blindness theory posits impaired mentalizing processes (i.e. decreased ability for establishing a representation of others' state of mind), while social motivation theory proposes that diminished reward value for social information leads to reduced social attention, social interactions, and social learning. Mentalizing and motivation are integral to typical social interactions, and neuroimaging evidence points to independent brain networks that support these processes in healthy individuals. However, the simultaneous function of these networks has not been explored in individuals with ASDs. We used a social, interactive fMRI task, the Domino game, to explore mentalizing- and motivation-related brain activation during a well-defined interval where participants respond to rewards or punishments (i.e. motivation) and concurrently process information about their opponent's potential next actions (i.e. mentalizing). Thirteen individuals with high-functioning ASDs, ages 12–24, and 14 healthy controls played fMRI Domino games against a computer-opponent and separately, what they were led to believe was a human-opponent. Results showed that while individuals with ASDs understood the game rules and played similarly to controls, they showed diminished neural activity during the human-opponent runs only (i.e. in a social context) in bilateral middle temporal gyrus (MTG) during mentalizing and right Nucleus Accumbens (NAcc) during reward-related motivation (Pcluster<0.05 FWE). Importantly, deficits were not observed in these areas when playing against a computer-opponent or in areas related to motor and visual processes. These results demonstrate that while MTG and NAcc, which are critical structures in the mentalizing and motivation networks, respectively, activate normally in a non-social context, they fail to respond in an otherwise identical social context in ASD compared to controls. We discuss implications to both the mind-blindness and social motivation theories of ASD and the importance of social context in research and treatment protocols

Nucleon-Gold Collisions at 200 AGeV Using Tagged d+Au Interactions in PHOBOS

Forward calorimetry in the PHOBOS detector has been used to study charged hadron production in d+Au, p+Au and n+Au collisions at sqrt(s_nn) = 200 GeV. The forward proton calorimeter detectors are described and a procedure for determining collision centrality with these detectors is detailed. The deposition of energy by deuteron spectator nucleons in the forward calorimeters is used to identify p+Au and n+Au collisions in the data. A weighted combination of the yield of p+Au and n+Au is constructed to build a reference for Au+Au collisions that better matches the isospin composition of the gold nucleus. The p_T and centrality dependence of the yield of this improved reference system is found to match that of d+Au. The shape of the charged particle transverse momentum distribution is observed to extrapolate smoothly from pbar+p to central d+Au as a function of the charged particle pseudorapidity density. The asymmetry of positively- and negatively-charged hadron production in p+Au is compared to that of n+Au. No significant asymmetry is observed at mid-rapidity. These studies augment recent results from experiments at the LHC and RHIC facilities to give a more complete description of particle production in p+A and d+A collisions, essential for the understanding the medium produced in high energy nucleus-nucleus collisions.Comment: 17 pages, 18 figure

Science and Ideology in Economic, Political, and Social Thought

This paper has two sources: One is my own research in three broad areas: business cycles, economic measurement and social choice. In all of these fields I attempted to apply the basic precepts of the scientific method as it is understood in the natural sciences. I found that my effort at using natural science methods in economics was met with little understanding and often considerable hostility. I found economics to be driven less by common sense and empirical evidence, then by various ideologies that exhibited either a political or a methodological bias, or both. This brings me to the second source: Several books have appeared recently that describe in historical terms the ideological forces that have shaped either the direct areas in which I worked, or a broader background. These books taught me that the ideological forces in the social sciences are even stronger than I imagined on the basis of my own experiences. The scientific method is the antipode to ideology. I feel that the scientific work that I have done on specific, long standing and fundamental problems in economics and political science have given me additional insights into the destructive role of ideology beyond the history of thought orientation of the works I will be discussing

TEFM (c17orf42) is necessary for transcription of human mtDNA

Here we show that c17orf42, hereafter TEFM (transcription elongation factor of mitochondria), makes a critical contribution to mitochondrial transcription. Inactivation of TEFM in cells by RNA interference results in respiratory incompetence owing to decreased levels of H- and L-strand promoter-distal mitochondrial transcripts. Affinity purification of TEFM from human mitochondria yielded a complex comprising mitochondrial transcripts, mitochondrial RNA polymerase (POLRMT), pentatricopeptide repeat domain 3 protein (PTCD3), and a putative DEAD-box RNA helicase, DHX30. After RNase treatment only POLRMT remained associated with TEFM, and in human cultured cells TEFM formed foci coincident with newly synthesized mitochondrial RNA. Based on deletion mutants, TEFM interacts with the catalytic region of POLRMT, and in vitro TEFM enhanced POLRMT processivity on ss- and dsDNA templates. TEFM contains two HhH motifs and a Ribonuclease H fold, similar to the nuclear transcription elongation regulator Spt6. These findings lead us to propose that TEFM is a mitochondrial transcription elongation factor

Unsupervised Analysis of Classical Biomedical Markers: Robustness and Medical Relevance of Patient Clustering Using Bioinformatics Tools

Motivation: It has been proposed that clustering clinical markers, such as blood test results, can be used to stratify patients. However, the robustness of clusters formed with this approach to data pre-processing and clustering algorithm choices has not been evaluated, nor has clustering reproducibility. Here, we made use of the NHANES survey to compare clusters generated with various combinations of pre-processing and clustering algorithms, and tested their reproducibility in two separate samples. Method: Values of 44 biomarkers and 19 health/life style traits were extracted from the National Health and Nutrition Examination Survey (NHANES). The 1999–2002 survey was used for training, while data from the 2003–2006 survey was tested as a validation set. Twelve combinations of pre-processing and clustering algorithms were applied to the training set. The quality of the resulting clusters was evaluated both by considering their properties and by comparative enrichment analysis. Cluster assignments were projected to the validation set (using an artificial neural network) and enrichment in health/life style traits in the resulting clusters was compared to the clusters generated from the original training set. Results: The clusters obtained with different pre-processing and clustering combinations differed both in terms of cluster quality measures and in terms of reproducibility of enrichment with health/life style properties. Z-score normalization, for example, dramatically improved cluster quality and enrichments, as compared to unprocessed data, regardless of the clustering algorithm used. Clustering diabetes patients revealed a group of patients enriched with retinopathies. This coul

Amino acid starvation has opposite effects on mitochondrial and cytosolic protein synthesis.

Amino acids are essential for cell growth and proliferation for they can serve as precursors of protein synthesis, be remodelled for nucleotide and fat biosynthesis, or be burnt as fuel. Mitochondria are energy producing organelles that additionally play a central role in amino acid homeostasis. One might expect mitochondrial metabolism to be geared towards the production and preservation of amino acids when cells are deprived of an exogenous supply. On the contrary, we find that human cells respond to amino acid starvation by upregulating the amino acid-consuming processes of respiration, protein synthesis, and amino acid catabolism in the mitochondria. The increased utilization of these nutrients in the organelle is not driven primarily by energy demand, as it occurs when glucose is plentiful. Instead it is proposed that the changes in the mitochondrial metabolism complement the repression of cytosolic protein synthesis to restrict cell growth and proliferation when amino acids are limiting. Therefore, stimulating mitochondrial function might offer a means of inhibiting nutrient-demanding anabolism that drives cellular proliferation

Measurement of the production cross section for W-bosons in association with jets in pp collisions at s=7 TeV with the ATLAS detector

This Letter reports on a first measurement of the inclusive W + jets cross section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC, with the ATLAS detector. Cross sections, in both the electron and muon decay modes of the W-boson, are presented as a function of jet multiplicity and of the transverse momentum of the leading and next-to-leading jets in the event. Measurements are also presented of the ratio of cross sections sigma (W + >= n)/sigma(W + >= n - 1) for inclusive jet multiplicities n = 1-4. The results, based on an integrated luminosity of 1.3 pb(-1), have been corrected for all known detector effects and are quoted in a limited and well-defined range of jet and lepton kinematics. The measured cross sections are compared to particle-level predictions based on perturbative QCD. Next-to-leading order calculations, studied here for n <= 2, are found in good agreement with the data. Leading-order multiparton event generators, normalized to the NNLO total cross section, describe the data well for all measured jet multiplicitie

Synthetic Biology Open Language (SBOL) Version 1.1.0

In this BioBricks Foundation Request for Comments (BBF RFC), we specify the Synthetic Biology Open Language (SBOL) Version 1.1.0 to enable the electronic exchange of information describing DNA components used in synthetic biology. We define: 1. the vocabulary, a set of preferred terms and 2. the core data model, a common computational representation

Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the biomarker-surrogacy (BioSurrogate) evaluation schema (BSES)

<p>Abstract</p> <p>Background</p> <p>Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit.</p> <p>Methods</p> <p>We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3).</p> <p>Results</p> <p>In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure.</p> <p>Conclusions</p> <p>In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.</p