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To assess the role of the kynurenine pathway in the pathology of Alzheimer's disease (AD), the expression and localization of key components of the kynurenine pathway including the key regulatory enzyme tryptophan 2,3 dioxygenase (TDO), and the metabolites tryptophan, kynurenine, kynurenic acid, quinolinic acid and picolinic acid were assessed in different brain regions of triple transgenic AD mice. The expression and cell distribution of TDO and quinolinic acid, and their co-localization with neurofibrillary tangles and senile β amyloid deposition were also determined in hippocampal sections from human AD brains. The expression of TDO mRNA was significantly increased in the cerebellum of AD mouse brain. Immunohistochemistry demonstrated that the density of TDO immuno-positive cells was significantly higher in the AD mice. The production of the excitotoxin quinolinic acid strongly increased in the hippocampus in a progressive and age-dependent manner in AD mice. Significantly higher TDO and indoleamine 2,3 dioxygenase 1 immunoreactivity was observed in the hippocampus of AD patients. Furthermore, TDO co-localizes with quinolinic acid, neurofibrillary tangles-tau and amyloid deposits in the hippocampus of AD. These results show that the kynurenine pathway is over-activated in AD mice. This is the first report demonstrating that TDO is highly expressed in the brains of AD mice and in AD patients, suggesting that TDO-mediated activation of the kynurenine pathway could be involved in neurofibrillary tangles formation and associated with senile plaque. Our study adds to the evidence that the kynurenine pathway may play important roles in the neurodegenerative processes of AD.

The NMDA-receptor antagonist ketamine has proven efficient in reducing symptoms of suicidality, although the mechanisms explaining this effect have not been detailed in psychiatric patients. Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively. We here measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. We assessed the patients clinically using the Suicide Intent Scale and the Montgomery Asberg Depression Rating Scale (MADRS). We found that QUIN, but not KYNA, was significantly elevated in the CSF of suicide attempters (Pandlt;0.001). As predicted, the increase in QUIN was associated with higher levels of CSF interleukin-6. Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality. Our findings have important implications for the detection and specific treatment of suicidal patients, and might explain the observed remedial effects of ketamine. Neuropsychopharmacology (2013) 38, 743-752; doi:10.1038/npp.2012.248; published online 9 January 2013 Funding Agencies|Swedish Research Council|2009-42842011-47872002-52972008-29222009-70522011-4795|Province of Scania clinical state grants (ALF)||American Foundation for Suicide Prevention|2-DIG-00030-0608-1208|Rebecca Cooper Foundation||National Health Medical Research Council in Australia (NHMRC)

Autism spectrum disorder (ASD) is a pervasive neuro-developmental disorder characterized by impaired social interaction, reduced/absent verbal and non-verbal communication, and repetitive behavior during early childhood. The etiology of this developmental disorder is poorly understood, and no biomarkers have been identified. Identification of novel biochemical markers related to autism would be advantageous for earlier clinical diagnosis and intervention. Studies suggest that oxidative stress-induced mechanisms and reduced antioxidant defense, mitochondrial dysfunction, and impaired energy metabolism (NAD+, NADH, ATP, pyruvate, and lactate), are major causes of ASD. This review provides renewed insight regarding current autism research related to oxidative stress, mitochondrial dysfunction, and altered tryptophan metabolism in ASD.

The kynurenine pathway (KP) and one of its end-products, the excitotoxin quinolinic acid (QUIN), are involved in the pathogenesis of several major neuroinflammatory brain diseases. A relevant animal model to study KP metabolism is now needed to assess whether intervention in this pathway may improve the outcome of such diseases. Humans and macaques share a very similar genetic makeup. In this study, we characterized the KP metabolism in macaque primary macrophages of three different species in comparison to human cells. We found that the KP profiles in simian macrophages were very similar to those in humans when challenged with inflammatory cytokines. Further, we found that macaque macrophages are capable of producing a pathophysiological concentration of QUIN. Our data validate the simian model as a relevant model to study the human cellular KP metabolism in the context of inflammation.

We propose an adaptive ensemble method to adapt coreference resolution across domains. This method has three features: (1) it can optimize for any user-specified objective measure; (2) it can make document-specific prediction rather than rely on a fixed base model or a fixed set of base models; (3) it can automatically adjust the active ensemble members during prediction. With simplification, this method can be used in the traditional within-domain case, while still retaining the above features. To the best of our knowledge, this work is the first to both (i) develop a domain adaptation algorithm for the coreference resolution problem and (ii) have the above features as an ensemble method. Empirically, we show the benefits of (i) on the six domains of the ACE 2005 data set in domain adaptation setting, and of (ii) on both the MUC-6 and the ACE 2005 data sets in within-domain setting. © 2012 Association for Computational Linguistics.

Clustering evaluation measures are frequently used to evaluate the performance of algorithms. However, most measures are not properly normalized and ignore some information in the inherent structure of clusterings. We model the relation between two clusterings as a bipartite graph and propose a general component-based decomposition formula based on the components of the graph. Most existing measures are examples of this formula. In order to satisfy consistency in the component, we further propose a split-merge framework for comparing clusterings of different data sets. Our framework gives measures that are conditionally normalized, and it can make use of data point information, such as feature vectors and pairwise distances. We use an entropy-based instance of the framework and a coreference resolution data set to demonstrate empirically the utility of our framework over other measures., Comment: Appears in Proceedings of the 29th International Conference on Machine Learning (ICML 2012)

This study examines the characteristics of cross-fertilization of knowledge of MIS and its related disciplines. The examination is conducted from the perspective of two significantly different models of scientific development. These are the internalist model and the externalist model. Citation data is used to develop a cross-fertilization network of scientific disciplines. The patterns of knowledgesharing among the disciplines are studied. MIS and its reference disciplines are analyzed in terms of the degree to which they remain open to the ideas of other fields. Results indicate that the patterns of cross-fertilization vary greatly among these scientific fields. This suggests that no one model of scientific development serves to describe adequately MIS and its related disciplines. The status of MIS as a scientific discipline is discussed. The authors argue that the multifaceted nature of MIS should be re-conceptualized as progress from multiple directions.

The kynurenine pathway is a major route ofl-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.

radiological outcome. Methods: For this retrospective-explorative study we chose 40 MS patients attending Stockholm MS Center and selected according to the following criteria: (1) Baseline CSF samples with available electrophoresis gels images in order to determineOCB status and number of OCBs; (2) Follow-up brain MRI assessments according to a MS specific protocol. The automated image software FreeSurfer 5.1.0 was used to calculate an index of global brain atrophy with the following formula: (total gray matter + total white matter) / total ventricular volume. Single linear regression (Y = global brain atrophy at follow-up; X = number of OCBs at baseline), and multiple linear regression models (backwards) (Y = global brain atrophy at follow-up; X = number of OCBs, gender, and age at baseline, and treatment duration and disease duration at follow-up) were performed. Results: OCB negative patients (n=16) showed less than 2 OCBs, consistent with the clinical definition of OCB negative MS. OCB positive patients (n=24) showed from 2 to 20 OCBs (mean = 10.6; sd = 5.3). The follow-up period ranged from 0.5 years to 14 years (mean = 6.5; sd = 3.5). Number of OCBs was a significant predictor of global brain atrophy (s = –.337; p = 0.034; df = 39) indicating that more OCBs was related to greater brain atrophy at follow-up. Interestingly, number of OCBs was only significant predictor in the long-term (follow-up > 7 years: s = –.444; p = 0.050; df = 19), but not in the short-term (follow-up b 7 years: s = –.075; p = 0.754; df = 19). Themultiple regressionmodel was significant too (F(2, 36)= 3.529; p= 0.040), showing that the number of OCB at baseline was the only significant predictor of brain atrophy at follow-up (s= –.345; p= 0.031). Age also remained in the finalmodel (s= –.265; p = 0.094). To investigate if number of OCBs in CSF predicts MS radiological outcome. Conclusions Number of OCB in CSF can possibly be a long-term predictor of global brain atrophy. Study Support: Stockholm County Council, Sweden.

Following discussion of the rationales for improving students' intercultural communication skills, this article described how the professors at the University of Rhode Island and their counterparts around the world use the Internet as a mechanism for improving a student's intercultural awareness and sensitivity. Using the Internet, students here and abroad debate on timely, relevant topics to become aware of how people of different cultures see things differently. In addition, they write and exchange cross-cultural dialogues and explanatory notes to become interculturally sensitive. In this way, the students meet with their future partners of the global workplace, while honing their computer skills, writing skills, and enhancing their intercultural awareness and sensitivity. However, those in higher education who want to implement this kind of Internet-based teaching technique on a permanent basis must first address several difficult issues, including how to find like-minded professors here and abroad who are willing to participate. If correctly used over time, these techniques (international e-mail debate and cross-cultural dialogues) can improve students' intercultural awareness and sensitivity. Assessment of whether or not this improvement lasts over a period of time presents a quantitative problem. Defining intercultural sensitivity practically and satisfactorily is the first task facing educators interested in following this path toward improved communication. One of the greatest challenges facing the institutions of higher education of the 21st Century is how to improve intercultural communication skills of their students. Accompanied by a yet-to-be-developed instrument for quantitative measurement of long-term outcomes, projects like the international e-mail debate and cross-cultural dialogue may well become the tools for understanding and negotiation in the new global environment.

Die sich beschleunigende Globalisierung von Wirtschaft, Gesellschaft und Politik führt immer mehr Menschen unterschiedlicher Kulturzugehörigkeit zusammen. Im 21. Jahrhundert werden die erfolgreiche Führung von Unternehmen und das friedliche Miteinander der Menschen stärker als je zuvor vom Umgang Init Kulturunterschieden abhängen. In nahezu allen Bereichen von Wirtschaft und Gesellschaft wird somit die interkulturelle Kompetenz zu einer Schlüsselqualifikation der Menschen heranwachsen. Dieser Entwicklung muß auch die Hochschulausbildung Rechnung tragen. Ein didaktisches Instrument, das u.a. der Erhöhung der interkulturellen Kompetenz der Studierenden dienen soll, stellt die internationale E-Mail Debate dar, die inzwischen an einigen Universitäten fester Bestandteil des Lehrprogramms ist. Eine empirische Untersuchung zeigt, daß die E-Mail Debate bisher lediglich Einzelaspekte der interkulturellen Kompetenz in der gewünschten Weise beeinflußt. Sie trägt aber dazu bei, die Wahrnehmung fremder Kulturen zum Teil zu verbessern und einige Hindernisse, die der kulturübergreifenden Kommunikation entgegenstehen, abzubauen. Diese Ergebnisse geben Anlaß zu der Hoffnung, daß ein verfeinertes und erweitertes Konzept der E-Mail Debate den günstigen Einfluß auf die interkulturelle Kompetenz der Studierenden stärker entfalten wird.