Rethinking metabotropic glutamate receptor 5 pathological findings in psychiatric disorders: implications for the future of novel therapeutics

Background Pharmacological modulation of metabotropic glutamate receptor 5 (mGluR5) is of marked interest as a novel therapeutic mechanism to treat schizophrenia and major depression. However, the status of mGluR5 in the pathophysiology of these disorders remains unknown. Discussion The majority of studies in the schizophrenia post-mortem brain indicate that total mGluR5 expression is unaltered. However, close examination of the literature suggests that these findings are superficial, and in actuality, a number of critical factors have not yet been considered; alterations may be highly dependent on brain region, neuronal population or molecular organisation in specific cellular compartments. A number of genetic knockout studies (mGluR5, Norbin, Homer1 etc.) continue to lend support to a role of mGluR5 in the pathology of schizophrenia, providing impetus to explore the regulation of mGluR5 beyond total mGluR5 protein and mRNA levels. With regards to major depression, preliminary evidence to date shows a reduction in total mGluR5 protein and mRNA levels; however, as in schizophrenia, there are no studies examining mGluR5 function or regulation in the pathological state. A comprehensive understanding of mGluR5 regulation in major depression, particularly in comparison to schizophrenia, is crucial as this has extensive implications for mGluR5 targeting novel therapeutics, especially considering that opposing modulation of mGluR5 is of therapeutic interest for these two disorders. Summary Despite the complexities, examinations of post-mortem human brain provide valuable insights into the pathologies of these inherently human disorders. It is important, especially with regards to the identification of novel therapeutic drug targets, to have an in depth understanding of the pathophysiologies of these disorders. We posit that brain region- and cell type-specific alterations exist in mGluR5 in schizophrenia and depression, with evidence pointing towards altered regulation of this receptor in psychiatric pathology. We consider the implications of these alterations, as well as the distinction between schizophrenia and depression, in the context of novel mGluR5 based therapeutics

Novel implications of Lingo-1 signaling in the prefrontal cortex and hippocampus of perinatal phencyclidine treated rats in a neurodevelopmental model of schizophrenia

Abstract of a poster presentation

Model study of tropospheric trace species distributions during PEM-West A

A three-dimensional mesoscale transport/photochemical model is used to study the transport and photochemical transformation of trace species over eastern Asia and western Pacific for the period from September 20 to October 6, 1991, of the Pacific Exploratory Mission-West A experiment. The influence of emissions from the continental boundary layer that was evident in the observed trace species distributions in the lower troposphere over the ocean is well simulated by the model. In the upper troposphere, species such as O3, NOy (total reactive nitrogen species), and SO2 which have a significant source in the stratosphere are also simulated well in the model, suggesting that the upper tropospheric abundances of these species are strongly influenced by stratospheric fluxes and upper tropospheric sources. In the case of SO2 the stratospheric flux is identified to be mostly from the Mount Pinatubo eruption. Concentrations in the upper troposphere for species such as CO and hydrocarbons, which are emitted in the continental boundary layer and have a sink in the troposphere, are significantly underestimated by the model. Two factors have been identified to contribute significantly to the underestimate: one is emissions upwind of the model domain (eastern Asia and western Pacific); the other is that vertical transport is underestimated in the model. Model results are also grouped by back trajectories to study the contrast between compositions of marine and continental air masses. The model-calculated altitude profiles of trace species in continental and marine air masses are found to be qualitatively consistent with observations. However, the difference in the median values of trace species between continental air and marine air is about twice as large for the observed values as for model results. This suggests that the model underestimates the outflow fluxes of trace species from the Asian continent and the Pacific rim countries to the ocean. Observed altitude profiles for species like CO and hydrocarbons show a negative gradient in continental air and a positive gradient in marine air. A mechanism which may be responsible for the altitude gradients is proposed

Valuing Consortial Resources: A Framework for Assessment

Grounded assessment begins with establishing the goals of an institution and its users, but there is an added layer of complexity in determining value at the consortial level, where individual institutions will naturally perceive the value of a particular resource differently. The shared resources of a consortium are also often diverse in both format and acquisition method. How should the relative value between e-books and streaming media be compared? Between leased and demand-driven acquisitions? Between open access and collaboratively owned models

The fairness, predictive validity and acceptability of multiple mini interview in an internationally diverse student population--a mixed methods study

BACKGROUND: International medical students, those attending medical school outside of their country of citizenship, account for a growing proportion of medical undergraduates worldwide. This study aimed to establish the fairness, predictive validity and acceptability of Multiple Mini Interview (MMI) in an internationally diverse student population. METHODS: This was an explanatory sequential, mixed methods study. All students in First Year Medicine, National University of Ireland Galway 2012 were eligible to sit a previously validated 10 station MMI. Quantitative data comprised: demographics, selection tool scores and First Year Assessment scores. Qualitative data comprised separate focus groups with MMI Assessors, EU and Non-EU students. RESULTS: 109 students participated (45% of class). Of this 41.3% (n = 45) were Non-EU and 35.8% (n = 39) did not have English as first language. Age, gender and socioeconomic class did not impact on MMI scores. Non-EU students and those for whom English was not a first language achieved significantly lower scores on MMI than their EU and English speaking counterparts (difference in mean 11.9% and 12.2% respectively, P<0.001). MMI score was associated with English language proficiency (IELTS) (r = 0.5, P<0.01). Correlations emerged between First Year results and IELTS (r = 0.44; p = 0.006; n = 38) and EU school exit exam (r = 0.52; p<0.001; n = 56). MMI predicted EU student OSCE performance (r = 0.27; p = 0.03; n = 64). In the analysis of focus group data two overarching themes emerged: Authenticity and Cultural Awareness. MMI was considered a highly authentic assessment that offered a deeper understanding of the applicant than traditional tools, with an immediate relevance to clinical practice. Cultural specificity of some stations and English language proficiency were seen to disadvantage international students. Recommendations included cultural awareness training for MMI assessors, designing and piloting culturally neutral stations, lengthening station duration and providing high quality advance information to candidates. CONCLUSION: MMI is a welcome addition to assessment armamentarium for selection, particularly with regard to stakeholder acceptability. Understanding the mediating and moderating influences for differences in performance of international candidates is essential to ensure that MMI complies with the metrics of good assessment practice and principles of both distributive and procedural justice for all applicants, irrespective of nationality and cultural background

Genetic and epigenetic regulation in Lingo-1 : Effects on cognitive function and white matter microstructure in a case-control study for schizophrenia

Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3′-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016–1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology

Driven Diffusive Systems with Disorder

We discuss recent work on the static and dynamical properties of the asymmetric exclusion process, generalized to include the effect of disorder. We study in turn: random disorder in the properties of particles; disorder in the spatial distribution of transition rates, both with a single easy direction and with random reversals of the easy direction; dynamical disorder, where particles move in a disordered landscape which itself evolves in time. In every case, the system exhibits phase separation; in some cases, it is of an unusual sort. The time-dependent properties of density fluctuations are in accord with the kinematic wave criterion that the dynamical universality class is unaffected by disorder if the kinematic wave velocity is nonzero.Comment: To appear in Physica A, Proc. of International Workshop on Common Trends in Traffic Systems (IIT, Kanpur,2006

'Chunks, schemata and retrieval structures: Past and current computational models

Copyright © 2015 Gobet, Lane and Lloyd-Kelly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.A recurring question in psychology and cognitive science concerns the expression of theories that are internally consistent and testable. Natural language is unsatisfactory, as theoretical concepts and mechanisms are not stated with sufficient precision (e.g., Newell et al., 1958; Newell and Simon, 1972; Farrell and Lewandowsky, 2010; Jones et al., 2014). Formal and, in particular, computational models avoid the problems of vagueness and under-specification by defining the processes and cognitive mechanisms that occur during a task. They additionally make quantitative and testable predictions, not only about the link between input and output, but also about fine-grained measures such as response times and eye movements. Further, such models can perform complex tasks and, when simulating learning, can use the statistical structure of the environment to help explain behavior. This Opinion article briefly reviews the extent to which computational modeling has been used to develop theories accounting for the learning and use of chunks, schemata, and retrieval structures. We use the following definitions. A chunk is a “meaningful unit of information built from smaller pieces of information” (Gobet and Lane, 2012, p. 541), with the qualification that this information should be of the same kind. A schema is “a cognitive structure for representing and retrieving classes of typical situations for which a similar response is required of the learner” (Lane et al., 2000, p. 776). Finally, a retrieval structure is “a set of retrieval cues [that] are organized in a stable structure” (Ericsson and Kintsch, 1995, p. 216). We should point out that there exist plenty of definitions for these terms, which is actually an issue for progress in our understanding. For example, Richman et al. (1991) consider that a retrieval structure is a schema in long-term memory. Even fuzzier is the concept of a “chunk.” For example, a chunk is a unit of declarative memory in ACT-R (Anderson et al., 2004) and a unit of procedural memory in Soar (Newell, 1990), with none of the two meanings corresponding to the definition provided above. For a discussion of the multiple meanings of this term, see Gobet et al. (in revision).Peer reviewedFinal Published versio

What's in a Name? The Multiple Meanings of "Chunk" and "Chunking"

© 2016 Gobet, Lloyd-Kelly and Lane. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The term chunk, denoting a unit, and the related term chunking, denoting a mechanism to construct that unit, are familiar terms within psychology and cognitive science. The Oxford English Dictionary provides several definitions for “chunk.” First, “a thick, more or less cuboidal, lump, cut off anything,” or, colloquially, “a large or substantial amount.” The Merriam-Webster dictionary provides similar definitions. OUP's Oxford Dictionary alone gives a computer-related meaning: “a section of information or data.” It is in this context, a chunk as a section of information, that the word is used within psychology and cognitive science. In these fields, a chunk typically refers to a single unit built from several smaller elements, and chunking to the process of creating a chunk. Gobet et al. (2001, p. 236) define a chunk as “a collection of elements having strong associations with one another, but weak associations with elements within other chunks.” However, in different contexts and with different authors, these two terms are used with a variety of meanings, which are very often conflated, leading to considerable confusion. Table 1 provides a taxonomy of the main meanings of “chunk” and “chunking,” which will be used to structure this article.Peer reviewedFinal Published versio