Locomotor hyperactivity in 14-3-3Zeta KO mice is associated with dopamine transporter dysfunction

Dopamine (DA) neurotransmission requires a complex series of enzymatic reactions that are tightly linked to catecholamine exocytosis and receptor interactions on pre- and postsynaptic neurons. Regulation of dopaminergic signalling is primarily achieved through reuptake of extracellular DA by the DA transporter (DAT) on presynaptic neurons. Aberrant regulation of DA signalling, and in particular hyperactivation, has been proposed as a key insult in the presentation of schizophrenia and related neuropsychiatric disorders. We recently identified 14-3-3ζ as an essential component of neurodevelopment and a central risk factor in the schizophrenia protein interaction network. Our analysis of 14-3-3ζ-deficient mice now shows that baseline hyperactivity of knockout (KO) mice is rescued by the antipsychotic drug clozapine. 14-3-3ζ KO mice displayed enhanced locomotor hyperactivity induced by the DA releaser amphetamine. Consistent with 14-3-3ζ having a role in DA signalling, we found increased levels of DA in the striatum of 14-3-3ζ KO mice. Although 14-3-3ζ is proposed to modulate activity of the rate-limiting DA biosynthesis enzyme, tyrosine hydroxylase (TH), we were unable to identify any differences in total TH levels, TH localization or TH activation in 14-3-3ζ KO mice. Rather, our analysis identified significantly reduced levels of DAT in the absence of notable differences in RNA or protein levels of DA receptors D1–D5. Providing insight into the mechanisms by which 14-3-3ζ controls DAT stability, we found a physical association between 14-3-3ζ and DAT by co-immunoprecipitation. Taken together, our results identify a novel role for 14-3-3ζ in DA neurotransmission and provide support to the hyperdopaminergic basis of pathologies associated with schizophrenia and related disorders.H Ramshaw, X Xu, EJ Jaehne, P McCarthy, Z Greenberg, E Saleh, B McClure, J Woodcock, S Kabbara, S Wiszniak, Ting-Yi Wang, C Parish, M van den Buuse, BT Baune, A Lopez and Q Schwar

Playing with language, creating complexity:has play contributed to the evolution of complex language?

We argue that enhanced play may have contributed to the emergence of complex language systems in modern humans (Homo sapiens). To support this idea, we first discuss evidence for an expansion of playing behavior connected to the extended childhood of modern human children, and the potential of this period for the transmission of complex cultural traits, including language. We then link two of the most important functions of play-exploration and innovation-to the potential for cumulative cultural evolution in general and for the emergence of complex language in particular. If correct, the shorter childhood of Neanderthals-involving restrictions on time to experiment and innovate-may have restricted their language (and other symbolic) system/s. Consequently, fully investigating the role that play may have had in the transmission of language and the development of symbolic cultures in both modern humans and Neanderthals provides a new avenue of research for Paleolithic archaeology and related disciplines.</p

The development of accounting in UK universities:an oral history

This article reports on the development of the accounting discipline in universities in England and Scotland from the 1960s. Drawing on the oral history narratives of six distinguished accounting scholars who played a significant role in the discipline, this article documents (1) the initial influences on the teaching of accounting in English universities, (2) the different influences on the teaching of accounting in Scottish universities and (3) the influence of US universities and their scholars on the development of academic accounting in the United Kingdom. With a focus on the second wave of accounting professoriate who followed the London School of Economics (LSE) ‘Triumvirate’ of William Baxter, Harold Edey and David Solomons, this article provides first-hand insights into the shape and spread of university accounting education at a crucial stage of its development. This, in turn, develops an understanding of the contemporary academic accounting discipline in the United Kingdom.PostprintPeer reviewe

Variation in Molybdenum Content Across Broadly Distributed Populations of Arabidopsis thaliana Is Controlled by a Mitochondrial Molybdenum Transporter (MOT1)

Molybdenum (Mo) is an essential micronutrient for plants, serving as a cofactor for enzymes involved in nitrate assimilation, sulfite detoxification, abscisic acid biosynthesis, and purine degradation. Here we show that natural variation in shoot Mo content across 92 Arabidopsis thaliana accessions is controlled by variation in a mitochondrially localized transporter (Molybdenum Transporter 1 - MOT1) that belongs to the sulfate transporter superfamily. A deletion in the MOT1 promoter is strongly associated with low shoot Mo, occurring in seven of the accessions with the lowest shoot content of Mo. Consistent with the low Mo phenotype, MOT1 expression in low Mo accessions is reduced. Reciprocal grafting experiments demonstrate that the roots of Ler-0 are responsible for the low Mo accumulation in shoot, and GUS localization demonstrates that MOT1 is expressed strongly in the roots. MOT1 contains an N-terminal mitochondrial targeting sequence and expression of MOT1 tagged with GFP in protoplasts and transgenic plants, establishing the mitochondrial localization of this protein. Furthermore, expression of MOT1 specifically enhances Mo accumulation in yeast by 5-fold, consistent with MOT1 functioning as a molybdate transporter. This work provides the first molecular insight into the processes that regulate Mo accumulation in plants and shows that novel loci can be detected by association mapping

Transmural Ultrasound-based Visualization of Patterns of Action Potential Wave Propagation in Cardiac Tissue

The pattern of action potential propagation during various tachyarrhythmias is strongly suspected to be composed of multiple re-entrant waves, but has never been imaged in detail deep within myocardial tissue. An understanding of the nature and dynamics of these waves is important in the development of appropriate electrical or pharmacological treatments for these pathological conditions. We propose a new imaging modality that uses ultrasound to visualize the patterns of propagation of these waves through the mechanical deformations they induce. The new method would have the distinct advantage of being able to visualize these waves deep within cardiac tissue. In this article, we describe one step that would be necessary in this imaging process—the conversion of these deformations into the action potential induced active stresses that produced them. We demonstrate that, because the active stress induced by an action potential is, to a good approximation, only nonzero along the local fiber direction, the problem in our case is actually overdetermined, allowing us to obtain a complete solution. Use of two- rather than three-dimensional displacement data, noise in these displacements, and/or errors in the measurements of the fiber orientations all produce substantial but acceptable errors in the solution. We conclude that the reconstruction of action potential-induced active stress from the deformation it causes appears possible, and that, therefore, the path is open to the development of the new imaging modality

Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation

A key step in heart development is the coordinated development of the atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that the developmentally important T-box factors Tbx2 and Tbx3, in a functionally redundant manner, maintain the AVC myocardium phenotype during the process of chamber differentiation. Expression profiling and ChIP-sequencing analysis of Tbx3 revealed that it directly interacts with and represses chamber myocardial genes, and induces the atrioventricular pacemaker-like phenotype by activating relevant genes. Moreover, mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa. Tbx2 and Tbx3 trigger development of the cushions through a regulatory feed-forward loop with Bmp2, thus providing a mechanism for the co-localization and coordination of these important processes in heart development

Mental disorders as risk factors: assessing the evidence for the Global Burden of Disease Study

Background: Mental disorders are associated with a considerable burden of disease as well as being risk factors for other health outcomes. The new Global Burden of Disease (GBD) Study will make estimates for both the disability and mortality directly associated with mental disorders, as well as the burden attributable to other health outcomes. Herein we discuss the process by which health outcomes in which mental disorders are risk factors are selected for inclusion in the GBD Study. We make suggestions for future research to strengthen the body of evidence for mental disorders as risk factors

Application of Consensus Scoring and Principal Component Analysis for Virtual Screening against β-Secretase (BACE-1)

BACKGROUND: In order to identify novel chemical classes of β-secretase (BACE-1) inhibitors, an alternative scoring protocol, Principal Component Analysis (PCA), was proposed to summarize most of the information from the original scoring functions and re-rank the results from the virtual screening against BACE-1. METHOD: Given a training set (50 BACE-1 inhibitors and 9950 inactive diverse compounds), three rank-based virtual screening methods, individual scoring, conventional consensus scoring and PCA, were judged by the hit number in the top 1% of the ranked list. The docking poses were generated by Surflex, five scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, and PMF_Score) were used for pose extraction. For each pose group, twelve scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, PMF_Score, LigScore1, LigScore2, PLP1, PLP2, jain, Ludi_1, and Ludi_2) were used for the pose rank. For a test set, 113,228 chemical compounds (Sigma-Aldrich® corporate chemical directory) were docked by Surflex, then ranked by the same three ranking methods motioned above to select the potential active compounds for experimental test. RESULTS: For the training set, the PCA approach yielded consistently superior rankings compared to conventional consensus scoring and single scoring. For the test set, the top 20 compounds according to conventional consensus scoring were experimentally tested, no inhibitor was found. Then, we relied on PCA scoring protocol to test another different top 20 compounds and two low micromolar inhibitors (S450588 and 276065) were emerged through the BACE-1 fluorescence resonance energy transfer (FRET) assay. CONCLUSION: The PCA method extends the conventional consensus scoring in a quantitative statistical manner and would appear to have considerable potential for chemical screening applications

A meta-analysis reveals the commonalities and differences in Arabidopsis thaliana response to different viral pathogens

Understanding the mechanisms by which plants trigger host defenses in response to viruses has been a challenging problem owing to the multiplicity of factors and complexity of interactions involved. The advent of genomic techniques, however, has opened the possibility to grasp a global picture of the interaction. Here, we used Arabidopsis thaliana to identify and compare genes that are differentially regulated upon infection with seven distinct (+)ssRNA and one ssDNA plant viruses. In the first approach, we established lists of genes differentially affected by each virus and compared their involvement in biological functions and metabolic processes. We found that phylogenetically related viruses significantly alter the expression of similar genes and that viruses naturally infecting Brassicaceae display a greater overlap in the plant response. In the second approach, virus-regulated genes were contextualized using models of transcriptional and protein-protein interaction networks of A. thaliana. Our results confirm that host cells undergo significant reprogramming of their transcriptome during infection, which is possibly a central requirement for the mounting of host defenses. We uncovered a general mode of action in which perturbations preferentially affect genes that are highly connected, central and organized in modules. © 2012 Rodrigo et al.This work was supported by the Spanish Ministerio de Ciencia e Innovacion (MICINN) grants BFU2009-06993 (S. F. E.) and BIO2006-13107 (C. L.) and by Generalitat Valenciana grant PROMETEO2010/016 (S. F. E.). G. R. is supported by a graduate fellowship from the Generalitat Valenciana (BFPI2007-160) and J.C. by a contract from MICINN grant TIN2006-12860. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Rodrigo Tarrega, G.; Carrera Montesinos, J.; Ruiz-Ferrer, V.; Del Toro, F.; Llave, C.; Voinnet, O.; Elena Fito, SF. (2012). A meta-analysis reveals the commonalities and differences in Arabidopsis thaliana response to different viral pathogens. PLoS ONE. 7(7):40526-40526. https://doi.org/10.1371/journal.pone.0040526S405264052677Peng, X., Chan, E. Y., Li, Y., Diamond, D. L., Korth, M. J., & Katze, M. G. (2009). Virus–host interactions: from systems biology to translational research. Current Opinion in Microbiology, 12(4), 432-438. doi:10.1016/j.mib.2009.06.003Dodds, P. N., & Rathjen, J. P. (2010). Plant immunity: towards an integrated view of plant–pathogen interactions. Nature Reviews Genetics, 11(8), 539-548. doi:10.1038/nrg2812Maule, A., Leh, V., & Lederer, C. (2002). The dialogue between viruses and hosts in compatible interactions. 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