Thalamocortical Connectivity Correlates with Phenotypic Variability in Dystonia

Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia

The visual perception of natural motion: abnormal task-related neural activity in DYT1 dystonia

Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of \u27natural\u27 versus \u27unnatural\u27 motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of \u27natural\u27 and \u27unnatural\u27 motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to \u27natural\u27 versus \u27unnatural\u27 motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P \u3c 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P \u3c 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P \u3c 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways

Early Galactic Evolution of Carbon, Nitrogen and Oxygen

We present results on carbon, nitrogen, and oxygen abundances for a sample of unevolved metal-poor stars with metallicities in the range -0.3< [Fe/H]< -3. Oxygen abundances derived from different indicators are compared showing consistently that in the range 0.3 >[Fe/H]>-3.0, the [O/Fe] ratio increases from approximately 0 to 1. We find a good agreement between abundances based on the forbidden line, the OH and IR triplet lines when gravities based on Hipparcos} parallaxes are considered for the sample stars. Gravities derived from LTE ionization balance in metal-poor stars with [Fe/H]< -1 are likely too low, and could be responsible for an underestimation of the oxygen abundances derived using the [OI] line. [C/Fe] and [N/Fe] ratios appear to be constant, independently of metallicity, in the same range. However, they show larger scatter than oxygen at a given metallicity, which could reflect the larger variety of stellar production sites for these other elements.Comment: 10 pages, 3 figures, To appear in the proceedings of the conference "The Chemical Evolution of The Milky Way: Stars versus Clusters", eds. F. Matteucci and F. Giovannelli, Vulcano, Italy, September 20-24 199

Fueling climate (in)action:How organizations engage in hegemonization to avoid transformational action on climate change

This study examines how organizations avoid the urgent need for transformational action on climate change by engaging in a hegemonization process. To show how this unfolds, we draw from Laclau and Mouffe’s discourse theory, focusing on the case of BP and its engagement with the climate change debate from 1990 to 2015. Our study takes a longitudinal approach to illustrate how BP defended its core business of producing and selling fossil fuel products by enacting three sequential hegemonization strategies. These included: adopting new signifiers; building ‘win-win’ relationships; and adapting nodal points. In doing so, we demonstrate how hegemonic construction enables organizations to both incorporate and evade various types of stakeholder critique, which, we argue, reproduces business-as-usual. Our study contributes to organization studies literature on hegemony by highlighting how the construction of hegemony operates accumulatively over an extended period of time. We also contribute more broadly to conversations around political contests and the natural environment by illustrating how the lack of effective climate responses is shaped by temporal dynamics

The Mere Exposure Effect in the Domain of Haptics

Background: Zajonc showed that the attitude towards stimuli that one had been previously exposed to is more positive than towards novel stimuli. This mere exposure effect (MEE) has been tested extensively using various visual stimuli. Research on the MEE is sparse, however, for other sensory modalities. Methodology/Principal Findings: We used objects of two material categories (stone and wood) and two complexity levels (simple and complex) to test the influence of exposure frequency (F0 = novel stimuli, F2 = stimuli exposed twice, F10 = stimuli exposed ten times) under two sensory modalities (haptics only and haptics &amp; vision). Effects of exposure frequency were found for high complex stimuli with significantly increasing liking from F0 to F2 and F10, but only for the stone category. Analysis of ‘‘Need for Touch’ ’ data showed the MEE in participants with high need for touch, which suggests different sensitivity or saturation levels of MEE. Conclusions/Significance: This different sensitivity or saturation levels might also reflect the effects of expertise on the haptic evaluation of objects. It seems that haptic and cross-modal MEEs are influenced by factors similar to those in the visual domain indicating a common cognitive basis

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application

Deep Sequencing Reveals Direct Targets of Gammaherpesvirus-Induced mRNA Decay and Suggests That Multiple Mechanisms Govern Cellular Transcript Escape

One characteristic of lytic infection with gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and murine herpesvirus 68 (MHV68), is the dramatic suppression of cellular gene expression in a process known as host shutoff. The alkaline exonuclease proteins (KSHV SOX, MHV-68 muSOX and EBV BGLF5) have been shown to induce shutoff by destabilizing cellular mRNAs. Here we extend previous analyses of cellular mRNA abundance during lytic infection to characterize the effects of SOX and muSOX, in the absence of other viral genes, utilizing deep sequencing technology (RNA-seq). Consistent with previous observations during lytic infection, the majority of transcripts are downregulated in cells expressing either SOX or muSOX, with muSOX acting as a more potent shutoff factor than SOX. Moreover, most cellular messages fall into the same expression class in both SOX- and muSOX-expressing cells, indicating that both factors target similar pools of mRNAs. More abundant mRNAs are more efficiently downregulated, suggesting a concentration effect in transcript targeting. However, even among highly expressed genes there are mRNAs that escape host shutoff. Further characterization of select escapees reveals multiple mechanisms by which cellular genes can evade downregulation. While some mRNAs are directly refractory to SOX, the steady state levels of others remain unchanged, presumably as a consequence of downstream effects on mRNA biogenesis. Collectively, these studies lay the framework for dissecting the mechanisms underlying the susceptibility of mRNA to destruction during lytic gammaherpesvirus infection

Seriously personal:The reasons that motivate entrepreneurs to address climate change

This is the author accepted manuscript. The final version is freely available from Springer Verlag via the DOI in this record.Scholars increasingly argue that entrepreneurs and their small- and medium-sized enterprises should play a central role in reducing the rate and magnitude of climate change. However, evidence suggests that while some entrepreneurs recognize their crucial role in addressing climate change, most do not. Why some entrepreneurs nevertheless concern themselves with climate change has largely been overlooked. Some initial work in this area tentatively suggests that these entrepreneurs may engage with climate change because of their personal values, which either focus on financial or socio-ecological reasons, or a combination of both. Yet, it is unclear if all for-profit entrepreneurs engage with climate change for the same reasons, or if indeed their motivations vary across business types. Over a period of four years, we examined entrepreneurs’ motivations to engage with climate change through a variety of qualitative research methods. Our findings illustrate how entrepreneurs who address climate change have motivations specific to their business activity/industry and level of maturity. In each instance, we link these motivations to distinct conceptualizations of time and place. We contend that, through a more differentiated understanding of entrepreneurial motivations, policy-makers can draft climate change-related policies tailored to entrepreneurial needs. Policies could both increase the number of entrepreneurs who already engage in climate change mitigation and leverage the impact of those entrepreneurs already mitigating climate change.This study was funded by the European Social Fund (09099NCO5). We acknowledge with thanks the participation of the entrepreneurs and the support of Business Leaders for Low Carbon, Cornwall Council, and Cornwall Sustainable Tourism Project. The authors wish to thank Professor John Amis, Professor Kenneth Amaeshi and the anonymous reviewers who provided useful feedback on earlier versions of the article

Future Imaginings: Organizing in Response to Climate Change

Climate change has rapidly emerged as a major threat to our future. Indeed the increasingly dire projections of increasing global average temperatures and escalating extreme weather events highlight the existential challenge that climate change presents for humanity. In this editorial article we outline how climate change not only presents real, physical threats but also challenges the way we conceive of the broader economic, political and social order. We asked ourselves (and the contributors to this special issue) how we can imagine alternatives to our current path of ever escalating greenhouse gas emissions and economic growth. Through reference to the contributions that make up this special issue, we suggest that critically engaging with the concept of social, economic and political imaginaries can assist in tackling the conceptual and organizational challenges climate change poses. Only by questioning current sanitised and market-oriented interpretations of the environment, and embracing the catharsis and loss that climate change will bring, can we open up space for new future imaginings