Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene.

BACKGROUND: In 1993, Chitayat et al., reported a newborn with hyperphalangism, facial anomalies, and bronchomalacia. We identified three additional families with similar findings. Features include bilateral accessory phalanx resulting in shortened index fingers; hallux valgus; distinctive face; respiratory compromise. OBJECTIVES: To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism. METHODS: Through ongoing collaboration, we had collected patients with strikingly-similar phenotype. Trio-based exome sequencing was first performed in Patient 2 through Deciphering Developmental Disorders study. Proband-only exome sequencing had previously been independently performed in Patient 4. Following identification of a candidate gene variant in Patient 2, the same variant was subsequently confirmed from exome data in Patient 4. Sanger sequencing was used to validate this variant in Patients 1, 3; confirm paternal inheritance in Patient 5. RESULTS: A recurrent, novel variant NM_006494.2:c.266A>G p.(Tyr89Cys) in ERF was identified in five affected individuals: de novo (patient 1, 2 and 3) and inherited from an affected father (patient 4 and 5). p.Tyr89Cys is an aromatic polar neutral to polar neutral amino acid substitution, at a highly conserved position and lies within the functionally important ETS-domain of the protein. The recurrent ERF c.266A>C p.(Tyr89Cys) variant causes Chitayat syndrome. DISCUSSION: ERF variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis. CONCLUSIONS: We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in ERF

4pi Models of CMEs and ICMEs

Coronal mass ejections (CMEs), which dynamically connect the solar surface to the far reaches of interplanetary space, represent a major anifestation of solar activity. They are not only of principal interest but also play a pivotal role in the context of space weather predictions. The steady improvement of both numerical methods and computational resources during recent years has allowed for the creation of increasingly realistic models of interplanetary CMEs (ICMEs), which can now be compared to high-quality observational data from various space-bound missions. This review discusses existing models of CMEs, characterizing them by scientific aim and scope, CME initiation method, and physical effects included, thereby stressing the importance of fully 3-D ('4pi') spatial coverage.Comment: 14 pages plus references. Comments welcome. Accepted for publication in Solar Physics (SUN-360 topical issue

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The historical universal: the role of cultural value in the historical sociology of Pierre Bourdieu

Best known for his pioneering study Distinction: A Social Critique of the Judgement of Taste, in which the aesthetic attitude of disinterestedness is accounted for as the expression of a class ethos, Bourdieu has become something of an icon of relativism. In thus effecting a Bakhtinian 'discrowning' of official hierarchies of the arts, he is often celebrated for his concern to place all tastes, popular and high, on a similar footing, equally rooted in specific class practices. Only a careless inattention could support such a conclusion. From his early interventions in French cultural policy debates up to and including The Rules of Art and Pascalian Meditations (1996), Bourdieu has consistently repudiated the view that a sociological approach to questions of aesthetic judgment must result in a levelling form of relativism. In exploring why this should be so, this paper considers the issues at stake in the forms of 'historical universalism' that are associated with Bourdieu's account of the autonomy of the aesthetic sphere. It does so with a view to identifying some of the difficulties underlying his understanding of sociology as a historical practice

Control of interfacial reactions during liquid phase processing of aluminum matrix composites reinforced with INCONEL 601 fibers

A comprehensive investigation is made of the parameters affecting the extent of interface reactions during squeeze casting of composites consisting of a matrix of either pure Al or alloy AS13 reinforced with fibers of INCONEL 601. The process parameters are the preform thickness and temperature, the fiber volume fraction, the temperature and mass of the liquid metal, and the temperature of the die. Adjustment of these process parameters made possible the full control of reactions. It is found that reactions proceed mainly in the solid state after decomposition of the oxide barrier layer covering the fibers. A simple kinetic model is developed that enlightens the role of this barrier layer. No trace of reaction could be detected in composites processed using preoxidized preforms. Alloying Al with Si also induces a drastic reduction of reactivity. The high ductility of the composites attests to the processing quality. An original procedure is proposed for measuring the activation energy for initiation of reactions by differential thermal analysis

Conceptualizing otherness: An exploration of the cosmopolitan schema

The Australian cosmopolitan is an important symbolic figure in popular discourse and the political landscape. Regardless of the actual scope and scale of 'cosmopolitanness' in Australia, the spectre of cosmopolitanism, and its close relatives such as tolerance of diversity or openness to difference, is a powerful figure in contemporary culture. The cosmopolitan willingness to accommodate otherness is perceived as a betrayal of Australian culture, yet continuing high levels of immigration from diverse sources demand cosmopolitan tolerance. Sociologists know that cosmopolitan people can accommodate diversity, but how this is achieved is the subject of much theoretical debate. It is reasonable to assume that cosmopolitans conceptualize otherness in ways that reduce or eliminate a sense of threat, but how can we reliably access individual conceptualizations? Informed by a cultural sociology approach, this project utilized the concept of cognitive schemas from psychology, and formal semantics from linguistics, to access cosmopolitan conceptualizations. Analysis of focus group data concluded that cosmopolitan schemas are constructed using a repertoire of strategies which compartmentalize categories of otherness into manageable portions. It is argued that, from the cosmopolitan perspective, Australian cultural integrity remains the intact and dominant host of smaller, harmless or manageable cultural fragments