A Case of Urogenital Human Schistosomiasis from a Non-endemic Area

© 2015 Calvo-Cano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article

DOCK6 Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies

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"It's making contacts" : notions of social capital and implications for widening access to medical education

Acknowledgements Our thanks to the Medical Schools Council (MSC) of the UK for funding Study A; REACH Scotland for funding Study B; and Queen Mary University of London, and to the medical school applicants and students who gave their time to be interviewed. Our thanks also to Dr Sean Zhou and Dr Sally Curtis, and Manjul Medhi, for their help with data collection for studies A and B respectively. Our thanks also to Dr Lara Varpio, Uniformed Services University of the USA, for her advice and guidance on collating data sets and her comments on the draft manuscript.Peer reviewedPublisher PD

Interacting mindreaders

Could interacting mindreaders be in a position to know things which they would be unable to know if they were manifestly passive observers? This paper argues that they could. Mindreading is sometimes reciprocal: the mindreader's target reciprocates by taking the mindreader as a target for mindreading. The paper explains how such reciprocity can significantly narrow the range of possible interpretations of behaviour where mindreaders are, or appear to be, in a position to interact. A consequence is that revisions and extensions are needed to standard theories of the evidential basis of mindreading. The view also has consequences for understanding how abilities to interact combined with comparatively simple forms of mindreading may explain the emergence, in evolution or development, of sophisticated forms of social cognition

Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS. METHODS AND RESULTS: Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway. CONCLUSIONS: These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders

Autobiography as unconventional history: Constructing the author

The experience of historians as autobiographers has led them to reconsider the nature of historical knowledge and the function of the historian as an intermediary between the past and present. In the new theoretical context of the social sciences and historiography, we can take this proposal further and consider autobiography as a valid form of history—or, at least, as ‘unconventional history’, understood as negotiations with history that transcend or subvert traditional chronological monographs, posit the ‘subjective’ as a useful form of knowledge, and engage the constructed nature of the text. Taking this hypothesis as a starting point, this article reads historians' autobiographical texts to explore if we can/should continue to defend the classic distinction between subject and object, historian scientist and historian author. In this article I compare the work of several historian autobiographers that permit us to identify different methodologies in approaching the story of the self that also reflects different theoretical conceptions of history. I argue that historians that may be considered ‘constructionist’, such as Fernand Braudel, Annie Kriegel, George Duby, and Eric Hobsbawm, design their autobiographies in the same way they articulate their historical texts: by foregrounding objectivity and establishing critical distance between the subject—the historian who narrates the story—and the object—one's own life. Unconventional or experimental approaches, such as those espoused by Robert Rosenstone, Dominick LaCapra, or Clifford Geertz, result in more self-conscious autobiographies, which are, paradoxically, often more realistic and more revealing of the epistemological nature of life writing. ----------------- La experiencia de los historiadores como autobiógrafos les ha llevado a reconsiderar la naturaleza del conocimiento histórico y la función del historiador como un intermediario entre el pasado y el presente. En el nuevo contexto teórico de las ciencias sociales y la historiografía podemos tomar esta propuesta más allá y considerar la autobiografía como una forma válida de historia-o, al menos, de historia ‘poco convencional’-, entendida como negociaciones con la historia que trascienden o subvierten las tradicionales monografías cronológicas, plantean lo "subjetivo" como una forma útil de conocimiento y participan de la naturaleza construida del texto. Tomando esta hipótesis como punto de partida, este artículo lee los textos autobiográficos de los historiadores para explorar si se puede / debe seguir defendiendo la clásica distinción entre sujeto y objeto, historiador científico e historiador escritor. En este artículo comparo el trabajo de varios historiadores autobiógrafos que nos permiten identificar las diferentes metodologías para acercarse a la historia del yo y que también reflejan las diferentes concepciones teóricas de la historia. Sostengo que los historiadores que pueden considerarse "constructivistas", como Fernand Braudel, Annie Kriegel, George Duby y Eric Hobsbawm, diseñan sus autobiografías de la misma forma que articulan sus textos históricos: poniendo en primer plano la objetividad y estableciendo una distancia crítica entre el sujeto -el historiador que narra la historia-y el objeto- la vida de cada uno. Enfoques no convencionales o experimentales, como los expuestos por Robert Rosenstone, Dominick LaCapra, o Clifford Geertz, resultan autobiografías más autoconscientes, que son, paradójicamente, a menudo más realistas y más reveladoras de la naturaleza epistemológica de la escritura de la vida

Academic self-concept, gender and single-sex schooling

This paper assesses gender differences in academic self-concept for a cohort of children born in 1958 (the National Child Development Study). We address the question of whether attending single-sex or co-educational schools affected students’ perceptions of their own academic abilities (academic self-concept). Academic selfconcept was found to be highly gendered, even controlling for prior test scores. Boys had higher self-concepts in maths and science, and girls in English. Single-sex schooling reduced the gender gap in self-concept, while selective schooling was linked to lower academic self-concept overall

Integrated Epigenome Profiling of Repressive Histone Modifications, DNA Methylation and Gene Expression in Normal and Malignant Urothelial Cells

Epigenetic regulation of gene expression is commonly altered in human cancer. We have observed alterations of DNA methylation and microRNA expression that reflect the biology of bladder cancer. This common disease arises by distinct pathways with low and high-grade differentiation. We hypothesized that epigenetic gene regulation reflects an interaction between histone and DNA modifications, and differences between normal and malignant urothelial cells represent carcinogenic events within bladder cancer. To test this we profiled two repressive histone modifications (H3K9m3 and H3K27m3) using ChIP-Seq, cytosine methylation using MeDIP and mRNA expression in normal and malignant urothelial cell lines. In genes with low expression we identified H3K27m3 and DNA methylation each in 20–30% of genes and both marks in 5% of genes. H3K9m3 was detected in 5–10% of genes but was not associated with overall expression. DNA methylation was more closely related to gene expression in malignant than normal cells. H3K27m3 was the epigenetic mark most specifically correlated to gene silencing. Our data suggest that urothelial carcinogenesis is accompanied by a loss of control of both DNA methylation and H3k27 methylation. From our observations we identified a panel of genes with cancer specific-epigenetic mediated aberrant expression including those with reported carcinogenic functions and members potentially mediating a positive epigenetic feedback loop. Pathway enrichment analysis revealed genes marked by H3K9m3 were involved with cell homeostasis, those marked by H3K27m3 mediated pro-carcinogenic processes and those marked with cytosine methylation were mixed in function. In 150 normal and malignant urothelial samples, our gene panel correctly estimated expression in 65% of its members. Hierarchical clustering revealed that this gene panel stratified samples according to the presence and phenotype of bladder cancer

Heterarchy of Transcription Factors Driving Basal and Luminal Cell Phenotypes in Human Urothelium

Cell differentiation is effected by complex networks of transcription factors that co-ordinate re-organisation of the chromatin landscape. The hierarchies of these relationships can be difficult to dissect. During in vitro differentiation of normal human uro-epithelial cells, formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and RNA-seq were used to identify alterations in chromatin accessibility and gene expression changes following activation of the nuclear receptor PPARG as a differentiation-initiating event. Regions of chromatin identified by FAIRE-seq as having altered accessibility during differentiation were found to be enriched with sequence-specific binding motifs for transcription factors predicted to be involved in driving basal and differentiated urothelial cell phenotypes, including FOXA1, P63, GRHL2, CTCF and GATA3. In addition, co-occurrence of GATA3 motifs was observed within sub-sets of differentiation-specific peaks containing P63 or FOXA1 after induction of differentiation. Changes in abundance of GRHL2, GATA3, and P63 were observed in immunoblots of chromatin-enriched extracts. Transient siRNA knockdown of P63 revealed that P63 favoured a basal-like phenotype by inhibiting differentiation and promoting expression of basal marker genes. GATA3 siRNA prevented differentiation-associated downregulation of P63 protein and transcript, and demonstrated positive feedback of GATA3 on PPARG transcript, but showed no effect on FOXA1 transcript or protein expression. This approach indicates that as a transcriptionally-regulated programme, urothelial differentiation operates as a heterarchy wherein GATA3 is able to co-operate with FOXA1 to drive expression of luminal marker genes, but that P63 has potential to transrepress expression of the same genes