A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), a G-protein coupled receptor that predominantly signals via G-protein subunit alpha-11 (Gα11 ) to regulate calcium homeostasis. FHH2 is the result of loss-of-function mutations in Gα11 , encoded by GNA11, and to date only two FHH2-associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss-of-function mutations of the adaptor protein-2 σ-subunit (AP2σ), which plays a pivotal role in clathrin-mediated endocytosis. We describe a 65-year-old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR-mediated intracellular calcium (Ca(2+) i ) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca(2+) o ) using flow cytometry. Three-dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild-type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca(2+) i responses after stimulation with Ca(2+) o of the mutant Met54 Gα11 led to a rightward shift of the concentration-response curve with a significantly (p < 0.01) increased mean half-maximal concentration (EC50 ) value of 3.88 mM (95% confidence interval [CI] 3.76-4.01 mM), when compared with the wild-type EC50 of 2.94 mM (95% CI 2.81-3.07 mM) consistent with a loss-of-function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca(2+) o homeostasis. © 2016 American Society for Bone and Mineral Research

Social Palimpsests - clouding the lens of the personal panopticon

The use of personal data has incredible potential to benefit both society and individuals, through increased understanding of behaviour, communication and support for emerging forms of socialisation and connectedness. However, there are risks associated with disclosing personal information, and present systems show a systematic asymmetry between the subjects of the data and those who control and manage the way that data is propagated and used. This leads to a tension between a desire to engage with online society and enjoy its benefits on one hand, and a distrust of those with whom the data is shared on the other. In this chapter, we explore a set of obfuscation techniques which may help to redress the balance of power when sharing personal data, and return agency and choice to users of online services

Analysis of C. elegans intestinal gene expression and polyadenylation by fluorescence-activated nuclei sorting and 3′-end-seq

Despite the many advantages of Caenorhabditis elegans, biochemical approaches to study tissue-specific gene expression in post-embryonic stages are challenging. Here, we report a novel experimental approach for efficient determination of tissue-specific transcriptomes involving the rapid release and purification of nuclei from major tissues of post-embryonic animals by fluorescence-activated nuclei sorting (FANS), followed by deep sequencing of linearly amplified 3′-end regions of transcripts (3′-end-seq). We employed these approaches to compile the transcriptome of the developed C. elegans intestine and used this to analyse tissue-specific cleavage and polyadenylation. In agreement with intestinal-specific gene expression, highly expressed genes have enriched GATA-elements in their promoter regions and their functional properties are associated with processes that are characteristic for the intestine. We systematically mapped pre-mRNA cleavage and polyadenylation sites, or polyA sites, including more than 3000 sites that have previously not been identified. The detailed analysis of the 3′-ends of the nuclear mRNA revealed widespread alternative polyA site use (APA) in intestinally expressed genes. Importantly, we found that intestinal polyA sites that undergo APA tend to have U-rich and/or A-rich upstream auxiliary elements that may contribute to the regulation of 3′-end formation in the intestin

Self Curation, Social Partitioning, Escaping from Prejudice and Harassment: the Many Dimensions of Lying Online

Portraying matters as other than they truly are is an important part of everyday human communication. In this paper, we use a survey to examine ways in which people fabricate, omit or alter the truth online. Many reasons are found, including creative expression, hiding sensitive information, role-playing, and avoiding harassment or discrimination. The results suggest lying is often used for benign purposes, and we conclude that its use may be essential to maintaining a humane online societ

Presentation of self on a decentralised web

Self presentation is evolving; with digital technologies, with the Web and personal publishing, and then with mainstream adoption of online social media. Where are we going next? One possibility is towards a world where we log and own vast amounts of data about ourselves. We choose to share - or not - the data as part of our identity, and in interactions with others; it contributes to our day-to-day personhood or sense of self. I imagine a world where the individual is empowered by their digital traces (not imprisoned), but this is a complex world. This thesis examines the many factors at play when we present ourselves through Web technologies. I optimistically look to a future where control over our digital identities are not in the hands of centralised actors, but our own, and both survey and contribute to the ongoing technical work which strives to make this a reality. Decentralisation changes things in unexpected ways. In the context of the bigger picture of our online selves, building on what we already know about self-presentation from decades of Social Science research, I examine what might change as we move towards decentralisation; how people could be affected, and what the possibilities are for a positive change. Finally I explore one possible way of self-presentation on a decentralised social Web through lightweight controls which allow an audience to set their expectations in order for the subject to meet them appropriately. I seek to acknowledge the multifaceted, complicated, messy, socially-shaped nature of the self in a way that makes sense to software developers. Technology may always fall short when dealing with humanness, but the framework outlined in this thesis can provide a foundation for more easily considering all of the factors surrounding individual self-presentation in order to build future systems which empower participants

IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

Increased numbers of innate lymphoid cells in patients with inflammatory bowel disease