SC3: consensus clustering of single-cell RNA-seq data

Single-cell RNA-seq enables the quantitative characterization of cell types based on global transcriptome profiles. We present single-cell consensus clustering (SC3), a user-friendly tool for unsupervised clustering, which achieves high accuracy and robustness by combining multiple clustering solutions through a consensus approach (http://bioconductor.org/packages/SC3). We demonstrate that SC3 is capable of identifying subclones from the transcriptomes of neoplastic cells collected from patients.V.Y.K., T.A., A.Y. and M.H. are supported by Wellcome Trust Grants. K.N.N. is supported by the Wellcome Trust Strategic Award 'Single cell genomics of mouse gastrulation'. M.T.S. acknowledges support from FRS-FNRS; the Belgian Network DYSCO (Dynamical Systems, Control and Optimisation), funded by the Interuniversity Attraction Poles Programme initiated by the Belgian State Science Policy Office; and the ARC (Action de Recherche Concerte) on Mining and Optimization of Big Data Models, funded by the Wallonia-Brussels Federation. M.B. acknowledges support from EPSRC (grant EP/N014529/1). T.C. was funded through a core funded fellowship by the Sanger Institute and a Chancellor′s fellowship from the University of Edinburgh. K.K. and A.R.G. are supported by Bloodwise (grant ref. 13003), the Wellcome Trust (grant ref. 104710/Z/14/Z), the Medical Research Council, the Kay Kendall Leukaemia Fund, the Cambridge NIHR Biomedical Research Center, the Cambridge Experimental Cancer Medicine Centre, the Leukemia and Lymphoma Society of America (grant ref. 07037) and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. W.R. was supported by BBSRC (grant ref. BB/K010867/1), the Wellcome Trust (grant ref. 095645/Z/11/Z), EU BLUEPRINT and EpiGeneSys

Clinical Update

Parvovirus B19 is notoriously a cause of normocytic anaemia in patients in an immunocompromised state, more so than in patients without prior disease. It is increasingly prevalent in children and adults in an HIV-induced immunocompromised state, and its presentation may be varied. Red-cell aplasia and normocytic anaemia are common presenting derangements found. Here, we note the typical presentation of red-cell aplasia re-entering healthcare, with a dire effect on the quality of life of this patient

Human dignity - Our supreme constitutional value

As far as constitutional interpretation and statutory interpretation in general is concerned, South Africa is undergoing a transformation from a formal, positivistic vision of law to a substantive, natural law vision of law. And the single most significant factor in this transformation is the existence of constitutional values. For the first time in South Africa, courts (in particular the Constitutional Court) must decide cases on the basis of these values. It is therefore simply erroneous and naive to say that 'the Constitutional Court has been so fixated with the role of 'values' in the first year of its existence' and that the court is 'obsessed' with the role of 'values'. Of these values, the three most fundamental in any open and democratic society are human dignity, equality and freedom. Amongst this trinity of values human dignity finds pride of place. Some of the pertinent questions briefly addressed in this article are: (1) What does human dignity entail?; (2) Is human dignity a right or a duty?; (3) How should it be understood in a plural society such as ours?; (4) What about the impact of modern technology on human dignity?; (5) Is our understanding of the concept/value/idea of human dignity not too European/Western in nature? For example, the issue of gays and lesbians is a human rights and human dignity question in the West, while other cultures find homosexuality abhorrent and uncivilized; and (6) Should we explore a religious and spiritual philosophy of human dignity

Dual action calcium-sensing receptor modulator unmasks novel mode-switching mechanism

Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility