A first order phase transition mechanism underlies protein aggregation in mammalian cells

The formation of misfolded protein aggregates is a hallmark of neurodegenerative diseases. The aggregate formation process exhibits an initial lag phase when precursor clusters spontaneously assemble. However, most experimental assays are blind to this lag phase. We develop a quantitative assay based on super-resolution imaging in fixed cells and light sheet imaging of living cells to study the early steps of aggregation in mammalian cells. We find that even under normal growth conditions mammalian cells have precursor clusters. The cluster size distribution is precisely that expected for a so-called super-saturated system in first order phase transition. This means there exists a nucleation barrier, and a critical size above which clusters grow and mature. Homeostasis is maintained through a Szilard model entailing the preferential clearance of super-critical clusters. We uncover a role for a putative chaperone (RuvBL) in this disassembly of large clusters. The results indicate early aggregates behave like condensates. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).National Institutes of Health (U.S.) (Grant DP2CA195769

Allo-network drugs: harnessing allostery in cellular networks

Allosteric drugs are increasingly used because they produce fewer side effects. Allosteric signal propagation does not stop at the 'end' of a protein, but may be dynamically transmitted across the cell. Here, we propose that the concept of allosteric drugs can be broadened to allo-network drugs, whose effects can propagate either within a protein, or across several proteins, to enhance or inhibit specific interactions along a pathway. We posit that current allosteric drugs are a special case of allo-network drugs, and suggest that allo-network drugs can achieve specific, limited changes at the systems level, and in this way can achieve fewer side effects and lower toxicity. Finally, we propose steps and methods to identify allo-network drug targets and sites outlining a new paradigm in systems-based drug design.Comment: 14 pages, 4 figures, 69 references, a cover story of the 2011 December issue of Trends in Pharmacological Science

Disorders of Sex Development

The birth of a new baby is one of the most dramatic events in a family, and the first question is usually "is it a boy or a girl?" The newborn infant with ambiguous external genitalia often comes as a surprise for the doctors as well as the parents and is sometimes described as an endocrine emergency situation presenting a problem of sex assignment. The nomenclature such as 'intersex', 'hermaphrodite', and 'pseudohermaphrodite' is out of date as well as confusing, and many urologists are concerned that these confusing terms could be perceived to be pejorative by some affected families. In response to concerns regarding outdated and controversial terms, the Chicago Consensus held in 2005 recommended new terminology based on the umbrella term disorders of sex differentiation (DSDs). The term DSD has a comprehensive definition including any problem noted at birth in which the genitalia are atypical in relation to the chromosomes or gonads. The karyotype is used as a prefix defining the classification of DSD. DSDs are rare and complex. The optimal management of patients with DSD must be individualized and multidisciplinary, considering all aspects, including psychological care and full disclosure of alternatives relating to surgery type and timing. Although further studies are necessary to confirm guidelines and recommendations fitting for the individual patients with DSD, this article is an attempt to provide a balanced perspective for new taxonomy, clinical evaluation, and medical, surgical, and psychological management of DSD

'So wide and varied': The origins and character of British information science

This paper examines some characteristics of the ‘British School’ of information science. Three main forces driving the development of the new subject in Britain are identified: the documentation movement; special libraries; and the need for better treatment of scientific and technical information. Five characteristics which, taken together, distinguish the early British approach to information science from those adopted elsewhere are identified: its subject-based nature; its broad approach to information and information science; its status as an academic subject with a strong professional remit; its involvement with, but distinction from, information technology; and its involvement with memory institutions. Lessons are drawn for the future development of the information sciences