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Regulated exocytosis of synaptic vesicles is substantially faster than of endocrine dense core vesicles despite similar molecular machineries. The reasons for this difference are unknown and could be due to different regulatory proteins, different spatial arrangements, different vesicle sizes, or other factors. To address these questions, we take a reconstitution approach and compare regulated SNARE-mediated fusion of purified synaptic and dense core chromaffin and insulin vesicles using a single vesicle-supported membrane fusion assay. In all cases, Munc18 and complexin are required to restrict fusion in the absence of calcium. Calcium triggers fusion of all docked vesicles. Munc13 (C1C2MUN domain) is required for synaptic and enhanced insulin vesicle fusion, but not for chromaffin vesicles, correlating inversely with the presence of CAPS protein on purified vesicles. Striking disparities in calcium-triggered fusion rates are observed, increasing with curvature with time constants 0.23 s (synaptic vesicles), 3.3 s (chromaffin vesicles), and 9.1 s (insulin vesicles) and correlating with rate differences in cells., Regulated exocytosis of neuronal synaptic vesicles is substantially faster than that of endocrine dense core vesicles despite similar molecular machineries. Here authors compare SNARE-mediated fusion of purified synaptic vesicles with insulin vesicles and see disparities in calcium-triggered fusion rates.

Scientific advances in methods of producing genetically modified (GM) animals continue, yet few such animals have reached commercial production. Existing regulations designed for early techniques of genetic modification pose formidable barriers to commercial applications. Radically improved techniques for producing GM animals invite a re-examination of current regulatory regimes. We critically examine current GM animal regulations, with a particular focus on the European Union, through a framework that recognises the importance of interactions among regulatory regimes, innovation outcomes and industry sectors. The current focus on the regulation of risk is necessary but is unable to discriminate among applications and tends to close down broad areas of application rather than facilitate innovation and positive industry interactions. Furthermore, the fields of innovative animal biosciences appear to lack networks of organisations with co-ordinated future oriented actions. Such networks could drive coherent programmes of innovation towards particular visions and contribute actively to the development of regulatory systems for GM animals. The analysis presented makes the case for regulatory consideration of each animal bioscience related innovation on the basis of the nature of the product itself and not the process by which it was developed.

As industry, governments and academia increasingly rely on patent landscapes to map scientific and technological trends, an interdisciplinary workshop provides recommendations for developing consistent and transparent landscaping practices.

Integrin-mediated adhesion regulates membrane binding sites for Rac1 within lipid rafts. Detachment of cells from the substratum triggers the clearance of rafts from the plasma membrane through caveolin-dependent internalization. The small GTPase Arf6 and microtubules also regulate Rac-dependent cell spreading and migration, but the mechanisms are poorly understood. Here we show that endocytosis of rafts after detachment requires F-actin, followed by microtubule-dependent trafficking to recycling endosomes. When cells are replated on fibronectin, rafts exit from recycling endosomes in an Arf6-dependent manner and return to the plasma membrane along microtubules. Both of these steps are required for the plasma membrane targeting of Rac1 and for its activation. These data therefore define a new membrane raft trafficking pathway that is crucial for anchorage-dependent signalling.

The distinction between the context ofdiscovery and the context of justificationrestricts philosophy of science to the rationalreconstruction of theories, and characterizesscientific discovery as rare, theoreticalupheavals that defy rational reconstruction. Kuhnian challenges to the two contextsdistinction show that non-rational elementspersist in the justification of theories, butgo no further to provide a positive account ofdiscovery. A gradualist theory of discoverydeveloped in this paper shows, with supportfrom ecological cases, that discoveries areroutinely made in ecology by extending modelsto new domains, or by making additions toearlier models. The logic of discovery isphilosophically accessible once it isappreciated that model truth is presumed, evenif counterfactually, in ecologists' applicationof models. A gradualist view shows thatmodels' heuristic power routinely leads todiscoveries.

The onset of schizophrenia for the first time in late life has been considered rare, and the nosology of the late-onset functional psychoses remains contentious. However, it is clear that a significant proportion of individuals with a diagnosis of schizophrenia do have the first onset of the illness in late and very late life. The clinical presentation of such patients shows some differences from patients with early-onset disease, particularly in having a lower prevalence of premorbid dysfunction, negative symptoms and formal thought disorder. The longitudinal course is variable, possibly a reflection of aetiological heterogeneity. Atypical antipsychotic agents would appear to have significant benefits in the treatment of this group of patients, given the particular vulnerability of the elderly to extrapyramidal adverse effects, notably tardive dyskinesia.

Work presented in this issue reveals the structure of a SNARE transmembrane domain and supports a model of exocytosis via hemifusion. Hemifusion may thus be a common intermediate in many, if not all, biological fusion reactions.

Nature 523, 337–341 (2015); doi:10.1038/nature14432 We would like to correct this Letter, which demonstrated the molecular characteristics and functional nature of lymphatics serving the central nervous system (CNS), by adding two reference citations, of which we became aware after publication. Foldi et al.

Black, Kenneth (ed.) 2001. Environmental impacts of aquaculture. Sheffield Academic Press, Sheffield. 214 pp. U.K. £ 69.00

Heterologous antibodies to gamma-glutamyl transferase (gamma GT), an ectoenzyme associated with the apical surface of many types of epithelial cells involved in secretion and transport, have been used to identify and partially characterize the spectrum of antigens in a series of epithelial tissues that exhibit a range of enzyme activities. In addition to antigens corresponding to the subunits of the active enzyme (mol wt 55K, 30K), antigens of mol wt approximately 85-greater than or equal to 95K have been detected using an antibody raised against the enzyme purified in nonionic detergent. The latter species are shown to share antigenic determinants with and to be structurally related to the enzyme subunits; however, they do not blind significantly to antibodies raised to protease-solubilized gamma GT. Further, they constitute the major antigens in tissues that exhibit relatively low levels of enzyme activity. These polypeptides are apparently larger than a recently characterized biosynthetic precursor of the gamma GT subunits. Although they do not have gamma GT activity themselves and their function is undefined, the possibility that they may represent highly glycosylated polypeptides related either to gamma GT precursors (that persist without processing) or to the large enzyme subunit merits consideration.