SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis

SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.     

The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm

In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca(2+) increase by a non-genomic mechanism. The Ca(2+) signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm. However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca(2+) channel. We found that both progesterone and alkaline pH stimulate a rapid Ca(2+) influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca(2+) signals evoked by alkaline pH and progesterone are inhibited by the Ca(v) channel blockers NNC 55-0396 and mibefradil. Patch-clamp recordings from sperm reveal an alkaline-activated current carried by mono- and divalent ions that exhibits all the hallmarks of sperm-specific CatSper Ca(2+) channels. Progesterone substantially enhances the CatSper current. The alkaline- and progesterone-activated CatSper current is inhibited by both drugs. Our results resolve a long-standing controversy over the non-genomic progesterone signalling. In human sperm, either the CatSper channel itself or an associated protein serves as the non-genomic progesterone receptor. The identification of CatSper channel blockers will greatly facilitate the study of Ca(2+) signalling in sperm and help to define further the physiological role of progesterone and CatSper.     

Identification of adult nephron progenitors capable of kidney regeneration in zebrafish

Loss of kidney function underlies many renal diseases. Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones. By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury, providing a model for understanding how mammalian renal regeneration may be therapeutically activated. Here we trace the source of new nephrons in the adult zebrafish to small cellular aggregates containing nephron progenitors. Transplantation of single aggregates comprising 10-30 cells is sufficient to engraft adults and generate multiple nephrons. Serial transplantation experiments to test self-renewal revealed that nephron progenitors are long-lived and possess significant replicative potential, consistent with stem-cell activity. Transplantation of mixed nephron progenitors tagged with either green or red fluorescent proteins yielded some mosaic nephrons, indicating that multiple nephron progenitors contribute to a single nephron. Consistent with this, live imaging of nephron formation in transparent larvae showed that nephrogenic aggregates form by the coalescence of multiple cells and then differentiate into nephrons. Taken together, these data demonstrate that the zebrafish kidney probably contains self-renewing nephron stem/progenitor cells. The identification of these cells paves the way to isolating or engineering the equivalent cells in mammals and developing novel renal regenerative therapies.     

Only full-sibling families evolved eusociality

Arising from M. A. Nowak, C. E. Tarnita & E. O. Wilson 466, 1057-1062 (2010); Nowak et al. reply. The paper by Nowak et al. has the evolution of eusociality as its title, but it is mostly about something else. It argues against inclusive fitness theory and offers an alternative modelling approach that is claimed to be more fundamental and general, but which, we believe, has no practical biological meaning for the evolution of eusociality. Nowak et al. overlook the robust empirical observation that eusociality has only arisen in clades where mothers are associated with their full-sibling offspring; that is, in families where the average relatedness of offspring to siblings is as high as to their own offspring, independent of population structure or ploidy. We believe that this omission makes the paper largely irrelevant for understanding the evolution of eusociality.     

Description of a Phyllorhynchus from Cerralvo Island, Gulf of California, Mexico

Phyllorhynchus decurtatus porelli ssp. nov. is described from a single specimen from Cerralvo Island, Gulf of California, Mexico, and is regarded as different from P. d. decuratus on the basis of an increased number of dorsal blotches (41 as compared to 18 – 33) and an increased number of supralabials (7 as compared to 6), combined with geographical isolation and the high degree of endemism found in other reptiles on Cerralvo Island.       

Shear instabilities in granular flows.

Unstable waves have been long studied in fluid shear layers. These waves affect transport in the atmosphere and oceans, in addition to slipstream stability behind ships, aeroplanes and heat-transfer devices. Corresponding instabilities in granular flows have not been previously documented, despite the importance of these flows in geophysical and industrial systems. Here we report that breaking waves can form at the interface between two streams of identical grains flowing on an inclined plane downstream of a splitter plate. Changes in either the shear rate or the angle of incline cause such waves to appear abruptly. We analyse a granular flow model that agrees qualitatively with our experimental data; the model suggests that the waves result from competition between shear and extensional strains in the flowing granular bed. We propose a dimensionless shear number that governs the transition between steady and wavy flows.     

Architecture and Technology: A Discontinuous Relation

Technology has a history structured by discontinuities. The first important philosophical expression of such a conception of technology was advanced by Walter Benjamin when he defined art works in relation to specific techniques of production. At the present art and architecture occur within an age defined by the move from ’technical reproducibility’ to digital reproducibility. The move has an impact on how technology is understood and its relation to architecture conceived. Adapting Walter Benjamin’s work in this area provides the basis for a response to Soren Riis’ important treatment of the relationship between architecture and technology in his paper “Dwelling in-between walls: the architectural surround”.     

Thomas Reid and the problem of induction: from common experience to common sense

By the middle of the eighteenth century the new science had challenged the intellectual primacy of common experience in favor of recondite, expert and even counter-intuitive knowledge increasingly mediated by specialized instruments. Meanwhile modern philosophy had also problematized the perceptions of common experience — in the case of David Hume this included our perception of causal relations in nature, a fundamental precondition of scientific endeavor.In this article I argue that, in responding to the ‘problem of induction’ as advanced by Hume, Reid reformulated Aristotelian foundationalism in distinctly modern terms. An educator and mathematician self-consciously working within the framework of the new science, Reid articulated a philosophical foundation for natural knowledge anchored in the human constitution and in processes of adjudication in an emerging modern public sphere of enlightened discourse. Reid thereby transformed one of the bases of Aristotelian science — common experience — into a philosophically and socially justified notion of ‘common sense’. Reid's intellectual concerns had as much to do with the philosophy of science as they did with moral philosophy or epistemology proper, and were bound up with wider social and scientific changes taking place in the early modern period.     

Notes on Viscainopelmatus davewerneri (Orthoptera: Gryllacrididae; Stenopelmatinae) from the Viscaino Desert, Baja California Sur, Mexico

A male nymph in stadium 3 of Viscainopelmatus davewerneri Tinkham is reported and illustrated. The specimen was taken near Laguna Scammon, Baja California Sur, Mexico.