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Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ?accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. "Regulated cell death" (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death Fil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Nomenclature Committee on Cell Death. Equipe 11 Apoptose, Cancer et Immunité. Centre de Recherche des Cordeliers; Francia

More and more journals relegate scientific data into Supplementary Information, which are often not seen by the scientific community. The amount of this ‘dead' data is often impressive, and papers may contain up to 30 Supplementary Figures of really high quality. Here we propose a solution by publishing them as a ‘Companion' paper. Conventional journals, such as Cell Death & Differentiation, operate within the constraints of a page budget, generally agreed on an annual basis between the Editor-in-Chief and the Publishers, although the limitations are not so tight with journals that are completely web-based, such as Cell Death & Disease. For conventional journals, therefore, this means that if the page budget is set at, say, 1000, then 200 papers of 5 pages can be published in one volume, but only 100 papers if their average length is 10 pages. It is obviously advantageous for the journal and for the scientific community, it serves, to publish more rather than fewer papers, and it is for this reason that there has developed greater reliance on including data that is not central to the message of the paper as Supplementary Information online. Indeed, of the 129 original papers published to date in Volume 18 (2011) of Cell Death & Differentiation, 108 (83.7%) included Supplementary Information of some sort. One problem in publishing Supplementary Information is whether readers, and indeed Editors and referees, bother to access it even though it is just another click on the webpage. Anecdotally, at the journal clubs we attend, group members will have downloaded the PDF of the main text, but not the Supplementary Information. Often, of course, Supplementary Information is just that; it supplements and even complements the data in the main text. There are times, however, when the Supplementary Information is sufficiently comprehensive to add another dimension to the story and would really justify the publication as a separate paper. A good example of the latter situation is the paper by Cesca et al.1 Here, the authors have investigated the role of kinase D interacting substrate of 220 kDa (Kidins 220; also known as ankyrin repeat-rich membrane spanning, ARMS), a membrane-bound scaffold protein for the neurotrophin receptor Trk and p75NTR signalling. To do this, they generated Kidins 220-/- mice and, obviously, a large amount of the data describes the generation of the mice and their characterisation. They demonstrate that the knockout mice die at a late embryonic stage with defects in the central nervous system (CNS) due to apoptosis of neurons. Moreover, primary neurons show reduced responsiveness to BDNF as assessed by the lower complexity of neurite outgrowth and by electrophysiological abnormalities. Kidins 220 was also shown to constitutively interact with VEGFR2. In the original submission, data was also included, as Supplementary Information, showing that the CNS abnormalities were accompanied by defects in the peripheral nervous system (PNS) and in the heart. In the PNS, as in the CNS, cell death occurs by apoptosis, and the cardiac phenotype includes defects in the outflow tract and in the ventricular wall. Finally, neuronal specific deletion of Kidins 220 allows live births, but the animals die early in postnatal life with profound CNS abnormalities. Because of the wealth of novel information they contain, these Supplementary Information have now been reformatted as an independent companion manuscript.2 Clearly, in this case, the original Supplementary Information require a full exposure to the scientific community as a self-standing publication,2 without detracting from the main paper.1 Could this be the solution to the exploding requests by editors and reviewers to add Supplementary Information to the majority of papers, and thus make more visible data which is often of considerable interest in its own right?

The HECT-type E3 ubiquitin ligase (E3) Itch is absent in the non-agouti-lethal 18H or Itchy mice, which develop a severe immunological disease, including lung and stomach inflammation and hyperplasia of lymphoid and hematopoietic cells. The involvement of Itch in multiple signaling pathways and pathological conditions is presently an area of extensive scientific interest. This review aims to bring together a growing body of work exploring Itch-regulated biological processes, and to highlight recent discoveries on the regulatory mechanisms modulating its catalytic activity and substrate recognition capability. Our contribution is also an endeavor to correlate Itch substrate specificity with the pathological defects manifested by the mutant Itchy mice.

The Brn-3a/POU4F1 POU transcription factor is critical for the survival and differentiation of specific sensory neurons during development or upon injury; by regulating expression of target genes, either directly or indirectly upon interaction with other proteins. In this study, we demonstrated the physical interaction of Brn-3a with different p73 isoforms and showed co-localization in sensory neurons arising from the neural crest. The biological effects of p73/ Brn-3a interaction depend on the particular p73 isoform, because co-expression of Brn-3a with TAp73 enhanced cell cycle arrest, whereas Brn-3a and DeltaNp73 cooperated to increase protection from apoptosis. Brn-3a antagonized TAp73 transactivation of pro-apoptotic Bax, but co-operated to increase transcription of the cell cycle regulator p21 CIP1/Waf1. The region 425-494 amino acids within the TAp73 C terminus were critical for Brn-3a to repress Bax transactivation, but not for cooperation on the p21 CIP1/Waf1 promoter. Our results suggest that co-factors binding to the p73 C terminus facilitate maximal activation on the Bax but not p21 CIP1/Waf1 promoter and that Brn-3a modulates this interaction. Thus, the physical interaction of Brn-3a with specific p73 isoforms will be critical for determining cell fate during neuronal development or in injured neurons expressing both factors.

Epidermal development requires the transcription factor p63, as p63-/- mice are born dead, without skin. The gene expresses two proteins, one with an amino-terminal transactivation domain (TAp63) and one without (deltaNp63), although their relative contribution to epidermal development is unknown. To address this issue, we reintroduced TAp63alpha and/or deltaNp63alpha under the K5 promoter into p63-/- mice by in vivo genetic complementation. Whereas p63-/- and p63-/-;TA mice showed extremely rare patches of poorly differentiated keratinocytes, p63-/-;deltaN mice showed significant epidermal basal layer formation. Double TAp63alpha/deltaNp63alpha complementation showed greater patches of differentiated skin; at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes. At the molecular level, deltaNp63 regulated expression of genes characteristic of the basal layer (K14), interacting (by Chip, luc assay) with the third p53 consensus site. Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin). Therefore, the two p63 isoforms appear to play distinct cooperative roles in epidermal formation.