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During development, pseudostratified epithelia undergo large scale morphogenetic events associated with increased mechanical stress. Using a variety of genetic and imaging approaches, we uncover that in the mouse E6.5 epiblast, where apical tension is highest, ASPP2 safeguards tissue integrity. It achieves this by preventing the most apical daughter cells from delaminating apically following division events. In this context, ASPP2 maintains the integrity and organisation of the filamentous actin cytoskeleton at apical junctions. ASPP2 is also essential during gastrulation in the primitive streak, in somites and in the head fold region, suggesting that it is required across a wide range of pseudostratified epithelia during morphogenetic events that are accompanied by intense tissue remodelling. Finally, our study also suggests that the interaction between ASPP2 and PP1 is essential to the tumour suppressor function of ASPP2, which may be particularly relevant in the context of tissues that are subject to increased mechanical stress.

We exploit Donald Trump’s nonpolitical background and surprise election victory to identify the value of sudden presidential ties among S&P 500 firms. In our setting firms did not choose to become politically connected, so we identify treatment effects comparatively free of selection bias prevalent in this literature. Firms with presidential ties enjoyed greater abnormal returns around the 2016 election. Since Trump’s inauguration, connected firms had better performance, received more government contracts, and were less subject to unfavorable regulatory actions. We rule out a number of confounding factors, including industry designation, sensitivity to Republican platforms, campaign finance, and lobbying expenditures.

Wittgenstein’s philosophy involves a general anti-platonism about properties or standards of similarity. On his view, what it is for one thing to have the same property as another is not dictated by reality itself; it depends on our classificatory practices and the standards of similarity they embody. Wittgenstein’s anti-platonism plays an important role in the private language sections and in his discussion of the conceptual problem of other minds. In sharp contrast to Wittgenstein’s views stands the contemporary doctrine of natural properties, which holds that there is an objective hierarchy of naturalness amongst properties, a hierarchy that is completely independent of our concepts or practices. Some authors have appealed to the natural properties view to offer an explicitly anti-Wittgensteinian account of sensation concepts. The paper discusses these competing views of properties and sensation concepts. It is argued that, if our account of concepts of conscious states starts from a commitment to natural properties, we are bound to recognize that our actual classificatory practices also play a crucial role in determining which properties our concepts pick out. On the other hand, if we start from the anti-platonist position, we are bound to recognize that we also need a notion of sameness of property that extends beyond our limited capacity to recognize similarity or sameness of property. The correct view, it is concluded, must occupy a middle position between an extreme anti-realism about properties and an extreme version of the natural properties view. It is suggested that Wittgenstein’s own view does just that.

Many philosophers think that there are phenomenal concepts: distinctive ways of thinking of experiences or sensations that can be grasped only by those who know what it is like to have those experiences or sensations. What light does Wittgenstein’s philosophy throw on this idea? In the literature, phenomenal concepts are often deployed for explicitly anti- Wittgensteinian purposes. Brian Loar and Christopher Peacocke, for example, both appeal to phenomenal concepts in arguing, against Wittgenstein, that a person can derive, from her own case, a concept of pain that can be applied to other people.1 And David Papineau and Katalin Balog argue that the existence of phenomenal concepts is inconsistent with Wittgenstein’s arguments against a private sensation language.2 Against these and similar views, I shall argue for the unorthodox view that a Wittgensteinian approach to sensations and sensation language can accommodate a version of the idea that there are distinctive concepts of sensations that are available only to those who know what it is like to have those sensations. For those who are interested in Wittgenstein, that is an important corrective to much that has been thought about the nature of a Wittgensteinian approach to these matters. For those who are interested in phenomenal concepts, my discussion helps to identify exactly what the existence of such concepts does and does not involve.

Wittgenstein’s philosophy involves a general anti-platonism about properties or standards of similarity. On his view, what it is for one thing to have the same property as another is not dictated by reality itself; it depends on our classificatory practices and the standards of similarity they embody. Wittgenstein’s anti-platonism plays an important role in the private language sections and in his discussion of the conceptual problem of other minds. In sharp contrast to Wittgenstein’s views stands the contemporary doctrine of natural properties, which holds that there is an objective hierarchy of naturalness amongst properties, a hierarchy that is completely independent of our concepts or practices. Some authors have appealed to the natural properties view to offer an explicitly anti-Wittgensteinian account of sensation concepts. The paper discusses these competing views of properties and sensation concepts. It is argued that, if our account of concepts of conscious states starts from a commitment to natural properties, we are bound to recognize that our actual classificatory practices also play a crucial role in determining which properties our concepts pick out. On the other hand, if we start from the anti-platonist position, we are bound to recognize that we also need a notion of sameness of property that extends beyond our limited capacity to recognize similarity or sameness of property. The correct view, it is concluded, must occupy a middle position between an extreme anti-realism about properties and an extreme version of the natural properties view. It is suggested that Wittgenstein’s own view does just that.

Wittgenstein writes: ‘The question can be raised: Is a state that I recognize on the basis of someone’s utterances really the same as the state he does not recognize this way?’ (Wittgenstein, Last Writings on Philosophy of Psychology, 8-9). Donald Davidson raises the same question: ‘If the mental states of others are known only through their behavioural and other outward manifestations, while this is not true of our own mental states, why should we think our own mental states are anything like those of others?’ (Davidson, ‘Three Varieties of Knowledge’, 207). And Davidson criticizes ‘Wittgensteinian’ accounts of our mental terms and concepts for failing to address the question. It is argued that Davidson’s own account of the asymmetry between first-person and third-person ascriptions of mental predicates itself fails to explain all that Davidson seems to suggest. And it is argued, contrary to many interpretations of Wittgenstein, that the question whether mental terms are univocal in their first-person and third-person uses is from a Wittgensteinian point of view legitimate and non-trivial. It is to be answered by achieving a reflective understanding of our practice of ascribing mental properties to ourselves and others – rather than by reference to supposedly more basic metaphysical facts about the sameness or difference of the properties our terms pick out. This approach is explained and defended.

Assisted reproductive technology (ART) has resulted in more than 5 million births worldwide. However, mainstream ART techniques are not always successful for an estimated 30% of infertile patients in whom gametes are nonviable. Most patients would clearly prefer genetic parenthood, currently possible only via the use of donated gametes or, in future, via the clinical use of artificial gametes (AGs) incorporating parental DNA. Despite much recent progress in the derivation of AGs, significant obstacles remain. Although it is possible to create artificial cells exhibiting some of the molecular and physiological traits of human gametes, they do not yet exhibit the same level of functionality as their in vivo counterparts. Most current effort pays scant attention to confirmation of molecular integrity and clinical applicability of AGs. Here we discuss the various clinical parameters used to assess gamete and embryo viability and discuss markers of gamete function that may be used within future studies attempting to derive AGs. The use of AGs may prove controversial to some members of the general public, and, as such, there is significant need for an appropriate ethical and legal framework governing the clinical use of such cells. However, provided these issues can be successfully overcome, it is highly likely that AGs will represent powerful biological tools for reproductive science, a valuable training resource for embryologists and for potential use in the clinical treatment of human infertility.

Debate continues over which morphological parameter is most important in selecting blastocysts for transfer. We aimed to investigate which parameter more accurately predicts the occurrence of a live birth by designing a retrospective cohort study of 1084 fresh elective single blastocyst transfers. Primary outcome was live birth rate (LBR) and secondary outcomes were implantation, clinical pregnancy and early pregnancy loss rates. Blastocyst expansion and inner cell mass (ICM), but not trophoectoderm, were associated with LBR in the definitive multivariable regression analysis. When ICM grade dropped from A to C the likelihood of achieving a live birth was reduced by 55% (OR=0.45, 95% CI 0.26-0.79, p = 0.005). These results were similar for clinical pregnancy rates. Early pregnancy loss rates of embryos with ICM grade C were more than double (38.0%) compared to those of grades A (15.95%) and B (17.17%, p = 0.002). The transfer of an embryo with an optimal inner cell mass reduces early pregnancy loss and increases the likelihood of a live birth. We did not find any significant association between trophectoderm and LBR in the multivariable analysis in contrast with recent studies.

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T-0). The median age at diagnosis was 58 years, and time from diagnosis to T-0 was 3.3 years. Following T-0, 213 (74%) patients had a treatment recorded with one or more regimens (median = 1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including >= partial response in 69 (32%). The median overall survival and event-free survival from T-0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs. Leukemia (2012) 26, 149-157; doi:10.1038/leu.2011.196; published online 29 July 2011

Interactions between invasive species and native fauna afford a unique opportunity to examine interspecific encounters as they first occur, without the complications introduced by coevolution. In northern Australia, the continuing invasion of the highly toxic cane toad Bufo marinus poses a threat to many frog-eating predators. Can predators learn to distinguish the novel toxic prey item from native prey (and thus, avoid being poisoned), or are longer-term genetically based changes to attack behaviour needed before predators can coexist with toads? To predict the short-term impact of cane toads on native predators, we need to know the proportion of individuals that will attack toads, the proportion surviving the encounter, and whether surviving predators learn to avoid toads. We quantified these traits in a dasyurid (common planigale, Planigale maculata) that inhabits tropical floodplains across northern Australia. Although 90% of naïve planigales attacked cane toads, 83% of these animals survived because they either rejected the toad unharmed, or killed and consumed the prey snout-first (thereby avoiding the toxin-laden parotoid glands). Most planigales showed one-trial learning and subsequently refused to attack cane toads for long time periods (up to 28 days). Toad-exposed planigales also avoided native frogs for up to 9 days, thereby providing an immediate benefit to native anurans. However, the predators gradually learnt to use chemical cues to discriminate between frogs and toads. Collectively, our results suggest that generalist predators can learn to distinguish and avoid novel toxic prey very rapidly - and hence, that small dasyurid predators can rapidly adapt to the cane toad invasion. Indeed, it may be feasible to teach especially vulnerable predators to avoid cane toads before the toads invade, by deploying low-toxicity baits that stimulate taste-aversion learning. © 2008 The Authors.