We discuss a case where clinical genomic investigation of muscle weakness unexpectedly found a genetic variant that might (or might not) predispose to kidney cancer. We argue that despite its off-target and uncertain nature, this variant should be discussed with the man who had the test, not because it is medical information, but because this discussion would allow the further clinical evaluation that might lead it to becoming so. We argue that while prominent ethical debates around genomics often take ‘results’ (...) as a starting point and ask questions as to whether to look for and how to react to them, the construction of genomic results is fraught with ethical complexity, although often couched as a primarily technical problem. We highlight the need for greater focus on, and appreciation of, the ethical work undertaken daily by scientists and clinicians working in genomic medicine and discuss how public conversations around genomics need to adapt to prepare future patients for potentially uncertain and unexpected outcomes from clinical genomic tests. (shrink)

All languages, both spoken and signed, make a formal distinction between two types of terms in a proposition – terms that identify what is to be talked about (nominals) and terms that say something about this topic (predicates). Here we explore conditions that could lead to this property by charting its development in a newly emerging language – Nicaraguan Sign Language (NSL). We examine how handshape is used in nominals vs. predicates in three Nicaraguan groups: (1) homesigners who are not (...) part of the Deaf com- munity and use their own gestures, called homesigns, to communicate; (2) NSL cohort 1 signers who fashioned the first stage of NSL; (3) NSL cohort 2 signers who learned NSL from cohort 1. We compare these three groups to a fourth: (4) native signers of American Sign Language (ASL), an established sign language. We focus on handshape in predicates that are part of a productive classifier system in ASL; handshape in these predicates varies sys- tematically across agent vs. no-agent contexts, unlike handshape in the nominals we study, which does not vary across these contexts. We found that all four groups, including home- signers, used handshape differently in nominals vs. predicates – they displayed variability in handshape form across agent vs. no-agent contexts in predicates, but not in nominals. Variability thus differed in predicates and nominals: (1) In predicates, the variability across grammatical contexts (agent vs. no-agent) was systematic in all four groups, suggesting that handshape functioned as a productive morphological marker on predicate signs, even in homesign. This grammatical use of handshape can thus appear in the earliest stages of an emerging language. (2) In nominals, there was no variability across grammatical con- texts (agent vs. no-agent), but there was variability within- and across-individuals in the handshape used in the nominal for a particular object. This variability was striking in homesigners (an individual homesigner did not necessarily use the same handshape in every nominal he produced for a particular object), but decreased in the first cohort of NSL and remained relatively constant in the second cohort. Stability in the lexical use of handshape in nominals thus does not seem to emerge unless there is pressure from a peer linguistic community. Taken together, our findings argue that a community of users is essential to arrive at a stable nominal lexicon, but not to establish a productive morpholog- ical marker in predicates. Examining the steps a manual communication system takes as it moves toward becoming a fully-fledged language offers a unique window onto factors that have made human language what it is. (shrink)

While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a subset (...) of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

It's not about any person who's going to pick it up. No, these addresses fix on a much more glorious, worthy, and fascinating topic: the God, the Creator, the Redeemer as revealed in the Bible. The study of God is like a brilliant diamondwe should keep holding it up to the light to see new details ofits beauty. Before the awe of such a God, what room is there to focus on man? Our only place is to respond to himand (...) even our response does not depend on us! We must not only worship him, but alsoif our worship is to be meaningful and not cheapenedlearn how he is to be worshiped. The Princeton Regional Conference on Reformed Theology presents the following pastor-scholars, who delve into the glory of God and into his grace in making sinners into worshipers: Bryan Chapell - God's Glory Revealed Charles D. Drew - Called by God to Worship Richard D. Phillips - Sought by Christ to Worship Joseph "Skip" Ryan - Guided by God's Sovereign Providence Philip Graham Ryken - Redeemed by God's Sovereign Mercy Michael S. Horton - Sanctifying Grace Richard D. Phillips - Our Holy Redeemer Michael A. G. Haykin - The Spirit of Holiness R. Albert Mohler - Know the Truth D. A. Carson -I Am the Truth Learn from these teachers about the glory of, the providential work of, and our proper response to the amazing God we worship. (shrink)

The contents of Scala Graduum Caloris are described, supplemented by unpublished material. Both temperature measurements by his linseed oil thermometer and those based upon his law of cooling are shown to be reasonably accurate to 300°C, but above that value they are much too low. The apparent agreement and the deviation are explained by the differences between the assumptions that Newton made in deriving his law of cooling and the conditions in which he used it. Newton's attempts to link terrestrial (...) and celestial science in applications in the Principia are shown to fail from his confounding the concepts of temperature, heat and radiant intensity and his ignorance of most factors affecting the temperature rise of irradiated materials. Other comments on varied aspects of heat, mainly published in the Queries, are set out and analysed. His originality is assessed. (shrink)

Interpretation of this ode has not been very happy in spite of the care lavished upon it by editors obviously determined to extract some sort of consistent sense. That Horace started from Pindar's Olymp. II. is evident enough; when and why, under what stimulus, or for what occasion he wrote is not so clear. The older commentators do not give much help. I believe, however, that in attending to the list of gods, demi-gods, and Roman heroes given in the ode (...) we have a chance of coming somewhere near to an adequate understanding of the poem. (shrink)

The role of scientific theories in classifying plants and animals is traced from Hennig's phylogenetics and the evolutionary taxonomy of Simpson and Mayr, through numerical phenetics, to present-day cladistics. Hennig limited biological classification to sister groups so that this one relation can be expressed unambiguously in classifications. Simpson and Mayr were willing to sacrifice precision in representation in order to include additional features of evolution in the construction of classifications. In order to make classifications more objective, precise and quantitative, numerical (...) pheneticists limited themselves to representing degrees of phenetic similarity. Finally, present-day cladists can be separated into phylogenetic cladists, who retain much of Hennig's theory of classification, and pattern cladists, who have stripped Hennig's system down to its bare essentials. (shrink)

The works of Mary Wollstonecraft ranged from the early _Thoughts on the Education of Daughters_ to _The Female Reader_, a selection of texts for girls, and included two novels. But her reputation is founded on _A Vindication of the Rights of Woman_ of 1792. This treatise is the first great document of feminism—and is now accepted as a core text in western tradition. It is not widely known that the germ of Wollstonecraft’s great work came out of an earlier and (...) much shorter vindication—A Vindication of the Rights of Men, written in the context of the issues raised by the French Revolution. This edition, which follows the model of other Broadview Editions in including a range of materials that help the reader to see the work in the context of its era out of which it emerged, is arranged chronologically, opening with Wollstonecraft’s “other vindication.” It also includes a wide range of other documents in appendices, as well as a comprehensive and authoritative introduction, chronology, and full index. (shrink)