Significant associations have been found between specific human leukocyte antigen (HLA) alleles and organ transplant rejection, autoimmune disease development, and the response to infection. Traditional searches for disease associations have conventionally measured risk associated with the presence of individual HLA alleles. However, given the high level of HLA polymorphism, the pattern of amino acid variability, and the fact that most of the HLA variation occurs at functionally important sites, it may be that a combination of variable amino acid sites shared (...) by several alleles (shared epitopes) are better descriptors of the actual causative genetic variants. Here we describe a novel approach to genetic association analysis in which genes/proteins are broken down into smaller sequence features and then variant types defined for each feature, allowing for independent analysis of disease association with each sequence feature variant type. We have used this approach to analyze a cohort of systemic sclerosis patients and show that a sequence feature composed of specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk for systemic sclerosis. (shrink)

BackgroundThe ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines are widely endorsed but compliance is limited. We sought to determine whether journal-requested completion of an ARRIVE checklist improves full compliance with the guidelines.MethodsIn a randomised controlled trial, manuscripts reporting in vivo animal research submitted to PLOS ONE (March–June 2015) were randomly allocated to either requested completion of an ARRIVE checklist or current standard practice. Authors, academic editors, and peer reviewers were blinded to group allocation. Trained reviewers performed outcome adjudication (...) in duplicate by assessing manuscripts against an operationalised version of the ARRIVE guidelines that consists 108 items. Our primary outcome was the between-group differences in the proportion of manuscripts meeting all ARRIVE guideline checklist subitems.ResultsWe randomised 1689 manuscripts (control: n = 844, intervention: n = 845), of which 1269 were sent for peer review and 762 (control: n = 340; intervention: n = 332) accepted for publication. No manuscript in either group achieved full compliance with the ARRIVE checklist. Details of animal husbandry (ARRIVE subitem 9b) was the only subitem to show improvements in reporting, with the proportion of compliant manuscripts rising from 52.1 to 74.1% (X2 = 34.0, df = 1, p = 2.1 × 10−7) in the control and intervention groups, respectively.ConclusionsThese results suggest that altering the editorial process to include requests for a completed ARRIVE checklist is not enough to improve compliance with the ARRIVE guidelines. Other approaches, such as more stringent editorial policies or a targeted approach on key quality items, may promote improvements in reporting. (shrink)

Saeculum: Gedenkschrift für Heinrich Otten anlässlich seines 100. Geburtstags. Edited by Andreas Müller-Karpe; Elisabeth Rieken; and Walter Sommerfeld. Studien zu den Boǧazköy-Texten, vol. 58. Wiesbaden: Harrassowitz Verlag, 2015. Pp. xi + 316, illus. €84.

R. S. Woolhouse; IV*—Leibniz's Reaction to Cartesian Interaction, Proceedings of the Aristotelian Society, Volume 86, Issue 1, 1 June 1986, Pages 69–82, https:/.

We generalize two well-known model-theoretic characterization theorems from propositional modal logic to first-order modal logic. We first study FML-definable frames and give a version of the Goldblatt–Thomason theorem for this logic. The advantage of this result, compared with the original Goldblatt–Thomason theorem, is that it does not need the condition of ultrafilter reflection and uses only closure under bounded morphic images, generated subframes and disjoint unions. We then investigate Lindström type theorems for first-order modal logic. We show that FML has (...) the maximal expressive power among the logics extending FML which satisfy compactness, bisimulation invariance and the Tarski union property. (shrink)

Upshot: Constructionism must return to its epistemological roots to make any lasting impact on education. Constructionism should be transformed from a framework of action into ways to conceptualize and record what people actually do in constructionist environments so that theories of knowledge-building acts can be tested and the designing of those environments can be made more effective.

The human person makes great demands on the physician and calls for unique attention. Hence the doctor-patient relationship calls for the highest ideals of kindness, patience, trustworthiness, generosity and skill. The Catholic physician brings to these demands a specific meaning: ministering to the sick is to see Christ in them and to show Him to them.

Summary One aim of this paper is to provide an assessment of the recent attempts to interpret the development of Galileo's theory of motion in the late Paduan period 1604?1610. In addition to this a new interpretation of this process of development is advanced. This interpretation is the first that proves able to provide a full account of all the features on folio 152r of volume 72 of the Galilean manuscripts which has been claimed to be of crucial significance. The (...) major feature of the interpretation is that it is the first to account for the relationship between Galileo's theoretical and experimental work in the period 1604?1610. (shrink)

The problems and the history of contacts between distant continents in bygone ages and long before the age of fast and easy travel, have always fascinated both professional scholars and the interested public. Was ancient history really nothing but the history of co-existing and isolated geographic, cultural and political “islands?” Already at school we learned too much about migrations of peoples, economic contacts, influences on art styles, conquests, and the rise, expansion and fall of empires to believe that. The (highly (...) improbable) theory that certain archaeological finds in America suggest, or even prove, Mediterranean influence (e.g., the arrival of Phoenician ships), or the alleged Viking discovery of America centuries before Columbus, or Thor Heyerdahl's adventurous journey to prove South American influence on remote Pacific islands did not fail to cause widespread interest and even excitement (although many scholars still feel that Heyerdahl's epic adventure, thrilling as it is, failed to prove what it set out to prove). The island of Madagascar is pretty close to the African continent, but its language exhibits more points of contact with Polynesian than with African tongues. And the blow-bellows used by Malagache smiths are similar to those used in Malaysia and unlike those known to African metalworkers. Clearly the Polynesians, those great ancient mariners, sailed further than originally seemed likely. Musicologists studying the cantillation of the Hebrew Bible in the liturgy of the ancient Jewish communities on the Malabar coast in India discovered to their surprise that it was similar to the cantillation not of the Babylonian but of the Yemenite Jews! This surprise was, of course, no surprise to those who knew anything about trade-winds and shipping routes between South Arabia and the Indian coast. Historians of religion, even more than general historians, studying the spread and expansion of religious ideas and movements have realised long ago that the beginning of all wisdom is a basic knowledge of economic geography. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:R. D. Ackerman BELIEVING IN A FICTION: WALLACE STEVENS AT THE LIMITS OF PHENOMENOLOGY The "ring of men" of "Sunday Morning" will chant their "devotion to the sun, / Not as a god, but as a god might be, / Naked among them, like a savage source" (CP, pp. 69-70).' Solar nakedness is deferred even as it is named. The problem for belief is the question of appearance and (...) representation. Things appear as and like.... The phenomenological return to things is also a turn to fiction, as Husserl understood: "If anyone loves a paradox, he can really say... that the element which makes up the life of phenomenology... is fiction. ' " The sun is divine, and it is not; it is both naked and clothed, savage and civilized, source (or end) and means. But such paradox is ultimately unsatisfying, and as we will see with Stevens, the need for belief—for an image or idea of totality—forces the issue of fiction and reality. The Stevens we will have in view is not the Stevens—as if there were such a creature. Our Stevens is the one most persuaded by promises such as those of phenomenology, the one most concerned with decreation (reduction) and fresh beginnings, with discovery and recognition, with imagination, the body, and the earth. This is the Stevens for whom the barrier of language presages at last not absence and difference but fictive recovery of presence and identity, the one for whom poetry represents a way of belief beyond mysticism even as it bodes mythic proximity. Finally, this is the Stevens who predominates throughout the prose (as well as in much of the poetry), who tries mightily to secure a belief while disencumbering himself of metaphysics—but alas, I think, with small success. Although Stevens's association of the problem of belief with the idea of fiction occurs in early poems such as "A High-Toned Old Christian 79 80Philosophy and Literature Woman" and "To the One of Fictive Music," his most intensive involvement with fiction as belief dates from the early 1940s and spans the period of his major essays and his last four volumes of poems. He recounts, for instance, a 1942 conversation with a student: "I said that I thought that we had reached a point at which we could no longer really believe in anything unless we recognized that it was a fiction. The student said that that was an impossibility, that there was no such thing as believing in something that one knew was not true. It is obvious, however, that we are doing that all the time" (L, p. 430). What does it mean to believe in a fiction? That is my main subject here, as we seek out the limits of the phenomenological Stevens. His letters of this period are preoccupied with the problem of fictive belief: "If one no longer believes in God (as truth), it is not possible merely to disbelieve; it becomes necessary to believe in something else.... A good deal of my poetry recently has concerned an identity for that thing.... In one of the short poems that I have just sent to the harvard advocate, I say that one's final belief must be in a fiction. I think that the history of belief will show that it has always been in a fiction" (L, p. 370). The poem referred to, "Asides on the Oboe," begins: The prologues are over. It is a question now, Of final belief. So, say that final belief Must be in a fiction. It is time to choose. (CP, p. 250) Acknowledging that "in the long run, poetry would be the supreme fiction" (L, pp. 430-31), Stevens nonetheless singles out the nominative function of poetry as the essence of its claim to supremacy: "Poetry means not the language of poetry but the thing itself.... The subject matter is what comes to mind when one says of the month of August... 'Thou art not August, unless I make thee so'" (L, p. 377). The quoted line (also from "Asides") underscores the paradox that for Stevens the essence of fiction (the nontrue) is its capacity to nominate the true or the real. This... (shrink)

Among Plato's later dialogues, the _Parmenides_ is one of the most significant. Not only a document of profound philosophical importance in its own right, it also contributes to the understanding of Platonic dialogues that followed it, and it exhibits the foundations of the physics and ontology that Aristotle offered in his _Physics_ and _Metaphysics _VII. In this book, R.E. Allen provides a superb translation of the _Parmenides_ along with a structural analysis that procedes on the assumption that formal elements, logical (...) and dramatic, are important to its interpretation and that the argument of the _Parmenides_ is aporetic, a statement of metaphysical perplexities. Allen's original translation of and commentary on the _Parmenides_ were published in 1983 to great acclaim and have now been revised by the author. (shrink)

Amongst the people who pester Peisthetaerus with unwanted help and advice in the latter part of the Birds is Meton, famous astronomer and mathematician, who produces and demonstrates with instruments a method of laying out the plan of the new town. Peisthetaerus makes no attempt to follow him and quickly bundles him out again without much ceremony. Commentators and readers with few exceptions treat him in a similar way. ʹΕπίτηδες δανόητα, δόλου νοηταίνε, παίζε—such are the comments of the scholiast, and (...) editors are mostly content with that. Van Leeuwen says, ‘Metonis haec verba intellegere velle, id est operam dare ut suo ioco frustretur cbtnicus.’ The passage is of course highly comical; to make it didactic and attribute to Aristophanes a serious excursion into geometry and town-planning would be perverse and pedantic; but in Aristophanes more than in most comic writers there is commonly a grain or two of truth among the chaff. These grains, though of little or no importance for the appreciation of the play as comedy, may still have some possible value in other ways, and should be carefully sifted. (shrink)