How do common and rare genetic polymorphisms contribute to quantitative traits or disease risk and progression? Multiple human traits have been extensively characterized at the genomic level, revealing their complex genetic architecture. However, it is difficult to resolve the mechanisms by which specific variants contribute to a phenotype. Recently, analyses of variant effects on molecular traits have uncovered intermediate mechanisms that link sequence variation to phenotypic changes. Yet, these methods only capture a fraction of genetic contributions to phenotype. Here, in (...) reviewing the field, it is proposed that complex traits can be understood by characterizing the dynamics of biochemical networks within living cells, and that the effects of genetic variation can be captured on these networks by using protein–protein interaction (PPI) methodologies. This synergy between PPI methodologies and the genetics of complex traits opens new avenues to investigate the molecular etiology of human diseases and to facilitate their prevention or treatment. (shrink)

Rationale: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI). Methods: Human patients undergoing Phase II invasive monitoring for (...) intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted (post hoc) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject’s medical history was unknown to the experimenters until after individual subject memory retention results were scored. Results: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment. Conclusion: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients. (shrink)

Anyone who has pondered the limitlessness of space and time, or the endlessness of numbers, or the perfection of God will recognize the special fascination of this question. Adrian Moore's historical study of the infinite covers all its aspects, from the mathematical to the mystical.

In this essay I consider the argument that Bernard Williams advances in ‘The Makropolus Case’ for the meaninglessness of immortality. I also consider various counter-arguments. I suggest that the more clearly these counter-arguments are targeted at the spirit of Williams's argument, rather than at its letter, the less clearly they pose a threat to it. I then turn to Nietzsche, whose views about the eternal recurrence might appear to make him an opponent of Williams. I argue that, properly interpreted, these (...) views in fact make him an ally. (shrink)

[A. W. Moore] There are criteria of ineffability whereby, even if the concept of ineffability can never serve to modify truth, it can sometimes serve to modify other things, specifically understanding. This allows for a reappraisal of the dispute between those who adopt a traditional reading of Wittgenstein's Tractatus and those who adopt the new reading recently championed by Diamond, Conant, and others. By maintaining that what the nonsense in the Tractatus is supposed to convey is ineffable understanding, rather than (...) ineffable truth, we can do considerable justice to each of these readings. We can also do considerable justice to the Tractatus. /// [Peter Sullivan] Moore proposes to cut between 'traditional' and 'new' approaches to the Tractatus, suggesting that Wittgenstein's intention is to convey, through the knowing use of nonsense, ineffable understanding. I argue, first, that there is indeed room for a proposal of Moore's general kind. Secondly, though, I question whether Moore's actual proposal is not more in tune with Wittgenstein's later thought than with the attitude of the Tractatus. (shrink)

This is a study of Frege's permutation argument in Part I, Section 10, of Frege's Basic Laws of Arithmetic.

This essay was written for a special issue of Philosophical Topics on the links between Kant and analytic philosophy. It explores these links through consideration of: Wittgenstein’s Tractatus; the logical positivism endorsed by Ayer; and the (very different) variation on that theme endorsed by Quine. It is argued that in all three cases we see analytic philosophers trying to attain and express a general philosophical understanding of why the bounds of sense should be drawn where they should—but thereby confronting the (...) aporia, which Kant too confronted, that it is impossible to do this without transgressing those very bounds. It is suggested in conclusion that the problem is in trying to attain and express such an understanding; in other words, that such an understanding is attainable, but not expressible. (shrink)

Eric Olsen argues from the fact that we once existed as fetal individuals to the conclusion that the Standard View of personal identity is mistaken. I shall establish that a similar argument focusing upon dead people opposes Olson’s favored Biological View of personal identity.

Two recent papers by Michael Burke bearing upon the persistence of people and commonplace things illustrate the fact that the quest for synchronic ontological economy is likely to encourage a disturbing diachronic proliferation of entities. This discussion argues that Burke's promise of ontological economy is seriously compromised by the fact that his proposed metaphysic does violence to standard intuitions concerning the persistence of people and commonplace things. In effect, Burke would have us achieve synchronic economy (rejection of coincident entities) by (...) postulating strongly counterintuitive transtemporal claims of numerical diversity. The argument is made that the price of Burkean economy is too high. (shrink)

In this paper we examine the study of minerals from the Renaissance to the early nineteenth century in the light of the work of Michel Foucault on the history of systems of thought. In spite of a certain number of theoretical problems, Foucault's enterprise opens up to the historian of science a vast terrain for exploration. But this is the place neither for a general exegesis nor for a general criticism of his position; our aim here is the more modest (...) one of taking certain points from Foucault's study,The order of things, and seeing how far they can be extended into an area not explicitly considered in that work. (shrink)

Two recent papers by Michael Burke bearing upon the persistence of people and commonplace things illustrate the fact that the quest for synchronic ontological economy is likely to encourage a disturbing diachronic proliferation of entities. This discussion argues that Burke’s promise of ontological economy is seriously compromised by the fact that his proposed metaphysic does violence to standard intuitions concerning the persistence of people and commonplace things. In effect, Burke would have us achieve synchronic economy (rejection of coincident entities) by (...) postulating strongly counterintuitive transtemporal claims of numerical diversity. The argument is made that the price of Burkean economy is too high. (shrink)

Until fairly recently a common way of doing history of science was to pick up an important strand of contemporary scientific thought and to trace its origin back to the philosophical tangle of the scientific revolution. This approach conveniently by-passed the breakdowns of once useful and pervasive theories, and neglected the long intellectual journeys along devious routes. History of science read like a success story; the pioneers who failed were neither dismissed nor excused; they were simply ignored. The historian knew (...) what he was hunting for and he was careful to limit his search to areas where his quarry was sure to be found. This method, which has been dubbed the precursor-view, stands in contrast—albeit, not in opposition—to the contextual method, which aims at a better understanding of the actual thought-processes of the early scientists. On this second view, history of science must not only account for present theories in the light of past developments, it must also assess old theories in terms of the scientist's conceptual framework, and judge them against the background of the world picture of his age. This may lead the historian down the blind alleys of the past, chasing spurious attempts at explaining the nature of physical reality, but it can clear the ground for a less anachronistic interpretation of the emergence of modern science and the actual process of discovery. History of science acts as a winnowing fork, but we cannot suppose that the discoverer himself always separated the wheat from the chaff, and we must be ever wary of equating the dream with the task. (shrink)

The paper „F. W. Bessel and Russian science by K. K. Lavrinovich published in NTM-Schriftenreihe contains several errors coming mainly from re-translations of German names and texts from Russian into German. The correct spelling of names and original texts are given here. Beside this, some additional information from sources not mentioned by the author is presented, and the kind of relationship between Bessel and W. Struve is discussed on the basis of their correspondence.

By an incomplete sentence we shall understand a declarative sentence that can be used, without variation in its meaning, to make different statements in different contexts. Although the point deserves supporting argument, which we will not provide, sentences whose grammatical subjects are indexical expressions or demonstratives are obvious, plausible examples of incomplete sentences. Uttered in one context the sentence ‘He is ill’ may be used to make one statement, for example, that George is ill, while in another context the very (...) same sentence may be used to make a quite different statement, for example, that Paul is ill. (shrink)

Two recent papers by Michael Burke bearing upon the persistence of people and commonplace things illustrate the fact that the quest for synchronic ontological economy is likely to encourage a disturbing diachronic proliferation of entities. This discussion argues that Burke’s promise of ontological economy is seriously compromised by the fact that his proposed metaphysic does violence to standard intuitions concerning the persistence of people and commonplace things. In effect, Burke would have us achieve synchronic economy (rejection of coincident entities) by (...) postulating strongly counterintuitive transtemporal claims of numerical diversity. The argument is made that the price of Burkean economy is too high. (shrink)

The precise relationship between Hobbes's political philosophy and his late history of the English Civil War remains something of a puzzle. Given his well known doubts about the epistemological status of history, Behemoth or the Long Parliament is often treated as little more than a procrustean effort at forcing complex historical events into the bed of abstract theory that he had developed earlier. On this view, even Noam Flinker, who offers one of the few studies devoted to a close reading (...) of Behemoth, argues that Hobbes intended the work to be self repudiating, and that the dialogue form and the apparent confusions of one of the participants were meant to point readers to �the less rhetorical logic of the Leviathan�. Others, more impressed by Hobbes�s pragmatic intentions than his methodological pretensions, note that a primary motive for his political arguments was a horror at first of the prospect and then of the reality of civil war. They thus emphasize the significance of Behemoth for Hobbes and his interpreters. Robert Kraynak, for example, argues that it �is a work of primary importance� in completing the �history of civilization which is the logical beginning point of Hobbes's thought�, and that a complete understanding of his political theory is impossible without his analysis of the way in which �doctrinal politics and disputative science� had created political chaos in England. This interpretation correctly emphasizes the role of ideas, as opposed to economic interests, in his explanation of civil conflict. It also rightly notes didactic continuities between Behemoth and his earlier work. However, I argue below that it overestimates the extent to which Hobbes treats the general idea of opinion as an eliminable product of �artificial� historical relations rather than as a permanent feature of human psychology and action. Thus, it discounts the extent to which his understanding of the relationship between opinion and civil war was a product of his philosophy rather than of a 'history of civilization'. (shrink)