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.

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

[A. W. Moore] Criteria of ineffability are presented which, it is claimed, preclude the possibility of truths that are ineffable, but not the possibility of other things that are ineffable—not even the possibility of other things that are non-trivially ineffable. Specifically, they do not preclude the possibility of states of understanding that are ineffable. This, it is argued, 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 Cora Diamond, James 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)

Implicit processes almost certainly preceded explicit processes in our evolutionary history, so they are likely to be more resistant to disruption according to the principles of evolutionary biology [Reber, A. S. . The cognitive unconscious: An evolutionary perspective. Consciousness and Cognition, 1, 93–133.]. Previous work . Knowledge, nerves and know-how: The role of explicit versus implicit knowledge in the breakdown of a complex motor skill under pressure. British Journal of Psychology, 83, 343–358.]) has shown that implicitly learned motor skills remain (...) stable under psychological pressure and concurrent cognitive demands, and recently [Poolton, J. M., Masters, R. S. W., & Maxwell, J. P. . Passing thoughts on the evolutionary stability of implicit motor behaviour: Performance retention under physiological fatigue. Consciousness and Cognition, 16, 456–468.] showed that they also remain stable under conditions of anaerobic fatigue that would have significantly challenged the survival skills of our ancestors. Here we examine the stability of an implicitly learned motor skill under fatigue conditions that primarily tax a different physiological system , but which have equally strong evolutionary connotations. Participants acquired a throwing task by means of an errorless learning method or an errorful method. Motor performance in the errorless condition, but not the errorful condition, remained stable following an exhaustive VO2 max. running test. Our findings replicate and extend the work of Poolton et al., providing further support for Reber’s evolutionary distinction between implicit and explicit processes. (shrink)

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)

The paradox that has challenged historians of abolitionism is how Britain’s outlawing of trafficking of enslaved Africans in 1807 could take place when the country’s involvement in the trade was as...