The origins of early modern experimental philosophy

This paper argues that early modern experimental philosophy emerged as the dominant member of a pair of methods in natural philosophy, the speculative versus the experimental, and that this pairing derives from an overarching distinction between speculative and operative philosophy that can be ultimately traced back to Aristotle. The paper examines the traditional classification of natural philosophy as a speculative discipline from the Stagirite to the seventeenth century; medieval and early modern attempts to articulate a scientia experimentalis; and the tensions in the classification of natural magic and mechanics that led to the introduction of an operative part of natural philosophy in the writings of Francis Bacon and John Johnston. The paper concludes with a summary of the salient discontinuities between the experimental/speculative distinction of the mid-seventeenth century and its predecessors and a statement of the developments that led to the ascendance of experimental philosophy from the 1660s

The Principled Enlightenment: Condillac, d'Alembert and Principle Minimalism

Abstract: There are many epithets for the European Enlightenment: ‘Radical Enlightenment’, ‘Pragmatic Enlightenment’, ‘Democratic Enlightenment’ and so on. This paper argues for one more, namely, ‘Principled Enlightenment’. It shows just how central the notion of principles was to many of the leading thinkers of the eighteenth century, paying special attention to the views of Etienne Bonnot de Condillac and Jean Le Rond d’Alembert. Principles are at the heart of their respective philosophical projects. Not only are their writings against systems predicated on a particular theory about how the principles of the sciences are discovered, but, it is argued, both philosophes are committed to a form of Principle Minimalism, whereby the fewer principles a science has the more fertile those principles are. And both believe that they have actually discovered just such a fertile principle, Condillac in his study of the origins of knowledge and d’Alembert in rational mechanics. Together these views of Condillac and d’Alembert are illustrative of the fact that there was indeed a principled Enlightenment

Locke, the Quakers and Enthusiasm

This paper argues that Locke’s interactions with the Quakers and his reflections on their doctrines and behaviour, provide the salient background for understanding the content and polemical orientation of the chapter on enthusiasm in An Essay concerning Human Understanding. The terms of reference and key features of the vocabulary of the chapter “Of Enthusiasm” that Locke added to the fourth edition of the Essay, derive from the Quakers and from Locke’s critical reflections on their doctrine of immediate inspiration. While Locke acknowledged that the phenomenon was to be found among other religious groups, it was the Quakers whom Locke had in mind when he formulated his philosophical critique of enthusiasm

In vivo parasitological measures of artemisinin susceptibility

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3-/y rat model of autism

Abstract Background Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. Methods This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3 −/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3 −/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results We observed that, unlike the wildtype, Nlgn3 −/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3 −/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3 −/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. Conclusions We describe altered fear responses in Nlgn3 −/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD

In Vivo Parasitological Measures of Artemisinin Susceptibility

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n = 14,539), moderate (n = 2077), and high (n = 2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/µL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/2

Teleconnections of the Quasi‐Biennial Oscillation in a multi‐model ensemble of QBO‐resolving models

The Quasi-biennial Oscillation (QBO) dominates the interannual variability of the tropical stratosphere and influences other regions of the atmosphere. The high predictability of the QBO implies that its teleconnections could lead to increased skill of seasonal and decadal forecasts provided the relevant mechanisms are accurately represented in models. Here modelling and sampling uncertainties of QBO teleconnections are examined using a multi-model ensemble of QBO-resolving atmospheric general circulation models that have carried out a set of coordinated experiments as part of the Stratosphere-troposphere Processes And their Role in Climate (SPARC) QBO initiative (QBOi). During Northern Hemisphere winter, the stratospheric polar vortex in most of these models strengthens when the QBO near 50 hPa is westerly and weakens when it is easterly, consistent with, but weaker than, the observed response. These weak responses are likely due to model errors, such as systematically weak QBO amplitudes near 50 hPa, affecting the teleconnection. The teleconnection to the North Atlantic Oscillation is less well captured overall, but of similar strength to the observed signal in the few models that do show it. The models do not show clear evidence of a QBO teleconnection to the Northern Hemisphere Pacific-sector subtropical jet

Direct observation of DNA threading in flap endonuclease complexes

Maintenance of genome integrity requires that branched nucleic acid molecules are accurately processed to produce double-helical DNA. Flap endonucleases are essential enzymes that trim such branched molecules generated by Okazaki fragment synthesis during replication. Here, we report crystal structures of bacteriophage T5 flap endonuclease in complexes with intact DNA substrates, and products, at resolutions of 1.9–2.2 Å. They reveal single-stranded DNA threading through a hole in the enzyme enclosed by an inverted Vshaped helical arch straddling the active site. Residues lining the hole induce an unusual barb-like conformation in the DNA substrate juxtaposing the scissile phosphate and essential catalytic metal ions. A series of complexes and biochemical analyses show how the substrate’s single-stranded branch approaches, threads through, and finally emerges on the far side of the enzyme. Our studies suggest that substrate recognition involves an unusual “flycasting, thread, bend and barb” mechanis