Aristotle on the Principles of Perceptible Body (Gen. Corr. 2.1-3)

With his clarification of the philosophical significance of the Pre- Socratic theories of elements Aristotle completes his discussion of the principles of perceptible bodies. He had embarked on this subject with the intent of explaining the first bodies and their role as principles of genesis and destruction. Jumping off from the theories of the Ionian philosophers who first proposed simple elemental bodies as principles of change, he probed behind these to discover even more fundamental principles, one of which was anticipated by another Ionian and by his teacher Plato. These ultimate principles will become for Aristotle the foundation of all explanations of material change in the natural world. In the end Aristotle’s exposition comes around full circle to those Ionians from which it began, to show them not so much as confused misadventurers in the quest for truth, but as successful explorers who, without realizing what they had really done, had caught a glimpse of the new world of imperceptible reality lying at the very foundations of the universe. By showing how even the errors of their incompatible and incorrect theories derived from the true structure of the natural world as he himself had come to understand it, Aristotle gained for his own theories the support of the wisest philosophers of the past and at the same time forged the first links with the phenomenal world that he proposed to explain

Aristotle\u27s De Philosophia and the Introduction of the Fifth Element

One of the most influential of Aristotle\u27s ideas, the idea that the heavenly bodies consist of a fifth element distinct from the four earthly elements (earth, water, air, and fire) is widely believed to have been introduced to the world for the first time in Aristotle\u27s lost dialogue De Philosophia. This assumption has created a host of problems which have not yet been solved

Origins of Stoic cosmology

(print) xix, 292 p. ; 24 cmPreface ix -- Abbreviations xi -- Introduction xiii -- I Corporealism 3 -- II Principles 29 -- III Cosmogony 57 -- IV Cosmology 91 -- V Cosmobiology 136 -- VI The Cosmic Cycle 185 -- VII Epilogue : The Definition of Nature and the Origins of Stoic Cosmology 200 -- Appendixes -- I. Influences on Stoicism According to the Biographical Tradition 219 -- II. The Contents of Book One of Chrysippus's Physics 238 -- III. Cleanthes' Cosmogony 240 -- IV. Accounts of the Stoic Proofs for the Immobility and Coherence of the Cosmos 249 -- V. Chrysippus's Statement on the Alleged Imperishability of the Cosmos 260 -- VI. Cleanthes' Proof for the Intelligence of the Cosmos 267 -- Indexes 27

Targeting of alpha(v) integrin identifies a core molecular pathway that regulates fibrosis in several organs

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb-Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl(4)-induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

A Neglected Stoic Argument for Human Responsibility

published or submitted for publicatio

Multicriteria analysis on rock moisture and streamflow in a rainfall-runoff model improves accuracy of model results

Although shallow ((Formula presented.) 1.5 m) soil water storage has been extensively studied, the significance of deeper unsaturated zone water storage to flow generation is poorly documented. However, a limited but growing body of empirical work shows that the weathered bedrock vadose zone, not soil, stores the majority of plant available water in many seasonally dry and semi-arid landscapes. Moreover, this storage dynamic mediates recharge to hillslope groundwater systems that generate stream discharge and support ecologically significant baseflows. Explicit representations of bedrock vadose zone processes are rarely incorporated into runoff models, due in part to a paucity of observations that can constrain simulations. Here, we develop a simple representation of the weathered bedrock vadose zone that is guided by in situ field observations. We incorporate this representation into a rainfall-runoff model, and calibrate it on streamflow alone, on rock moisture (i.e., weathered bedrock vadose zone moisture) alone, and on both using the concept of Pareto optimality. We find that the model is capable of accurately simultaneously simulating dynamics in rock moisture and streamflow, in terms of Kling-Gupta Efficiency, when using Pareto optimal parameter sets. Calibration on streamflow alone, however, is insufficient to accurately simulate rock moisture dynamics. We further find that the posterior distributions of some model parameters are sensitive to choice of calibration scenario. The posterior distribution of high-performing model parameters resulting from the streamflow only calibration scenario include physically unrealistic values that are not yielded by the rock moisture only or Pareto calibration strategies. These results suggest that the accuracy of some model results can be increased and parameter uncertainty decreased via incorporation of rock moisture data in calibration, without sacrificing streamflow simulation quality. Emerging recognition of the global significance of weathered bedrock water storage in seasonally dry and semi-arid regions motivates more observations of weathered bedrock moisture and integration of this variable into earth system models

Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates.

Strong genetic data link the Tyrosine kinase receptor B (TrkB) and its major endogenous ligand brain-derived neurotrophic factor (BDNF) to the regulation of energy homeostasis, with loss-of-function mutations in either gene causing severe obesity in both mice and humans. It has previously been reported that peripheral administration of the endogenous TrkB agonist ligand neurotrophin-4 (NT-4) profoundly decreases food intake and body weight in rodents, while paradoxically increasing these same parameters in monkeys. We generated a humanized TrkB agonist antibody, TAM-163, and characterized its therapeutic potential in several models of type 2 diabetes and obesity. In vitro, TAM-163 bound to human and rodent TrkB with high affinity, activated all aspects of the TrkB signaling cascade and induced TrkB internalization and degradation in a manner similar to BDNF. In vivo, peripheral administration of TAM-163 decreased food intake and/or body weight in mice, rats, hamsters, and dogs, but increased food intake and body weight in monkeys. The magnitude of weight change was similar in rodents and non-human primates, occurred at doses where there was no appreciable penetration into deep structures of the brain, and could not be explained by differences in exposures between species. Rather, peripherally administered TAM-163 localized to areas in the hypothalamus and the brain stem located outside the blood-brain barrier in a similar manner between rodents and non-human primates, suggesting differences in neuroanatomy across species. Our data demonstrate that a TrkB agonist antibody, administered peripherally, causes species-dependent effects on body weight similar to the endogenous TrkB ligand NT-4. The possible clinical utility of TrkB agonism in treating weight regulatory disorder, such as obesity or cachexia, will require evaluation in man