Interactions among Toxins That Inhibit N-type and P-type Calcium Channels

A number of peptide toxins from venoms of spiders and cone snails are high affinity ligands for voltage-gated calcium channels and are useful tools for studying calcium channel function and structure. Using whole-cell recordings from rat sympathetic ganglion and cerebellar Purkinje neurons, we studied toxins that target neuronal N-type (CaV2.2) and P-type (CaV2.1) calcium channels. We asked whether different toxins targeting the same channels bind to the same or different sites on the channel. Five toxins (ω-conotoxin-GVIA, ω-conotoxin MVIIC, ω-agatoxin-IIIA, ω-grammotoxin-SIA, and ω-agatoxin-IVA) were applied in pairwise combinations to either N- or P-type channels. Differences in the characteristics of inhibition, including voltage dependence, reversal kinetics, and fractional inhibition of current, were used to detect additive or mutually occlusive effects of toxins. Results suggest at least two distinct toxin binding sites on the N-type channel and three on the P-type channel. On N-type channels, results are consistent with blockade of the channel pore by ω-CgTx-GVIA, ω-Aga-IIIA, and ω-CTx-MVIIC, whereas grammotoxin likely binds to a separate region coupled to channel gating. ω-Aga-IIIA produces partial channel block by decreasing single-channel conductance. On P-type channels, ω-CTx-MVIIC and ω-Aga-IIIA both likely bind near the mouth of the pore. ω-Aga-IVA and grammotoxin each bind to distinct regions associated with channel gating that do not overlap with the binding region of pore blockers. For both N- and P-type channels, ω-CTx-MVIIC binding produces complete channel block, but is prevented by previous partial channel block by ω-Aga-IIIA, suggesting that ω-CTx-MVIIC binds closer to the external mouth of the pore than does ω-Aga-IIIA

Teleology and Realism in Leibniz's Philosophy of Science

This paper argues for an interpretation of Leibniz’s claim that physics requires both mechanical and teleological principles as a view regarding the interpretation of physical theories. Granting that Leibniz’s fundamental ontology remains non-physical, or mentalistic, it argues that teleological principles nevertheless ground a realist commitment about mechanical descriptions of phenomena. The empirical results of the new sciences, according to Leibniz, have genuine truth conditions: there is a fact of the matter about the regularities observed in experience. Taking this stance, however, requires bringing non-empirical reasons to bear upon mechanical causal claims. This paper first evaluates extant interpretations of Leibniz’s thesis that there are two realms in physics as describing parallel, self-sufficient sets of laws. It then examines Leibniz’s use of teleological principles to interpret scientific results in the context of his interventions in debates in seventeenth-century kinematic theory, and in the teaching of Copernicanism. Leibniz’s use of the principle of continuity and the principle of simplicity, for instance, reveal an underlying commitment to the truth-aptness, or approximate truth-aptness, of the new natural sciences. The paper concludes with a brief remark on the relation between metaphysics, theology, and physics in Leibniz

Cues to intention bias action perception toward the most efficient trajectory

Abstract Humans interpret others’ behaviour as intentional and expect them to take the most energy-efficient path to achieve their goals. Recent studies show that these expectations of efficient action take the form of a prediction of an ideal “reference” trajectory, against which observed actions are evaluated, distorting their perceptual representation towards this expected path. Here we tested whether these predictions depend upon the implied intentionality of the stimulus. Participants saw videos of an actor reaching either efficiently (straight towards an object or arched over an obstacle) or inefficiently (straight towards obstacle or arched over empty space). The hand disappeared mid-trajectory and participants reported the last seen position on a touch-screen. As in prior research, judgments of inefficient actions were biased toward efficiency expectations (straight trajectories upwards to avoid obstacles, arched trajectories downward towards goals). In two further experimental groups, intentionality cues were removed by replacing the hand with a non-agentive ball (group 2), and by removing the action’s biological motion profile (group 3). Removing these cues substantially reduced perceptual biases. Our results therefore confirm that the perception of others’ actions is guided by expectations of efficient actions, which are triggered by the perception of semantic and motion cues to intentionality

Studies of MCP-PMTs in the miniTimeCube neutrino detector

This report highlights two different types of cross-talk in the photodetectors of the miniTimeCube neutrino experiment. The miniTimeCube detector has 24 $8 \times 8$-anode Photonis MCP-PMTs Planacon XP85012, totalling 1536 individual pixels viewing the 2-liter cube of plastic scintillator

Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility

Germline mutations in the von Hippel–Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma(RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-a subunits (and hence expression of the HIF-a transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (nZ82) and inherited RCC (nZ64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC

Affordance matching predictively shapes the perceptual representation of others’ ongoing actions.

Matthew Hudson is now at the School of Business, National College of Ireland. Patric Bach is now at the School of Psychology, University of Aberdeen.A preprint of this article has been uploaded to PsyArXiv and is available at https://psyarxiv.com/mbea2. The data in this article are available at https://osf.io/des8x/. The results have been presented as a poster at the Future of Social Cognition conference (University of East Anglia, United Kingdom, 2018), MeeTo (University of Turin, Italy, 2018), and the British Association for Cognitive Neuroscience Annual Meeting (University of Plymouth, United Kingdom, 2017). Katrina L. McDonough, Marcello Costantini, Matthew Hudson, Eleanor Ward, and Patric Bach devised the experiment. Stimuli were created by Marcello Costantini and edited by Katrina L. McDonough. The program was developed by Matthew Hudson and Katrina L. McDonough. Data were collected by Katrina L. McDonough. Data were analyzed by Katrina L. McDonough, Eleanor Ward, and Patric Bach. The manuscript was written by Katrina L. McDonough, Patric Bach, and Matthew Hudson, and Eleanor Ward provided critical feedback. All authors gave final approval for publication. This work was supported by the Economic and Social Research Council (Grant ES/J019178/1) awarded to Patric Bach, and a University of Plymouth doctoral student grant awarded to Katrina L. McDonough.Peer reviewedPublisher PD

Oceans and Human Health: A Rising Tide of Challenges and Opportunities for Europe

The European Marine Board recently published a position paper on linking oceans and human health as a strategic research priority for Europe. With this position paper as a reference, the March 2014 Cornwall Oceans and Human Health Workshop brought together key scientists, policy makers, funders, business, and non governmental organisations from Europe and the US to review the recent interdisciplinary and cutting edge research in oceans and human health specifically the growing evidence of the impacts of oceans and seas on human health and wellbeing (and the effects of humans on the oceans). These impacts are a complex mixture of negative influences (e.g. from climate change and extreme weather to harmful algal blooms and chemical pollution) and beneficial factors (e.g. from natural products including seafood to marine renewable energy and wellbeing from interactions with coastal environments). Integrated approaches across disciplines, institutions, and nations in science and policy are needed to protect both the oceans and human health and wellbeing now and in the future