Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations.

The capsaicin receptor transient receptor potential vanilloid (TRPV)1 is a highly heat-sensitive ion channel. Although chemical activation and heat activation of TRPV1 elicit similar pungent, painful sensation, the molecular mechanism underlying synergistic activation remains mysterious. In particular, where the temperature sensor is located and whether heat and capsaicin share a common activation pathway are debated. To address these fundamental issues, we searched for channel mutations that selectively affected one form of activation. We found that deletion of the first 10 amino acids of the pore turret significantly reduced the heat response amplitude and shifted the heat activation threshold, whereas capsaicin activation remained unchanged. Removing larger portions of the turret disrupted channel function. Introducing an artificial sequence to replace the deleted region restored sensitive capsaicin activation in these nonfunctional channels. The heat activation, however, remained significantly impaired, with the current exhibiting diminishing heat sensitivity to a level indistinguishable from that of a voltage-gated potassium channel, Kv7.4. Our results demonstrate that heat and capsaicin activation of TRPV1 are structurally and mechanistically distinct processes, and the pore turret is an indispensible channel structure involved in the heat activation process but is not part of the capsaicin activation pathway. Synergistic effect of heat and capsaicin on TRPV1 activation may originate from convergence of the two pathways on a common activation gate

Numerical analysis of a downsized 2-stroke uniflow engine

In order to optimize the 2-stroke uniflow engine performance on vehicle applications, numerical analysis has been introduced, 3D CFD model has been built for the optimization of intake charge organization. The scavenging process was investigated and the intake port design details were improved. Then the output data from 3D CFD calculation were applied to a 1D engine model to process the analysis on engine performance. The boost system optimization of the engine has been carried out also. Furthermore, a vehicle model was also set up to investigate the engine in-vehicle performance

The Nonequilibrium Thermodynamics of Small Systems

The interactions of tiny objects with their environment are dominated by thermal fluctuations. Guided by theory and assisted by micromanipulation tools, scientists have begun to study such interactions in detail.Comment: PDF file, 13 pages. Long version of the paper published in Physics Toda

Symmetry and the thermodynamics of currents in open quantum systems

Symmetry is a powerful concept in physics, and its recent application to understand nonequilibrium behavior is providing deep insights and groundbreaking exact results. Here we show how to harness symmetry to control transport and statistics in open quantum systems. Such control is enabled by a first-order-type dynamic phase transition in current statistics and the associated coexistence of different transport channels (or nonequilibrium steady states) classified by symmetry. Microreversibility then ensues, via the Gallavotti-Cohen fluctuation theorem, a twin dynamic phase transition for rare current fluctuations. Interestingly, the symmetry present in the initial state is spontaneously broken at the fluctuating level, where the quantum system selects the symmetry sector that maximally facilitates a given fluctuation. We illustrate these results in a qubit network model motivated by the problem of coherent energy harvesting in photosynthetic complexes, and introduce the concept of a symmetry-controlled quantum thermal switch, suggesting symmetry-based design strategies for quantum devices with controllable transport properties.Comment: 12 pages, 6 figure

Coupling a model of human thermoregulation with computational fluid dynamics for predicting human-environment interaction

This paper describes the methods developed to couple a commercial CFD program with a multi-segmented model of human thermal comfort and physiology. A CFD model is able to predict detailed temperatures and velocities of airflow around a human body, whilst a thermal comfort model is able to predict the response of a human to the environment surrounding it. By coupling the two models and exchanging information about the heat transfer at the body surface the coupled system can potentially predict the response of a human body to detailed local environmental conditions. This paper presents a method of exchanging data, using shared files, to provide a means of dynamically exchanging simulation data with the IESD-Fiala model during the CFD solution process. Additional code is used to set boundary conditions for the CFD simulation at the body surface as determined by the IESD-Fiala model and to return information about local environmental conditions adjacent to the body surface as determined by the CFD simulation. The coupled system is used to model a human subject in a naturally ventilated environment. The resulting ventilation flow pattern agrees well with other numerical and experimental work

Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR

Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265Funder: European Molecular Biology Organization; FundRef: http://dx.doi.org/10.13039/100004410Coupling of endoplasmic reticulum (ER) stress to dimerisation-dependent activation of the UPR transducer IRE1 is incompletely understood. Whilst the luminal co-chaperone ERdj4 promotes a complex between the Hsp70 BiP and IRE1’s stress-sensing luminal domain (IRE1LD) that favours the latter’s monomeric inactive state and loss of ERdj4 de-represses IRE1, evidence linking these cellular and in vitro observations is presently lacking. We report that enforced loading of endogenous BiP onto endogenous IRE1α repressed UPR signalling in CHO cells and deletions in the IRE1α locus that de-repressed the UPR in cells, encode flexible regions of IRE1LD that mediated BiP-induced monomerisation in vitro. Changes in the hydrogen exchange mass spectrometry profile of IRE1LD induced by ERdj4 and BiP confirmed monomerisation and were consistent with active destabilisation of the IRE1LD dimer. Together, these observations support a competition model whereby waning ER stress passively partitions ERdj4 and BiP to IRE1LD to initiate active repression of UPR signalling

Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR

Coupling of endoplasmic reticulum stress to dimerisation‑dependent activation of the UPR transducer IRE1 is incompletely understood. Whilst the luminal co-chaperone ERdj4 promotes a complex between the Hsp70 BiP and IRE1's stress-sensing luminal domain (IRE1LD) that favours the latter's monomeric inactive state and loss of ERdj4 de-represses IRE1, evidence linking these cellular and in vitro observations is presently lacking. We report that enforced loading of endogenous BiP onto endogenous IRE1α repressed UPR signalling in CHO cells and deletions in the IRE1α locus that de-repressed the UPR in cells, encode flexible regions of IRE1LD that mediated BiP‑induced monomerisation in vitro. Changes in the hydrogen exchange mass spectrometry profile of IRE1LD induced by ERdj4 and BiP confirmed monomerisation and were consistent with active destabilisation of the IRE1LD dimer. Together, these observations support a competition model whereby waning ER stress passively partitions ERdj4 and BiP to IRE1LD to initiate active repression of UPR signalling

Final Causality in the Thought of Thomas Aquinas

Throughout his corpus, Thomas Aquinas develops an account of final causality that is both philosophically nuanced and interesting. The aim of my dissertation is to provide a systematic reconstruction of this account of final causality, one that clarifies its motivation and appeal. The body of my dissertation consists of four chapters. In Chapter 1, I examine the metaphysical underpinnings of Aquinas’s account of final causality by focusing on how Aquinas understands the causality of the final cause. I argue that Aquinas holds that an end is a cause because it is the determinate effect toward which an agent’s action is directed. I proceed by first presenting the general framework of causality within which Aquinas understands final causality. I then consider how Aquinas justifies the reality of each of the four kinds of cause, placing special emphasis on the final cause. In Chapter 2, I consider final causality from the perspective of goodness and explore the reasons why Aquinas thinks that the end of an action is always good. For even if one was convinced that the end of an action is indeed a cause, one might still resist attributing any normative or evaluative properties to the end, much less a positively-valenced normative property like goodness. In this chapter, I show how, given Aquinas’s metaphysics of powers and his characterization of goodness as that which all desire, it follows that every action is for the sake of some good. In Chapter 3, I consider Aquinas’s account of the relation between final causality and cognition. In many passages throughout his corpus—most famously in the fifth of his Five Ways—Aquinas advances the claim that cognition plays an essential role in final causality. In this chapter, I explore Aquinas’s account of the relation between final causality and cognition by reconstructing his Fifth Way and investigating the metaphysical foundations on which it rests. While the first three chapters of my dissertation focus on Aquinas’s account of final causality from the perspective of the ends of individual agents, in Chapter 4 I broaden my focus to consider the way in which the account of final causality developed in these earlier chapters shapes Aquinas’s philosophical cosmology. I argue that, on Aquinas’s view, when an individual agent acts for an end, it is plays a role in a larger system, e.g. a polis, an ecosystem, or the universe itself

Coupling a model of human thermoregulation with computational fluid dynamics for predicting human-environment interaction

This paper describes the methods developed to couple a commercial CFD program with a multi-segmented model of human thermal comfort and physiology. A CFD model is able to predict detailed temperatures and velocities of airflow around a human body, whilst a thermal comfort model is able to predict the response of a human to the environment surrounding it. By coupling the two models and exchanging information about the heat transfer at the body surface the coupled system can potentially predict the response of a human body to detailed local environmental conditions. This paper presents a method of exchanging data, using shared files, to provide a means of dynamically exchanging simulation data with the IESD-Fiala model during the CFD solution process. Additional code is used to set boundary conditions for the CFD simulation at the body surface as determined by the IESD-Fiala model and to return information about local environmental conditions adjacent to the body surface as determined by the CFD simulation. The coupled system is used to model a human subject in a naturally ventilated environment. The resulting ventilation flow pattern agrees well with other numerical and experimental work

Development of Economic Water Usage Sensor and Cyber-Physical Systems Co-Simulation Platform for Home Energy Saving

In this thesis, two Cyber-Physical Systems (CPS) approaches were considered to reduce residential building energy consumption. First, a flow sensor was developed for residential gas and electric storage water heaters. The sensor utilizes unique temperature changes of tank inlet and outlet pipes upon water draw to provide occupant hot water usage. Post processing of measured pipe temperature data was able to detect water draw events. Conservation of energy was applied to heater pipes to determine relative internal water flow rate based on transient temperature measurements. Correlations between calculated flow and actual flow were significant at a 95% confidence level. Using this methodology, a CPS water heater controller can activate existing residential storage water heaters according to occupant hot water demand. The second CPS approach integrated an open-source building simulation tool, EnergyPlus, into a CPS simulation platform developed by the National Institute of Standards and Technology (NIST). The NIST platform utilizes the High Level Architecture (HLA) co-simulation protocol for logical timing control and data communication. By modifying existing EnergyPlus co-simulation capabilities, NIST’s open-source platform was able to execute an uninterrupted simulation between a residential house in EnergyPlus and an externally connected thermostat controller. The developed EnergyPlus wrapper for HLA co-simulation can allow active replacement of traditional real-time data collection for building CPS development. As such, occupant sensors and simple home CPS product can allow greater residential participation in energy saving practices, saving up to 33% on home energy consumption nationally