An Inactivation Stabilizer of the Na+ Channel Acts as an Opportunistic Pore Blocker Modulated by External Na+

The Na+ channel is the primary target of anticonvulsants carbamazepine, phenytoin, and lamotrigine. These drugs modify Na+ channel gating as they have much higher binding affinity to the inactivated state than to the resting state of the channel. It has been proposed that these drugs bind to the Na+ channel pore with a common diphenyl structural motif. Diclofenac is a widely prescribed anti-inflammatory agent that has a similar diphenyl motif in its structure. In this study, we found that diclofenac modifies Na+ channel gating in a way similar to the foregoing anticonvulsants. The dissociation constants of diclofenac binding to the resting, activated, and inactivated Na+ channels are ∼880 μM, ∼88 μM, and ∼7 μM, respectively. The changing affinity well depicts the gradual shaping of a use-dependent receptor along the gating process. Most interestingly, diclofenac does not show the pore-blocking effect of carbamazepine on the Na+ channel when the external solution contains 150 mM Na+, but is turned into an effective Na+ channel pore blocker if the extracellular solution contains no Na+. In contrast, internal Na+ has only negligible effect on the functional consequences of diclofenac binding. Diclofenac thus acts as an “opportunistic” pore blocker modulated by external but not internal Na+, indicating that the diclofenac binding site is located at the junction of a widened part and an acutely narrowed part of the ion conduction pathway, and faces the extracellular rather than the intracellular solution. The diclofenac binding site thus is most likely located at the external pore mouth, and undergoes delicate conformational changes modulated by external Na+ along the gating process of the Na+ channel

A Study of the Establishment of the Evaluation Index System for Tourist Attraction Disaster Resilience

Tourism industry is highly depended on the natural environment and climate. Compared to other industries, it is more susceptible to environment and climate. Taiwan belongs to a sea island country and located in the subtropical monsoon zone. The events of climate variability, frequency of typhoons and rainfalls raged are caused regularly serious disaster. In traditional disaster assessment, it usually focuses on the disaster damage and risk assessment, which is short of the features from different industries to understand the impact of the restoring force in post-disaster resilience and the main factors that constitute resilience. The object of this study is based on disaster recovery experience of tourism area and to understand the main factors affecting the tourist area of disaster resilience. The combinations of literature review and interviews with experts are prepared an early indicator system of the disaster resilience. Then, it is screened through a Fuzzy Delphi Method and Analytic Network Process for weight analysis. Finally, this study will establish the tourism disaster resilience evaluation index system considering the Taiwan's tourism industry characteristics. We hope that be able to enhance disaster resilience after tourist areas and increases the sustainability of industrial development. It is expected to provide government departments the tourism industry as the future owner of the assets in extreme climates responses

Absorption of phi mesons in near-threshold proton-nucleus reactions

In the framework of the nuclear spectral function approach for incoherent primary proton--nucleon and secondary pion--nucleon production processes we study the inclusive $\phi$ meson production in the interaction of 2.83 GeV protons with nuclei. In particular, the A-dependences of the absolute and relative $\phi$ meson yields are investigated within the different scenarios for its in-medium width as well as for the cross section ratio $\sigma_{pn \to pn{\phi}}/{\sigma_{pp \to pp{\phi}}}$. Our model calculations take into account the acceptance window of the ANKE facility used in a recent experiment performed at COSY. They show that the pion--nucleon production channel contributes distinctly to the $\phi$ creation in heavy nuclei in the chosen kinematics and, hence, has to be taken into consideration on close examination of the dependences of the phi meson yields on the target mass number with the aim to get information on its width in the medium. They also demonstrate that the experimentally unknown ratio $\sigma_{pn \to pn{\phi}}/{\sigma_{pp \to pp{\phi}}}$ has a weak effect on the A-dependence of the relative $\phi$ meson production cross section at incident energy of present interest, whereas it is found to be appreciably sensitive to the phi in-medium width, which means that this relative observable can indeed be useful to help determine the above width from the direct comparison the results of our calculations with the future data from the respective ANKE-at-COSY experiment.Comment: 16 pages, 9 figure

Improving the Bounds of the Online Dynamic Power Management Problem

We investigate the power-down mechanism which decides when a machine transitions between states such that the total energy consumption, characterized by execution cost, idle cost and switching cost, is minimized. In contrast to most of the previous studies on the offline model, we focus on the online model in which a sequence of jobs with their release time, execution time and deadline, arrive in an online fashion. More precisely, we exploit a different switching on and off strategy and present an upper bound of 3, and further show a lower bound of 2.1, in a dual-machine model, introduced by Chen et al. in 2014 [STACS 2014: 226-238], both of which beat the currently best result

Block of Tetrodotoxin-resistant Na+ Channel Pore by Multivalent Cations: Gating Modification and Na+ Flow Dependence

Tetrodotoxin-resistant (TTX-R) Na+ channels are much less susceptible to external TTX but more susceptible to external Cd2+ block than tetrodotoxin-sensitive (TTX-S) Na+ channels. Both TTX and Cd2+ seem to block the channel near the “DEKA” ring, which is probably part of a multi-ion single-file region adjacent to the external pore mouth and is involved in the selectivity filter of the channel. In this study we demonstrate that other multivalent transitional metal ions such as La3+, Zn2+, Ni2+, Co2+, and Mn2+ also block the TTX-R channels in dorsal root ganglion neurons. Just like Cd2+, the blocking effect has little intrinsic voltage dependence, but is profoundly influenced by Na+ flow. The apparent dissociation constants of the blocking ions are always significantly smaller in inward Na+ currents than those in outward Na+ current, signaling exit of the blocker along with the Na+ flow and a high internal energy barrier for “permeation” of these multivalent blocking ions through the pore. Most interestingly, the activation and especially the inactivation kinetics are slowed by the blocking ions. Moreover, the gating changes induced by the same concentration of a blocking ion are evidently different in different directions of Na+ current flow, but can always be correlated with the extent of pore block. Further quantitative analyses indicate that the apparent slowing of channel activation is chiefly ascribable to Na+ flow–dependent unblocking of the bound La3+ from the open Na+ channel, whereas channel inactivation cannot happen with any discernible speed in the La3+-blocked channel. Thus, the selectivity filter of Na+ channel is probably contiguous to a single-file multi-ion region at the external pore mouth, a region itself being nonselective in terms of significant binding of different multivalent cations. This region is “open” to the external solution even if the channel is “closed” (“deactivated”), but undergoes imperative conformational changes during the gating (especially the inactivation) process of the channel