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

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

Effect of Na+ Flow on Cd2+ Block of Tetrodotoxin-resistant Na+ Channels

Tetrodotoxin-resistant (TTX-R) Na+ channels are 1,000-fold less sensitive to TTX than TTX-sensitive (TTX-S) Na+ channels. On the other hand, TTX-R channels are much more susceptible to external Cd2+ block than TTX-S channels. A cysteine (or serine) residue situated just next to the aspartate residue of the presumable selectivity filter “DEKA” ring of the TTX-R channel has been identified as the key ligand determining the binding affinity of both TTX and Cd2+. In this study we demonstrate that the binding affinity of Cd2+ to the TTX-R channels in neurons from dorsal root ganglia has little intrinsic voltage dependence, but is significantly influenced by the direction of Na+ current flow. In the presence of inward Na+ current, the apparent dissociation constant of Cd2+ (∼200 μM) is ∼9 times smaller than that in the presence of outward Na+ current. The Na+ flow–dependent binding affinity change of Cd2+ block is true no matter whether the direction of Na+ current is secured by asymmetrical chemical gradient (e.g., 150 mM Na+ vs. 150 mM Cs+ on different sides of the membrane, 0 mV) or by asymmetrical electrical gradient (e.g., 150 mM Na+ on both sides of the membrane, −20 mV vs. 20 mV). These findings suggest that Cd2+ is a pore blocker of TTX-R channels with its binding site located in a multiion, single-file region near the external pore mouth. Quantitative analysis of the flow dependence with the flux-coupling equation reveals that at least two Na+ ions coexist with the blocking Cd2+ ion in this pore region in the presence of 150 mM ambient Na+. Thus, the selectivity filter of the TTX-R Na+ channels in dorsal root ganglion neurons might be located in or close to a multiion single-file pore segment connected externally to a wide vestibule, a molecular feature probably shared by other voltage-gated cationic channels, such as some Ca2+ and K+ channels

Applying Time-Stack Wave Image to Separate Incident and Reflected Waves in Random Waves

Source: ICHE Conference Archive - https://mdi-de.baw.de/icheArchiv

Qubit Mapping Toward Quantum Advantage

Qubit Mapping is a pivotal stage in quantum compilation flow. Its goal is to convert logical circuits into physical circuits so that a quantum algorithm can be executed on real-world non-fully connected quantum devices. Qubit Mapping techniques nowadays still lack the key to quantum advantage, scalability. Several studies have proved that at least thousands of logical qubits are required to achieve quantum computational advantage. However, to our best knowledge, there is no previous research with the ability to solve the qubit mapping problem with the necessary number of qubits for quantum advantage in a reasonable time. In this work, we provide the first qubit mapping framework with the scalability to achieve quantum advantage while accomplishing a fairly good performance. The framework also boasts its flexibility for quantum circuits of different characteristics. Experimental results show that the proposed mapping method outperforms the state-of-the-art methods on quantum circuit benchmarks by improving over 5% of the cost complexity in one-tenth of the program running time. Moreover, we demonstrate the scalability of our method by accomplishing mapping of an 11,969-qubit Quantum Fourier Transform within five hours

Superior effects of eccentric to concentric knee extensor resistance training on physical fitness, insulin sensitivity and lipid profiles of elderly men

It has been reported that eccentric training of knee extensors is effective for improving blood insulin sensitivity and lipid profiles to a greater extent than concentric training in young women. However, it is not known whether this is also the case for elderly individuals. Thus, the present study tested the hypothesis that eccentric training of the knee extensors would improve physical function and health parameters (e.g., blood lipid profiles) of older adults better than concentric training. Healthy elderly men (60–76 years) were assigned to either eccentric training or concentric training group (n=13/group), and performed 30–60 eccentric or concentric contractions of knee extensors once a week. The intensity was progressively increased over 12 weeks from 10 to 100% of maximal concentric strength for eccentric training and from 50 to 100% for concentric training. Outcome measures were taken before and 4 days after the training period. The results showed that no sings of muscle damage were observed after any sessions. Functional physical fitness (e.g., 30-s chair stand) and maximal concentric contraction strength of the knee extensors increased greater (P ≤ 0.05) after eccentric training than concentric training. Homeostasis model assessment, oral glucose tolerance test and whole blood glycosylated hemoglobin

A Real World Report on Intravenous High-Dose and Non-High-Dose Proton-Pump Inhibitors Therapy in Patients with Endoscopically Treated High-Risk Peptic Ulcer Bleeding

Background and Study Aims. The optimal dose of intravenous proton-pump inhibitor (PPI) therapy for the prevention of peptic ulcer (PU) rebleeding remains controversial. This study aimed to understand the real world experiences in prescribing high-dose PPI and non-high-dose PPI for preventing rebleeding after endoscopic treatment of high-risk PU. Patients and Methods. A total of 220 subjects who received high-dose and non-high-dose pantoprazole for confirmed acute PU bleeding that were successfully treated endoscopically were enrolled. They were divided into rebleeding (n = 177) and non-rebleeding groups (n = 43). Randomized matching of the treatment-control group was performed. Patients were randomly selected for non-high-dose and high-dose PPI groups (n = 44 in each group). Results. Univariate analysis showed, significant variables related to rebleeding were female, higher creatinine levels, and higher Rockall scores ( 6). Before case-control matching, the high-dose PPI group had higher creatinine level, higher percentage of shock at presentation, and higher Rockall scores. After randomized treatment-control matching, no statistical differences were observed for rebleeding rates between the high-dose and non-high-dose groups after casecontrol matching. Conclusion. This study suggests that intravenous high-dose pantoprazole may not be superior to non-high-dose regimen in reducing rebleeding in high-risk peptic ulcer bleeding after successful endoscopic therapy

Evaluating the Primary Prevention of Ischemic Stroke of Oral Antithrombotic Therapy in Head and Neck Cancer Patients with Radiation Therapy

Although previous studies demonstrated the risk of ischemic stroke (IS) in patients with head and neck cancer (HNC), the impact of oral antithrombotic therapy (OAT) on this risk has not yet been assessed. We aimed to evaluate the effectiveness and safety of OAT in patients with HNC treated with RT. This retrospective cohort study was performed using the National Health Insurance Research Database of Taiwan. A total of 37,638 patients diagnosed with HNC included in the study were classified as users and nonusers of OAT. Primary outcome was IS or transient ischemic attack (TIA), and secondary outcomes were death and major bleeding. The Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). There was no significant difference in the risk of IS or TIA between patients on continuous OAT and nonusers (adjusted HR, 0.812; 95% CI,). The risk of major bleeding was not significantly different between the groups. From a national population database, we did not find an association between OAT and decreasing risk of ischemic stroke/TIA or increasing hazard of major bleeding