Role of Nucleotides in Stabilization of the Phospholamban/Cardiac Ca2+ Pump Inhibitory Complex Examined by Metal Fluorides

Phospholamban (PLB) inhibits the activity of the cardiac calcium pump SERCA2a. We previously showed that PLB with engineered Cys residues only cross-linked with the Ca2+-free E2 intermediate of SERCA2a. Formation of E2•PLB prevents Ca2+ binding at the high-affinity Ca2+ binding sites, blocking the enzyme kinetic cycle. Here we further studied the synergistic action of PLB and ATP on E2 in terms of prevention of formation of the phosphorylated E2P-like states stabilized by metal fluorides. SERCA2a was co-expressed in insect cell microsomes with PLB mutants of normal or super-inhibitory strength, with cross-linkable mutations at either the cytosolic side (N30C) or the luminal side (V49C) of PLB. For normal-strength PLB mutants, in the absence of nucleotide, metal fluorides totally inhibited both SERCA2a enzyme activity and cross-linking of PLB to SERCA2a at both sites, suggesting that PLB dissociates from SERCA2a in the E2P-like states. However, under the same conditions, super-inhibitory PLB mutants prevented total enzyme inhibition by metal fluorides. Further, the cross-linking of super-inhibitory PLB to SERCA2a was only partially inhibited by metal fluorides, but was drastically restored upon sequential addition of ATP. These results revealed the equilibrium between E2•PLB, E2•ATP, or E2•ATP•PLB states and E2P-like states, suggesting that the synergistic binding of ATP and PLB to SERCA is very strong, sufficient to prevent formation of E2 phosphoenzymes, even when stabilized by metal fluorides

ALens: An Adaptive Domain-Oriented Abstract Writing Training Tool for Novice Researchers

The significance of novice researchers acquiring proficiency in writing abstracts has been extensively documented in the field of higher education, where they often encounter challenges in this process. Traditionally, students have been advised to enroll in writing training courses as a means to develop their abstract writing skills. Nevertheless, this approach frequently falls short in providing students with personalized and adaptable feedback on their abstract writing. To address this gap, we initially conducted a formative study to ascertain the user requirements for an abstract writing training tool. Subsequently, we proposed a domain-specific abstract writing training tool called ALens, which employs rhetorical structure parsing to identify key concepts, evaluates abstract drafts based on linguistic features, and employs visualization techniques to analyze the writing patterns of exemplary abstracts. A comparative user study involving an alternative abstract writing training tool has been conducted to demonstrate the efficacy of our approach.Comment: Accepted by HHME/CHCI 202

Unlocking the Psychology of Online Travel Booking: How Price Expectations Affect Consumers

Price fluctuation is a major concern for consumers in making travel plans, such as booking flights or hotels. Thus, consumers tend to hesitate over whether to make a booking or not. Online travel booking platforms such as Kayak, Hopper, and Google Flights, have been adopting various digital nudges to influence consumers’ price expectations. For example, they may inform users that “Prices are unlikely to decrease within 7 days” (reassurance) or “Prices may rise within 7 days” (alert). Despite the pervasive adoption of reassurance and alert nudges in online travel booking, little is known about how they influence consumers’ price expectations and travel booking behavior, and why. We plan to conduct a lab experiment and a randomized field experiment in collaboration with a leading travel metasearch platform to investigate how digital nudges like reassurance and alert may affect individuals’ emotions, price expectations, and subsequent online travel booking behavior

Numerical simulations of the sliding impact between an ice floe and a ship hull structure in ABAQUS

This paper studies the hull structural responses of a steel grillage subjected to sliding ice loads, which have been rarely investigated in the literature. Sliding ice loads are modelled using nonlinear finite element analysis (NLFEA) method; and Abaqus Explicit is adopted as the numerical solver. Deformations and damages of ice and steel are both considered. A rigid ice model is also simulated for comparison purposes. The hull’s local structural responses under different load cases, including deformation, contact forces, and energy distribution, have been analysed. The effects of static structure-to-structure friction coefficient and the relative stiffness between ice and structure are studied. It is found that the deformation of structures will increase the total friction coefficient, which is defined as the ratio of the friction force (the tangential contact force) to the normal contact force. When the ice floe is considered rigid, the static friction coefficient has little effect on the local structural responses of the hull. If using a higher-strength steel material for hull structures in the ice-classed ship design, the hull’s deflection and total friction decrease, and the hull dissipates less energy as expected. Moreover, stationary load cases with the same loading condition in the normal direction as sliding load cases are also simulated. When using the deformable ice material model, the simulation results show that the hull’s final contact forces and deflection in stationary load cases are larger than those in sliding load cases. Besides, the effect of steel material is more significant in stationary load cases than in sliding load cases.publishedVersio

Antiarrhythmic and proarrhythmic effects of subcutaneous nerve stimulation in ambulatory dogs

Background High output subcutaneous nerve stimulation (ScNS) remodels the stellate ganglia and suppresses cardiac arrhythmia. Objective To test the hypothesis that long duration low output ScNS causes cardiac nerve sprouting, increases plasma norepinephrine concentration and the durations of paroxysmal atrial tachycardia (PAT) in ambulatory dogs. Methods We prospectively randomized 22 dogs (11 males and 11 females) into 5 different output groups for 2 months of ScNS: 0 mA (sham) (N=6), 0.25 mA (N=4), 1.5 mA (N=4), 2.5 mA (N=4) and 3.5 mA (N=4). Results As compared with baseline, the changes of the durations of PAT episodes per 48 hours were significantly different among different groups (sham, -5.0±9.5 s; 0.25 mA 95.5±71.0 s; 1.5 mA, -99.3±39.6 s; 2.5 mA, -155.3±87.8 s and 3.5 mA, -76.3±44.8 s, p<0.001). The 3.5 mA group had greater reduction of sinus heart rate than the sham group (-29.8±15.0 bpm vs -14.5±3.0 bpm, p=0.038). Immunohistochemical studies showed that the 0.25 mA group had a significantly increased while 2.5 mA and 3.5 mA stimulation had a significantly reduced growth-associated protein 43 nerve densities in both atria and ventricles. The plasma Norepinephrine concentrations in 0.25 mA group was 5063.0±4366.0 pg/ml, which was significantly higher than other groups of dogs (739.3±946.3, p=0.009). There were no significant differences in the effects of simulation between males and females. Conclusions In ambulatory dogs, low output ScNS causes cardiac nerve sprouting, increases plasma norepinephrine concentration and the duration of PAT episodes while high output ScNS is antiarrhythmic

CoLight: Learning Network-level Cooperation for Traffic Signal Control

Cooperation among the traffic signals enables vehicles to move through intersections more quickly. Conventional transportation approaches implement cooperation by pre-calculating the offsets between two intersections. Such pre-calculated offsets are not suitable for dynamic traffic environments. To enable cooperation of traffic signals, in this paper, we propose a model, CoLight, which uses graph attentional networks to facilitate communication. Specifically, for a target intersection in a network, CoLight can not only incorporate the temporal and spatial influences of neighboring intersections to the target intersection, but also build up index-free modeling of neighboring intersections. To the best of our knowledge, we are the first to use graph attentional networks in the setting of reinforcement learning for traffic signal control and to conduct experiments on the large-scale road network with hundreds of traffic signals. In experiments, we demonstrate that by learning the communication, the proposed model can achieve superior performance against the state-of-the-art methods.Comment: 10 pages. Proceedings of the 28th ACM International on Conference on Information and Knowledge Management. ACM, 201

The Structural Basis for Phospholamban Inhibition of the Calcium Pump in Sarcoplasmic Reticulum

P-type ATPases are a large family of enzymes that actively transport ions across biological membranes by interconverting between high (E1) and low (E2) ion-affinity states; these transmembrane transporters carry out critical processes in nearly all forms of life. In striated muscle, the archetype P-type ATPase, SERCA (sarco(endo)plasmic reticulum Ca2+-ATPase), pumps contractile-dependent Ca2+ ions into the lumen of sarcoplasmic reticulum, which initiates myocyte relaxation and refills the sarcoplasmic reticulum in preparation for the next contraction. In cardiac muscle, SERCA is regulated by phospholamban (PLB), a small inhibitory phosphoprotein that decreases the Ca2+ affinity of SERCA and attenuates contractile strength. cAMP-dependent phosphorylation of PLB reverses Ca2+-ATPase inhibition with powerful contractile effects. Here we present the long sought crystal structure of the PLB-SERCA complex at 2.8-Å resolution. The structure was solved in the absence of Ca2+ in a novel detergent system employing alkyl mannosides. The structure shows PLB bound to a previously undescribed conformation of SERCA in which the Ca2+ binding sites are collapsed and devoid of divalent cations (E2-PLB). This new structure represents one of the key unsolved conformational states of SERCA and provides a structural explanation for how dephosphorylated PLB decreases Ca2+ affinity and depresses cardiac contractility