A non-transmembrane channel formed by Ca2+-bound calsequestrin-2

Although it is well known that ion channels conduct ions across biomembranes, whether ions are conducted by some non-membrane proteins is not known because of the lack of a detection method. Calsequestrin-2 (CSQ2) is a sarcoplasmic reticulum (SR) Ca2+-binding protein suppling Ca2+ for the ryanodine receptor Ca2+ release during the excitation–contraction coupling in cardiomyocytes. CSQ2 mutations, even in some heterozygous occasions, causes catecholaminergic polymorphic ventricular tachycardia (CPVT2), suggesting that CSQ2 may function beyond a Ca2+ buffer. Here, we identify a non-transmembrane channel in Ca2+-enriched CSQ2 dimers, which facilitates fast Ca2+ mobilization. Using crystallography, we solved the high-resolution structure of Ca2+-bound CSQ2 and discovered that the negatively charged residues at the dimer interface encompassed a tubular channel-like structure, dubbed “tunnel,” in which ∼15 Ca2+ ions aligned across the ∼5 nm tunnel path. To determine the potential tunnel conductance, we developed a graphene-based nanoelectronic technology to connect a CSQ2 dimer into a nanocircuit. In the Tyrode solution containing 1 mM Ca2+, a CSQ2 dimer exhibited a conductance one order of magnitude higher than the background level. This conductance was Ca2+ dependent, and was largely suppressed by the single-residue mutation D309N at the bottleneck region of the tunnel path, indicating that the tunnel conducted Ca2+ fluxes. When the D309N mutant CSQ2 was expressed in wild-type rat cardiomyocytes by adenoviral vectors, isoproterenol treatment induced chaotic Ca2+ waves, delayed after-depolarizations and trigged activities resembling those occurring in CPVT2 models. This dominant negative effect of CSQ2 mutation agreed well with our structural observation that CSQ2 tunnels were interconnected to form a tunnel network. Taken together, these results revealed that CSQ2 builds a nano-highway network for energy-efficient Ca2+ mobilization in the SR. Factors that block the Ca2+ highway may lead to arrhythmogenesis.

Generalized Link-Cost Function and Network Design for Dedicated Truck-Platoon Lanes to Improve Energy, Pavement Sustainability, and Traffic Efficiency

Recent development of autonomous and connected trucks (ACT) has provided the freight industry with the option of using truck platooning to improve fuel efficiency, traffic throughput, and safety. However, closely spaced and longitudinally aligned trucks impose frequent and concentrated loading on pavements, which often accelerates pavement deterioration and increases the life cycle costs for the highway agency. Also, effectiveness of truck platooning can be maximized only in dedicated lanes; and its benefits and costs need to be properly balanced between stakeholders. This paper proposes a network-design model to optimize (i) placement of dedicated truck-platoon lanes and toll price in a highway network, (ii) pooling and routing of ACT traffic from multiple origins and destinations to utilize these lanes, and (iii) configuration of truck platoons within these lanes (e.g., lateral displacements and vehicle separations). The problem is formulated as an integrated bi-level optimization model. The upper level makes decisions on converting existing highway lanes into dedicated platoon lanes, as well as setting user fees. The lower-level decisions are made by independent shippers regarding the choice of routes and use of platoon lanes vs. regular lanes; and they collectively determine truck traffic in all lanes. Link-cost functions for platoon lanes are obtained by simultaneously optimizing, through dynamic programming, pavement-rehabilitation activities and platoon configuration in the pavement's life cycle. A numerical case study is used to demonstrate the applicability and performance of the proposed model framework over the Illinois freeway system. It is shown that the freight traffic is effectively channelized on a few corridors of platoon lanes and, by setting proper user fees to cover pavement-rehabilitation costs, systemwide improvements for both freight shippers and highway agencies can be achieved.

Research on resilience recovery strategy optimization of highway network after disaster based on genetic algorithm

In order to effectively improve the recovery efficiency of the highway network after the disaster and make the road network quickly recover to the normal operation level, the recovery strategy of the highway network after the disaster aiming at the optimal toughness was studied and formulated. First clear the toughness in this paper the definition and put forward the two toughness indexes, then constructs the model of road network resilience restored after a disaster, in considering the time, money, resources and cost conditions, through the corresponding genetic algorithm to solve, it is concluded that the shortest road repair, restore minimum loss in the process of recovery program. Finally, an example is given to illustrate how to use the model established in this paper. The results show that from the beginning of repair to the end of repair, the repair team can achieve the expected task in a faster time, which minimizes the performance loss of the road network and saves the cost.

Development and verification of winter traffic hazard models for the Alberta highway network

This paper develops a weather traffic model and verifies its validity through temporal transferability within the context of the Alberta highway network. This research used traffic data and weather data collected at four weigh-in-motion (WIM) sites and weather stations for five years to develop models for two-vehicle classes. We collected an additional year of traffic data from the exact four WIM locations to conduct a temporal transferability test. We evaluated the estimation accuracy resulting from the temporal transferability by measuring the value of R</sup><sup>2 and the magnitude of five error measures. All in all, the developed models were transferred successfully to a different year. The study results reveal that different structural types of models could be better suitable for each vehicle type at other road functions.

The New Distribution: Spatio-Temporal Analysis of Large Distribution Warehouse Premises in England and Wales

This research addresses the deficit of empirical investigation of changes in industrial and warehouse property markets in the UK. It uses business rates (rating list) data for England and Wales to reveal changes in the quantum and distribution of premises over the last decade. Spatio-temporal analysis using geographical information systems identifies where new industrial and warehouse premises have been developed and examines spatial changes in the distribution of premises between the two sectors. The research focuses on the development of new large distribution warehouses (LDWs) to investigate whether there is a new pattern of warehouse premises located in close proximity to junctions on the national highway network. Findings confirm the emergence of a dynamic distribution warehouse property market where “super sheds” have been developed in areas with high levels of multi-modal connectivity. The comprehensive spatio-temporal analysis of all industrial and warehouse premises in England and Wales reconfigures the previously recognised Midlands “Golden Triangle” of distribution warehouses to a “Golden Pointer” and reveals the emergence of a rival “Northern Dumbbell” of distribution warehouse premises in the North of England. Further analysis using isochrones confirms that 85% of the population of Great Britain is situated within four hours average heavy goods vehicle drive time of these two concentrations of super sheds and over 60% of all LDWs floorspace is within 30 minutes’ drive of intermodal rail freight interchanges.

Highways, Market Access, and Spatial Sorting

We design a parsimonious spatial equilibrium model featuring workers embodied with heterogeneous skills and non-homothetic preferences. In equilibrium, locations with improved commuting access become relatively more attractive to high-income earners. We empirically analyse the effects of the construction of the Swiss highway network between 1960 and 2010 on the population size and composition of municipalities. We find that the advent of a new highway access led to a long-term 24% increase in the share of top-income taxpayers and a 8% decrease in the share of low-income taxpayers, impacting segregation by income. Highways also contributed to job and residential urban sprawl.