Over-expression of TRESK K(+) channels reduces the excitability of trigeminal ganglion nociceptors

TWIK-related spinal cord K(+) (TRESK) channel is abundantly expressed in trigeminal ganglion (TG) and dorsal root ganglion neurons and is one of the major background K(+) channels in primary afferent neurons. Mutations in TRESK channels are associated with familial and sporadic migraine. In rats, both chronic nerve injury and inflammation alter the expression level of TRESK mRNA. Functional studies indicate that reduction of endogenous TRESK channel activity results in hyper-excitation of primary afferent neurons, suggesting that TRESK is a potential target for the development of new analgesics. However, whether and how enhancing TRESK channel activity would decrease the excitability of primary afferent neurons has not been directly tested. Here, we over-expressed TRESK subunits in cultured mouse TG neurons by lipofectamine-mediated transfection and investigated how this altered the membrane properties and the excitability of the small-diameter TG population. To account for the heterogeneity of neurons, we further divided small TG neurons into two groups, based on their ability to bind to fluorescently-labeled isolectin B (IB4). The transfected TG neurons showed a 2-fold increase in the level of TRESK proteins. This was accompanied by a significant increase in the fraction of lamotrigine-sensitive persistent K(+) currents as well as the size of total background K(+) currents. Consequently, both IB4-positive and IB4-negative TG neurons over-expressing TRESK subunits exhibited a lower input resistance and a 2-fold increase in the current threshold for action potential initiation. IB4-negative TG neurons over-expressing TRESK subunits also showed a significant reduction of the spike frequency in response to supra-threshold stimuli. Importantly, an increase in TRESK channel activity effectively inhibited capsaicin-evoked spikes in TG neurons. Taken together, our results suggest that potent and specific TRESK channel openers likely would reduce the excitability of primary afferent neurons and therefore are potential therapeutics for the treatment of migraine and other chronic pain symptoms

A novel ion channel formed by interaction of TRPML3 with TRPV5.

TRPML3 and TRPV5 are members of the mucolipin (TRPML) and TRPV subfamilies of transient receptor potential (TRP) cation channels. Based on sequence similarities of the pore forming regions and on structure-function evidence, we hypothesized that the pore forming domains of TRPML and TRPV5/TRPV6 channels have similarities that indicate possible functional interactions between these TRP channel subfamilies. Here we show that TRPML3 and TRPV5 associate to form a novel heteromeric ion channel. This novel conductance is detectable under conditions that do not activate either TRPML3 or TRPV5. It has pharmacological similarity with TRPML3 and requires functional TRPML3 as well as functional TRPV5. Single channel analyses revealed that TRPML3 and TRPV5 heteromers have different features than the respective homomers, and furthermore, that they occur in potentially distinct stoichiometric configurations. Based on overlapping expression of TRPML3 and TRPV5 in the kidney and the inner ear, we propose that TRPML3 and TRPV5 heteromers could have a biological function in these organs

Multi-Hazard Assessment of Seismic and Scour Effects on Rural Bridges with Unknown Foundations

This chapter proposes a probabilistic framework for assessing seismic and scour effects on existing river-crossing bridge structures. The emphasis is on bridge structures in rural areas, for which it has been recognized that a large number of rural bridges have unknown foundation types and further are subject to both flooding-induced scour and seismic damage. With a review of the US-based rural bridges, this chapter presents a probabilistic framework for bridge performance assessment. Using a representative rural bridge model, the fragility results for the bridge reveal that scour tends to be beneficial in reducing structural damage at slight to moderate seismic intensities and to be detrimental in increasing collapse potential at high-level intensities. The demand hazard curves further quantify probabilistically the occurrence of local damage and global collapse, and systematically reveal the complex effects of scour as a hydraulic hazard on bridge structures

Emergence of Bending Power Law in Higher-Order Networks

In the past two decades, a series of important results have been established in the empirical and theoretical modeling of complex networks, although considered are mainly pairwise networks. However, with the development of science and technology, an increasing number of higher-order networks with many-body interactions have gradually moved to the center stage of research when real-life systems are investigated. In the paper, the concept of higher-order degree is introduced to higher-order networks, and a bending power law (BPL) model with continuous-time growth is proposed. The evolution mechanism and topological properties of the general higher-order network are studied. The batch effect of low dimensional simplex is considered. The model is analyzed by using the mean-field method and Poisson process theory. The stationary average higher-order degree distribution of simplices is expressed analytically. The obtained analytical results agree well with those observed through simulations. In particular, this paper shows that the higher-order degree distribution of simplices in the network processes a property of bending power law, and the scale-free property of the higher-order degree is controlled by the higher-order edge, the simplex dimension and the feature parameter of the model. The BPL model of higher-order networks not only generalizes the NGF model, but also the famous scale-free model of complex networks to higher-order networks

DESIGN AND OPTIMIZATION OF THE VARIABLE-DENSITY LATTICE STRUCTURE BASED ON LOAD PATHS

Lattice structure is more and more widely used in engineering by replacing solid structure. But its mechanical performances are constrained by the external shape if the unit cells are directly filled in the design domain, and the traditional topology optimization methods are difficult to give the explicitly mechanical guidance for the distribution of internal unit cells. In this paper, a novel design and optimization method of variable-density lattice structure is proposed in order to simultaneously optimize the external shape and the internal unit cells. First of all, the envelope model of any given structure should be established, and the load paths need to be visualized by the theory of load path. Then, the design criteria of external shape are established based on the principle of smoother load paths in the structure. An index of load flow capacity is defined to indicate the load paths density and to control the density distribution of unit cells, and a detailed optimization strategy is given. Finally, three examples of a cantilever plate, an L-shaped bracket and a classical three-point bending beam are used to verify the method. The results show that the models designed by the proposed method have better mechanical performances, lower material usage and less printing time

Effect of intracranial electrical stimulation on dynamic functional connectivity in medically refractory epilepsy

ObjectiveThe objective of this study was to explore the distributed network effects of intracranial electrical stimulation in patients with medically refractory epilepsy using dynamic functional connectivity (dFC) and graph indicators.MethodsThe time-varying connectivity patterns of dFC (state-based metrics) as well as topological properties of static functional connectivity (sFC) and dFC (graph indicators) were assessed before and after the intracranial electrical stimulation. The sliding window method and k-means clustering were used for the analysis of dFC states, which were characterized by connectivity strength, occupancy rate, dwell time, and transition. Graph indicators for sFC and dFC were obtained using group statistical tests.ResultsDFCs were clustered into two connectivity configurations: a strongly connected state (state 1) and a sparsely connected state (state 2). After electrical stimulation, the dwell time and occupancy rate of state 1 decreased, while that of state 2 increased. Connectivity strengths of both state 1 and state 2 decreased. For graph indicators, the clustering coefficient, k-core, global efficiency, and local efficiency of patients showed a significant decrease, but the brain networks of patients exhibited higher modularity after electrical stimulation. Especially, for state 1, there was a significant decrease in functional connectivity strength after stimulation within and between the frontal lobe and temporary lobe, both of which are associated with the seizure onset.ConclusionOur findings demonstrated that intracranial electrical stimulation significantly changed the time-varying connectivity patterns and graph indicators of the brain in patients with medically refractory epilepsy. Specifically, the electrical stimulation decreased functional connectivity strength in both local-level and global-level networks. This might provide a mechanism of understanding for the distributed network effects of intracranial electrical stimulation and extend the knowledge of the pathophysiological network of medically refractory epilepsy

Optimization and Planning of Emergency Evacuation Routes Considering Traffic Control

Emergencies, especially major ones, happen fast, randomly, as well as unpredictably, and generally will bring great harm to people’s life and the economy. Therefore, governments and lots of professionals devote themselves to taking effective measures and providing optimal evacuation plans. This paper establishes two different emergency evacuation models on the basis of the maximum flow model (MFM) and the minimum-cost maximum flow model (MC-MFM), and proposes corresponding algorithms for the evacuation from one source node to one designated destination (one-to-one evacuation). Ulteriorly, we extend our evaluation model from one source node to many designated destinations (one-to-many evacuation). At last, we make case analysis of evacuation optimization and planning in Beijing, and obtain the desired evacuation routes and effective traffic control measures from the perspective of sufficiency and practicability. Both analytical and numerical results support that our models are feasible and practical

Low-dose interleukin-2 reverses chronic migraine-related sensitizations through peripheral interleukin-10 and transforming growth factor beta-1 signaling

Low-dose interleukin-2 (LD-IL-2) treatment has been shown to effectively reverse chronic migraine-related behaviors and the sensitization of trigeminal ganglion (TG) neurons through expansion and activation of peripheral regulatory T cells (Tregs) in mice. In this study, we investigated the molecular mechanisms underlying the effects of LD-IL-2 and Treg cells. LD-IL-2 treatment increases the production of cytokines interleukin-10 (IL-10) and transforming growth factor beta-1 (TGFβ1) in T cells, especially Treg cells, suggesting that they may mediate the therapeutic effect of LD-IL-2. Indeed, neutralizing antibodies against either IL-10 or TGFβ completely blocked the effects of LD-IL-2 on the facial mechanical hypersensitivity as well as the sensitization of TG neurons resulting from repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration in mice, indicating that LD-IL-2 and Treg cells engage both peripheral IL-10 and TGFβ signaling pathways to reverse chronic-migraine related sensitizations. In a

Optimal Inventory Policy under Permissible Payment Delay in Fashion Supply Chains

This paper investigates a retailer’s optimal inventory cycle and the corresponding time of payment in fashion supply chains where a supplier allows the payment delay. Here according to the established model we first analyze the retailer's reaction, and then find out the retailer’s optimal inventory policy and time of payment to maximize its total profit. Our result shows that it is not always the best choice for retailers of fashion supply chains to choose the discount way to replenish stocks, but the retailer can decide the optimal credit period and inventory cycle. Moreover, numerical examples are provided to illustrate the model’s feasibility and rationality