The traditional service of car navigation system is provided by the in-car navigation. When the route programming for driving is formulated, only a few factors, such as the shortest distance to the ...destination, the shortest traveling time, whether or not passing some point and whether or not avoiding some road, are taken into account, but some important real-time traffic information of roads, e.g., traffic jam or road maintenance, are not take into consideration. It makes that the navigation device be unable to provide personalized service and the route programming be sometime unfeasible. In this paper, firstly the context-aware based architecture of car navigation service recommendation system is presented. By this recommendation system user may customize navigation service to the recommendation system by means of the navigation device in car, and the latter searches and computes the optimal paths according to the real-time traffic information of the roads, and dynamically adjust the optimal paths in line with the real-time traffic information and provides dynamic navigation service to the former. Then the model of assessing the context information and routing optimization is proposed. Q-method is used to compute optimal driving paths based on real-time information about dynamic traffic networks. Finally a simple data case is employed to verify the model of assessing the context information and routing optimization and the result shows that the method proposed in this paper is superior to the traditional one.
As a potent autophagy inducer, Beclin 1 is essential for the initiation of autophagic cell death, and triggering extensive autophagy by targeted delivery of Beclin 1 to tumors has enormous potential ...to inhibit tumor growth. Yet, the therapeutic application of Beclin 1 is hampered by its inability to internalize into cells and nonselective biodistribution in vivo. To tackle this challenge, we employed a novel Beclin 1 delivery manner by constructing a functional protein (Trx-pHLIP-Beclin 1, TpB) composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), and an evolutionarily conserved motif of Beclin 1. This protein could effectively transport Beclin 1 to breast and ovarian cancer cell lines under weakly acidic conditions (pH 6.5), markedly inhibit tumor cell growth and proliferation, and induce obvious autophagy. Furthermore, the in vivo antitumor efficacy of the functional Beclin 1 against an SKOV3 xenograft tumor mouse model was tested via intravenous injection. TpB preferentially accumulated in tumors and exhibited a significantly higher tumor growth inhibition than the nontargeted Beclin 1 control, whereas no overt side effects were observed. Taken together, this study sheds light on the potential application of TpB as a highly efficient yet safe antitumor agent for cancer treatment.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral ...therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab–Gn–Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection.
This paper addresses the optimization problem of a container liner ship's routing programming and scheduling. Firstly, the mathematical model of the container liner ship's routing programming and ...scheduling is proposed based on the mode of hub-and-spoke. The mathematical model aims to determine how to divide the set of all candidate ports into the hub port set and spoke port set, how to make the route programming for the liner ship and how to interlink each spoke port to one of the hub port with the objective of maximizing profit of the container liner corporation. The uncertainty of container transferring cost is taken into account and transferring price factor is employed to adjust the transferring cost of transporting containers between one of the hub port and a spoke port in order to meet the need of route programming under the different circumstances. Then the optimization problem of a container liner ship's routing programming and scheduling is verified to be NP-hard problem by analyzing the mathematical model. Nextly the approach based on ant colony optimization and heuristic policies is designed to solve the problem. Finally the simulation results show that the route programming of container liner ship with the hub-and-spoke transporting mode can make the container liner corporation get more profit than with traditional transporting mode.
This paper addresses the optimization problem of the coordination of the multi-echelon inventories for the supply chain which is composed of a supplier with unlimited inventory, two manufacturers and ...a distributor and in which the demands involve not only the determined order but also random demands. All of the manufacturers and the distributor apply the hybrid policy (T, s, S) to manage their inventories of the products and raw materials. Firstly, the mathematical model is proposed to describe the optimization problem of the coordination of the multi-echelon inventories of the supply chain, which determines the safe inventories and maximum inventories of the each node to minimize the average inventory management cost of the system per unit time and the lead time of the order demand, maximize satisfaction rate of the customer demand. Then the simulation based optimization method, which is composed of the simulation model of the multi-echelon inventory system and the GA based optimization algorithm, is employed to solve the problem. The simulation software Arena is employed to design and implement the simulation model of the system and optimization algorithm. Finally, the simulated data cases are computed to verify the effectiveness of the method proposed in this paper.
Glucose-regulated protein of 78 kDa (GRP78) has become an attractive and novel target for tumor therapy. Design and construction of powerful delivery systems that could efficiently transport ...doxorubicin (DOX) to a tumor-cell nucleus remains a formidable challenge for improving the tumor therapeutic index and mitigating side effects to normal tissues. Herein, a novel doxorubicin prodrug (NDP) with GRP78 recognition and nucleus-targeting ability was synthesized by a facile chemical route. NDP exhibited an enhanced antiproliferative activity against colorectal cancer cells and could efficiently enter the cell nucleus. Furthermore, it is inspiring to note that NDP displayed a much stronger inhibitory efficacy against the growth of colorectal cancer xenografts in nude mice than free DOX and showed superior in vivo safety. Together, the work provides a novel GRP78 and nucleus-targeting strategy, and the NDP holds great promise to be used as a potent and safe chemotherapeutic agent.
Corncob and Graphene oxide were used to prepare and characterize corncob/graphene oxide (GO/CC) composites. The adsorption performance of GO/CC on dye wastewater was studied, and the factors ...affecting the adsorption effect were investigated. The results showed that GO/CC had rich functional groups which could provide sufficient binding sites for Congo red. It could remove Congo red solution strongly, and the removal rate was as high as 80%. GO/SP was endothermic in the process of Congo red adsorption. The reaction was mainly based on chemical adsorption.
Postsynaptic density protein‐95 (PSD‐95) localizes AMPA‐type glutamate receptors (AMPARs) to postsynaptic sites of glutamatergic synapses. Its postsynaptic displacement is necessary for loss of ...AMPARs during homeostatic scaling down of synapses. Here, we demonstrate that upon Ca2+ influx, Ca2+/calmodulin (Ca2+/CaM) binding to the N‐terminus of PSD‐95 mediates postsynaptic loss of PSD‐95 and AMPARs during homeostatic scaling down. Our NMR structural analysis identified E17 within the PSD‐95 N‐terminus as important for binding to Ca2+/CaM by interacting with R126 on CaM. Mutating E17 to R prevented homeostatic scaling down in primary hippocampal neurons, which is rescued via charge inversion by ectopic expression of CaMR126E, as determined by analysis of miniature excitatory postsynaptic currents. Accordingly, increased binding of Ca2+/CaM to PSD‐95 induced by a chronic increase in Ca2+ influx is a critical molecular event in homeostatic downscaling of glutamatergic synaptic transmission.
Synopsis
Binding of Ca2+/CaM to PSD‐95 displaces PSD‐95 and AMPARs from synapses in homeostatic synaptic downscaling. This finding reveals a molecular mechanism for scaling down, linking activity‐induced Ca2+ influx to the reduction in synaptic strength.
R126 of Ca2+/calmodulin forms a salt bridge with E17 in the N‐terminus of PSD‐95.
PSD‐95–CaM interaction is required for destabilization of PSD‐95 in dendritic spines during homeostatic synaptic scaling down.
Homeostatic synaptic scaling down is accompanied by a reduction in PSD‐95 palmitoylation.
Scaling down of postsynaptic AMPARs requires PSD‐95–CaM interaction.
Structure‐based abrogation of calmodulin/PSD‐95 interaction reveals how activity‐induced calcium influx couples to AMPA receptor displacement and reduction in synaptic strength.
Secondhand smoke (SHS) has significant detrimental vascular effects, including enhanced vasoconstriction and hypertension. Yet, the mechanisms linking SHS exposure to these complications are unclear. ...Although the multifactorial nature of these changes is well appreciated (e.g. endothelial dysfunction, aberrant central control regulation), impaired vascular smooth muscle (VSM) function may also be a key, yet poorly explored, contributing factor. In this study, we tested the hypothesis that vascular reactivity of small diameter mesenteric arteries is altered in mice exposed to SHS. Mice were randomized into control (filter air, FA) and experimental (SHS) groups and exposed to either FA or SHS (Total Suspended Particle, TSP = 3 ± 1 mg/m3; 6 hrs/day, 5 days/week) for a 12 weeks period. After 12 weeks, mesenteric arteries from mice exposed to SHS showed higher (P < 0.05) myogenic tone compared to arteries from the FA group (15.7 ± 2 vs. 23.2 ± 2 FA vs. SHS, respectively). Moreover, we found reduced ACh‐induced vasodilation in SHS arteries (p < 0.05). Consistent with elevated myogenic tone, the resting membrane potential (Vm) of VSM cells isolated from mesenteric arteries of mice exposed to SHS was more depolarized (p < 0.05) than in cells from arteries from the FA group (−42.3 ± 3 vs. −35 ± 2, FA vs. SHS, respectively). Our next series of experiments will examine mechanisms mediating changes in Vm in VSM from SHS versus FA. Our results suggest that SHS have deleterious effects on the vasculature that may involve changes in VSM function.
Support or Funding Information
This work was supported by NIH R01ES025229, R01HL098200, R01HL121059, and NIH‐T32 HL086350.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Crossing the blood-brain barrier in primates is a major obstacle for gene delivery to the brain. Adeno-associated viruses (AAVs) promise robust, non-invasive gene delivery from the bloodstream to the ...brain. However, unlike in rodents, few neurotropic AAVs efficiently cross the blood-brain barrier in non-human primates. Here we report on AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques, which has improved delivery efficiency in the brains of multiple non-human primate species: marmoset, rhesus macaque and green monkey. CAP-Mac is neuron biased in infant Old World primates, exhibits broad tropism in adult rhesus macaques and is vasculature biased in adult marmosets. We demonstrate applications of a single, intravenous dose of CAP-Mac to deliver functional GCaMP for ex vivo calcium imaging across multiple brain areas, or a cocktail of fluorescent reporters for Brainbow-like labelling throughout the macaque brain, circumventing the need for germline manipulations in Old World primates. As such, CAP-Mac is shown to have potential for non-invasive systemic gene transfer in the brains of non-human primates.
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