Multiple Precaching Vehicle Selection Scheme Based on Set Ranking in Intermittently Connected Vehicular Networks.

In vehicular networks, vehicles download vehicular information for various applications, including safety, convenience, entertainment, and social interaction, from the corresponding content servers via stationary roadside units. Since sufficient RSUs might be difficult to deploy due to rough geographical conditions or high deployment costs, vehicular networks can feature uncovered outage zones between two neighboring RSUs. In these outage zones, vehicles cannot download content, and thus the vehicle networks are defined as intermittently connected vehicular networks. In intermittently connected vehicular networks, the download delay and traffic overhead on the backhaul links are increased due to the large size of the content requested by vehicle users and the long distances between RSUs. Using the mobility information of vehicles, several schemes have been proposed to solve this issue by precaching and relaying content via multiple relaying vehicles in the outage zone. However, because they involved the individual ranking of vehicles for precaching and allocated all of the available precaching amounts to the top-ranking vehicles, they decreased the success rate of content requests and the fairness of vehicle precaching. To overcome the problem of these previous schemes, this paper proposes a multiple precaching vehicle selection (MPVS) scheme that efficiently selects a content-precaching vehicle group with multiple precaching vehicles to precache relayed content in outage zones. To achieve this, we first designed numerical models to decide the necessity and the amount of precaching and to calculate the available precaching amounts of vehicles. Next, MPVS calculates all available vehicle sets and ranks each set based on the available precaching amount. Then, the content-precaching vehicle group is identified from the sets by considering both set rankings and vehicle communication overheads. MPVS also provides a content downloading process through the content-precaching vehicle group in the outage zone. Simulation results conducted in various environments with a content request model and a highway mobility model verified that MPVS was superior to a representative previous scheme.

Implicit Overhearing Node-Based Multi-Hop Communication Scheme in IoT LoRa Networks.

Long range (LoRa) is a low-power wide-area technology because it is eminent for robust long-distance, low-bitrate, and low-power communications in the unlicensed sub-GHz spectrum used for the Internet of things (IoT) networks. Recently, several multi-hop LoRa networks have proposed schemes with explicit relay nodes to partially mitigate the path loss and longer transmission time bottlenecks of the conventional single-hop LoRa by focusing more on coverage expansion. However, they do not consider improving the packet delivery success ratio (PDSR) and the packet reduction ratio (PRR) by using the overhearing technique. Thus, this paper proposes an implicit overhearing node-based multi-hop communication (IOMC) scheme in IoT LoRa networks, which exploits implicit relay nodes for performing the overhearing to promote relay operation while satisfying the duty cycle regulation. In IOMC, implicit relay nodes are selected as overhearing nodes (OHs) among end devices with a low spreading factor (SF) in order to improve PDSR and PRR for distant end devices (EDs). A theoretical framework for designing and determining the OH nodes to execute the relay operations was developed with consideration of the LoRaWAN MAC protocol. Simulation results verify that IOMC significantly increases the probability of successful transmission, performs best in high node density, and is more resilient to poor RSSI than the existing schemes.

SF-Partition-Based Clustering and Relaying Scheme for Resolving Near-Far Unfairness in IoT Multihop LoRa Networks.

Long range (LoRa) is one of the most successful low-power wide-area networking technologies because it is ideally suited for long-distance, low-bit rate, and low-power communications in the unlicensed sub-GHz spectrum utilized for Internet of things (IoT) networks. The effectiveness of LoRa depends on the link budget (i.e., spreading factor (SF), bandwidth (BW), and transmission power (TX)). Due to the near-far effect, the allocation of a link budget to LoRa devices (LDs) in large coverage regions is unfair between them depending on their distance to the GW. Thus, more transmission opportunities are given to some LDs to the detriment of other LD's opportunities. Numerous studies have been conducted to address the prevalent near-far fairness problem. Due to the absence of a tractable analytical model for fairness in the LoRa network, however, it is still difficult to solve this problem completely. Thus, we propose an SF-partition-based clustering and relaying (SFPCR) scheme to achieve enormous LD connectivity with fairness in IoT multihop LoRa networks. For the SF partition, the SFPCR scheme determines the suitable partitioning threshold point for bridging packet delivery success probability gaps between SF regions, namely, the lower SF zone (LSFZ) and the higher SF zone (HSFZ). To avoid long-distance transmissions to the GW, the HSFZ constructs a density-based subspace clustering that generates clusters of arbitrary shape for adjacent LDs and selects cluster headers by using a binary score representation. To support reliable data transmissions to the GW by multihop communications, the LSFZ offers a relay LD selection that ideally chooses the best relay LD to extend uplink transmissions from LDs in the HSFZ. Through simulations, we show that the proposed SFPCR scheme exhibits the highest success probability of 65.7%, followed by the FSRC scheme at 44.6%, the mesh scheme at 34.2%, and lastly the cluster-based scheme at 29.4%, and it conserves the energy of LDs compared with the existing schemes.

Optimized Distributed Proactive Caching Based on Movement Probability of Vehicles in Content-Centric Vehicular Networks.

Content-centric vehicular networks (CCVNs) have considered distributed proactive caching as an attractive approach for the timely provision of emerging services. The naïve caching schemes cache all of the contents to only one selected roadside unit (RSU) for requested vehicles to decrease the data acquisition delay between the data source and the vehicles. Due to the high deployment cost for RSUs and their limited capacity of caching, the vehicular networks could support only a limited number of vehicles and a limited amount of content and thus decrease the cache hit ratio. This paper proposes a mobility-aware distributed proactive caching protocol (MDPC) in CCVNs. MDPC caches contents to the selected RSUs according to the movement of vehicles. To reduce the redundancy and the burden of caching for each RSU, MDPC distributes to cache partial contents by the movement pattern, the probability to predict the next locations (RSUs) on the Markov model based on the current RSU. For recovery of prediction failures, MDPC allows each RSU to request partial missing contents to relatively closer neighbor RSUs with a short delay. Next, we expand the protocol with traffic optimization called MDPC_TO to minimize the amount of traffic for achieving proactive caching in CCVNs. In proportion to the mobility probability of a vehicle toward each of the next RSUs, MDPC_TO controls the amount of pre-cached contents in each of the next RSUs. Then, MDPC_TO has constraints to provide enough content from other next RSUs through backhaul links to remove the delay due to prediction failures. Simulation results verify that MDPC_TO produces less traffic than MDPC.

Video Packet Distribution Scheme for Multimedia Streaming Services in VANETs.

By leveraging the development of mobile communication technologies and due to the increased capabilities of mobile devices, mobile multimedia services have gained prominence for supporting high-quality video streaming services. In vehicular ad-hoc networks (VANETs), high-quality video streaming services are focused on providing safety and infotainment applications to vehicles on the roads. Video streaming data require elastic and continuous video packet distributions to vehicles to present interactive real-time views of meaningful scenarios on the road. However, the high mobility of vehicles is one of the fundamental and important challenging issues for video streaming services in VANETs. Nevertheless, previous studies neither dealt with suitable data caching for supporting the mobility of vehicles nor provided appropriate seamless packet forwarding for ensuring the quality of service (QoS) and quality of experience (QoE) of real-time video streaming services. To address this problem, this paper proposes a video packet distribution scheme named Clone, which integrates vehicle-to-vehicle and vehicle-to-infrastructure communications to disseminate video packets for video streaming services in VANETs. First, an indicator called current network quality information (CNQI) is defined to measure the feature of data forwarding of each node to its neighbor nodes in terms of data delivery ratio and delay. Based on the CNQI value of each node and the trajectory of the destination vehicle, access points called clones are selected to cache video data packets from data sources. Subsequently, packet distribution optimization is conducted to determine the number of video packets to cache in each clone. Finally, data delivery synchronization is established to support seamless streaming data delivery from a clone to the destination vehicle. The experimental results show that the proposed scheme achieves high-quality video streaming services in terms of QoS and QoE compared with existing schemes.

Adaptive Content Precaching Scheme Based on the Predictive Speed of Vehicles in Content-Centric Vehicular Networks.

Content-Centric Vehicular Networks (CCVNs) are considered as an attractive technology to efficiently distribute and share contents among vehicles in vehicular environments. Due to the large size of contents such as multimedia data, it might be difficult for a vehicle to download the whole of a content within the coverage of its current RoadSide Unit (RSU). To address this issue, many studies exploit mobility-based content precaching in the next RSU on the trajectory of the vehicle. To calculate the amount of the content precaching, they use a constant speed such as the current speed of the vehicle requesting the content or the average speed of vehicles in the next RSU. However, since they do not appropriately reflect the practical speed of the vehicle in the next RSU, they could incorrectly calculate the amount of the content precaching. Therefore, we propose an adaptive content precaching scheme (ACPS) that correctly estimates the predictive speed of a requester vehicle to reflect its practical speed and calculates the amount of the content precaching using its predictive speed. ACPS adjusts the predictive speed to the average speed starting from the current speed with the optimized adaptive value. To compensate for a subtle error between the predictive and the practical speeds, ACPS appropriately adds a guardband area to the precaching amount. Simulation results verify that ACPS achieves better performance than previous schemes with the current or the average speeds in terms of the content download delay and the backhaul traffic overhead.

Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase.

Altered expression or hyperactivation of anaplastic lymphoma kinase (ALK), as a consequence of translocations or point mutations, is one of the main oncogenic drivers in non-small cell lung cancer. Using structure-based design and in vitro enzyme assays, we identified 3-heteroarylcoumarin as a new template for the development of novel fluorescent ALK inhibitors. Molecular simulation provided structural insights for the design of 3-heteroarylcoumarin derivatives, which were easily prepared through efficient synthetic approaches including direct C-H cross coupling. Importantly, these coumarin-based ALK inhibitors can be tracked using microscopy techniques: we illustrated the use of the most potent compound in this series, 5a, (ALK/IC50 = 0.51 µM, λemi = 500 nm, φF = 0.29) to monitor its subcellular distribution pattern by confocal fluorescence microscopy.

Application of Fragment-Based de Novo Design to the Discovery of Selective Picomolar Inhibitors of Glycogen Synthase Kinase-3 Beta.

A systematic fragment-based de novo design procedure was developed and applied to discover new potent and selective inhibitors of glycogen synthase kinase-3 beta (GSK3ß). Candidate inhibitors were generated to simultaneously maximize the biochemical potency and the specificity for GSK3ß through three design steps: identification of the optimal molecular fragments for the three sub-binding regions, design of proper linking moieties to connect the fragmental building blocks, and final scoring of the generated molecules. By virtue of modifying the ligand hydration free energy term in the scoring function using hybrid scaled particle theory and the extended solvent-contact model, we identified several GSK3ß inhibitors with biochemical potencies ranging from low nanomolar to picomolar levels. Among them, the two most potent inhibitors (12 and 27) are anticipated to serve as promising starting points of drug discovery for various diseases caused by GSK3ß because of the high specificity for the inhibition of GSK3ß.

Optimization and biological evaluation of aminopyrimidine-based IκB kinase ß inhibitors with potent anti-inflammatory effects.

Targeting IκB kinase ß (IKKß) can be a promising strategy in the development of a therapeutic treatment of inflammatory diseases because IKKß is well-recognized as a key mediator of the NF-κB signaling pathway. In this study, we have successfully developed a structure-activity relationship (SAR) profile of the aminopyrimidine-based IKKß inhibitors through the structure-based design strategy to improve the physicochemical properties and cellular activity in terms of the anti-inflammatory effects. Representative compounds exhibited desirable activity in nitric oxide (NO) reduction by inhibiting the synthesis of inducible nitric oxide synthase (iNOS), and strongly inhibited the expression of pro-inflammatory cytokines (IL-1α, IL-6, and TNF-α). The inhibitory effects of 8e on the phosphorylation in the NF-κB pathway further supported that the suppression of the NF-κB signaling pathway induced the anti-inflammatory effect in LPS-stimulated Raw 264.7 cells.

Efficient synthesis of frutinone†A and its derivatives through palladium-catalyzed C - H activation/carbonylation.

Frutinone A, a biologically active ingredient of an antimicrobial herbal extract, demonstrates potent inhibitory activity towards the CYP1A2 enzyme. A three-step total synthesis of frutinone A with an overall yield of 44 % is presented. The construction of the chromone-annelated coumarin core was achieved through palladium-catalyzed CH carbonylation of 2-phenolchromones. The straightforward synthetic route allowed facile substitutions around the frutinone A core and thus rapid exploration of the structure-activity relationship (SAR) profile of the derivatives. The inhibitory activity of the synthesized frutinone A derivatives were determined for CYP1A2, and ten compounds exhibited one-to-two digit nanomolar inhibitory activity towards the CYP1A2 enzyme.

Computational design and discovery of nanomolar inhibitors of IκB kinase ß.

IκB kinase ß (IKKß) is a useful target for the discovery of new medicines for cancer and inflammatory diseases. In this study, we aimed to identify new classes of potent IKKß inhibitors based on structure-based virtual screening, de novo design, and chemical synthesis. To increase the probability of finding actual inhibitors, we improved the scoring function for the estimation of the IKKß-inhibitor binding affinity by introducing proper solvation free energy and conformational destabilization energy terms for putative inhibitors. Using this modified scoring function, we have been able to identify 15 submicromolar-level IKKß inhibitors that possess the phenyl-(4-phenyl-pyrimidin-2-yl)-amine moiety as the molecular core. Decomposition analysis of the calculated binding free energies showed that a high biochemical potency could be achieved by lowering the desolvation cost and the conformational destabilization for the inhibitor required for binding to IKKß as well as by strengthening the interactions in the ATP-binding site. The formation of two hydrogen bonds with backbone amide groups of Cys99 in the hinge region was found to be necessary for tight binding of the inhibitors in the ATP-binding site. From molecular dynamics simulations of IKKß-inhibitor complexes, we also found that complete dynamic stability of the bidentate hydrogen bond with Cys99 was required for low nanomolar-level inhibitory activity. This implies that the scoring function for virtual screening and de novo design would be further optimized by introducing an additional energy term to measure the dynamic stability of the key interactions in enzyme-inhibitor complexes.

Discovery of biological evaluation of pyrazole/imidazole amides as mGlu5 receptor negative allosteric modulators.

Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4-acylpyridinyl imidazoles series of mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new insight for the design of potent mGluR5 negative allosteric modulators with anti-depressant activities.

Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors.

A series of 3-aryl-3-azolylpropan-1-amines was prepared and screened for its capability of inhibiting monoamine reuptake. Analogs with nanomolar potency, good human in vitro microsomal stability, and low drug-drug interaction potential were described. In vivo models were used to evaluate the compound 19r for antidepressive, anxiolytic, and analgesic activity.