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•Mammalian bHLH-PAS proteins are heterodimeric transcription factors.•Dimerization involves the bHLH, PAS-A and PAS-B domains.•Crystal structures of heterodimeric complexes reveal ...asymmetric architectures.•These proteins may also bind to distinct ligands through PAS domains.•Their variable C-terminal regions form interactions with regulatory proteins.
The mammalian basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factors share common architectural features that include a bHLH DNA-binding domain and tandemly positioned PAS domains. The sixteen members of this family include the hypoxia-inducible factors (HIF-1α and HIF-2α), ARNT (also known as HIF-1β), CLOCK and BMAL1. Most bHLH-PAS proteins have been genetically linked to variety of diseases in humans, including cancers, metabolic syndromes and psychiatric conditions. To function as transcription factors, the bHLH-PAS proteins must form heterodimeric complexes. Recent crystallographic studies of HIF-α-ARNT and CLOCK-BMAL1 complexes have unveiled the organization of their multi-domain bHLH-PAS-A-PAS-B segments, revealing how these architectures can give rise to unique patterns of heterodimerization. As our structural understanding becomes better integrated with ligand-discovery and target gene identification, a more comprehensive picture of their architectural and functional properties will emerge.
To offload and alleviate the heavy base station (BS) traffic load caused by the rapidly growing video services, device-to-device (D2D) communication, as one of the most indispensable technologies of ...the future cellular networks, can be potentially exploited by mobile users to distribute videos for a BS. In this paper, an effective pricing-based multicast video distribution system and a grid-based clustering method are proposed to support the distribution. Moreover, with the consideration of users' mobility and social characteristics, we classify them into multicast and core types by studying the user stay probability and familiarity. In particular, core users can cooperate with the BS to distribute videos to the multicast users through intracluster D2D multicast. However, core users cannot selflessly help the BS to distribute videos; instead, they will evaluate their personal benefits before distributing the videos to the multicast users. Further, a Stackelberg game-based pricing mechanism is proposed to inspire the core users to distribute videos. Simulation results demonstrate that the proposed mechanism can not only effectively alleviate the BS traffic load, but also significantly improve the effectiveness and reliability of video transmission.
The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote ...the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we describe crystal structures for each of mouse HIF-2α-ARNT and HIF-1α-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2α-ARNT and HIF-1α-ARNT, wherein ARNT spirals around the outside of each HIF-α subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-α mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.
To relieve the current overload of cellular networks caused by the continuously growing multimedia service, mobile edge collaboration, which exploits edge users to distribute videos for base station ...(BS), provides an effective way to share the heavy BS load. With the emergence of mobile edge technologies for Internet-of-Things applications, such as device to device and machine to machine, how to exploit users' social characteristics and mobility to minimize the number of transmissions of BS and how to improve the quality of experience of users have become the key challenges. In this paper, we study two aspects that are critical to these issues. One is the two-step detection mechanism, namely the establishment of virtual communities and collaborative clusters. Specifically, we take into consideration user preference for content and location. First of all, a virtual community is established, which exploits the coalition game based on the user's preference list to dynamically divide users into multiple communities. Then, to take full advantage of the temporary link established between users, a grid-based clustering method is proposed to manage the video requesting users. On the other hand, we propose a scalable video coding sharing scheme based on user's social attributes. This approach makes video distribution more flexible at the edge of mobile network through collaboration among users, and effectively reduces transmission energy consumption of transmitters. Numerical results show that the proposed mechanism can not only effectively alleviate the BS load, but also dramatically improve the reliability and adaptability of video distribution.
Battery packs with a large number of battery cells are becoming more and more widely adopted in electronic systems, such as robotics, renewable energy systems, energy storage in smart grids, and ...electronic vehicles. Therefore, a well-designed battery pack is essential for battery applications. In the literature, the majority of research in battery pack design focuses on battery management system, safety circuit, and cell-balancing strategies. Recently, the reconfigurable battery pack design has gained increasing attentions as a promising solution to solve the problems existing in the conventional battery packs and associated battery management systems, such as low energy efficiency, short pack lifespan, safety issues, and low reliability. One of the most prominent features of reconfigurable battery packs is that the battery cell topology can be dynamically reconfigured in the real-time fashion based on the current condition (in terms of the state of charge and the state of health) of battery cells. So far, there are several reconfigurable battery schemes having been proposed and validated in the literature, all sharing the advantage of cell topology reconfiguration that ensures balanced cell states during charging and discharging, meanwhile providing strong fault tolerance ability. This survey is undertaken with the intent of identifying the state-of-the-art technologies of reconfigurable battery as well as providing review on related technologies and insight on future research in this emerging area.
Hypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2α subunit and its obligate partner subunit ARNT. Enhanced HIF-2 ...activity drives some cancers, whereas reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. Here, we explored HIF-2α chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF-2α PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2α agonists and found that they significantly displaced pocket residue Y281. Its dramatic side chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF-2α PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2α-ARNT heterodimerization.
Robotic sensor networks provide an effective approach for underground pipeline inspection. Such networks are comprised of sensor nodes (SNs) and relay nodes (RNs) carried by robots for information ...sensing and communication, and are able to perform accurate and realtime inspection, especially in adverse environments. SN localization is critical in such networks because localization results can be used not only for locating and pinpointing leaks, but also for maneuvering mobile SNs in a pipeline of complex configuration. However, both the underground operational environment and the limited resources of the SNs pose significant challenges for SN localization. This paper presents algorithms for SN localization in robotic sensor networks for underground pipeline inspection. Specifically, self-localization of underground in-pipe SNs were investigated by taking into account SN movement dynamics, and using the measurements of the SN's velocity and the received signal strength (RSS) of the radio signal from aboveground RNs. Depending on the availability of the RSS at the SN, different localization algorithms based on the Kalman filter are proposed for different scenarios. Simulation results show the efficacy of the proposed algorithms. The framework also provides insight into the design of robotic sensor networks for the inspection and maintenance of other types of pipeline systems, such as oil and gas pipelines.
Nonribosomal peptide synthetases containing starter condensation domains direct the biosynthesis of nonribosomal lipopeptides, which generally exhibit wide bioactivities. The acyl chain has strong ...impacts on bioactivity and toxicity, but the lack of an in-depth understanding of starter condensation domain-mediated lipoinitiation limits the bioengineering of NRPSs to obtain novel derivatives with desired acyl chains. Here, we show that the acyl chains of the lipopeptides rhizomide, holrhizin, and glidobactin were modified by engineering the starter condensation domain, suggesting a workable approach to change the acyl chain. Based on the structure of the mutated starter condensation domain of rhizomide biosynthetic enzyme RzmA in complex with octanoyl-CoA and related point mutation experiments, we identify a set of residues responsible for the selectivity of substrate acyl chains and extend the acyl chains from acetyl to palmitoyl. Furthermore, we illustrate three possible conformational states of starter condensation domains during the reaction cycle of the lipoinitiation process. Our studies provide further insights into the mechanism of lipoinitiation and the engineering of nonribosomal peptide synthetases.
The medium access probability (MAP) of a random access protocol can severely impact network throughput especially for delay-sensitive applications, since it determines whether a node should transmit ...packets in a given slot or not. This paper focuses on network throughput maximization through optimizing the MAPs of all users under delay quality-of-service constraints in wireless interference-limited networks. Specifically, first, the total delay for transmitting one packet for a user is analyzed and derived based on an M/G/1 model. Then, the stochastic property of the aggregated interference is analyzed and its distribution is modeled as a log-normal distribution. Based on the delay and interference models, an optimization problem is formulated to derive the optimal MAPs so that the network throughput is maximized under the delay constraints. Two network traffic scenarios, homogeneous and heterogeneous user traffic, are discussed, respectively. For the case of homogeneous traffic, a closed-form expression of the optimal MAP is derived; for the case of heterogeneous traffic, a global E-optimal algorithm based on the branch-and-bound framework and convex relaxation technology is proposed with relatively low complexity. Simulations results show that the proposed algorithms can achieve superior network throughput performance over existing schemes.
The neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric ...disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.
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