Structure Mechanism Research Articles

Abstract 3062: Unraveling the role of RCC2 in glioblastoma by mutational analysis and a murine model of glioma

Abstract Glioblastoma (GBM) is a brain malignancy characterized by being highly aggressive, lethal, yet treatment modalities remain limited. Recent studies have implicated Regulator of Chromosome Condensation 2 (RCC2), a guanine nucleotide exchange factor (GEF) for RalA, as a potential regulator in glioblastoma pathogenesis. RCC2 has been shown to play a role in promoting glucose metabolism through BACH1-dependent upregulation of hexokinase II (HK2)(1). In this study, we investigated the functional mechanism of RCC2 in gliomagenesis using two complementary approaches. First, the relevance of RCC2 structural regions on its downstream functions were examined. By superimposing the three-dimensional crystal structure of RCC2 onto RCC1 (Regulator of Chromosome Condensation 1), a related GEF, we identified several unique regions within the RCC1-like domain of RCC2. A panel of point, substitution, and deletion mutants were generated, and pulldown experiments were performed to assess their relative binding affinity with BACH1. Additional assays to assess their relative ability to modulate the expression of HK2 and other cellular parameters will be discussed. The structure-functional characterization of distinct regions within RCC2 may identify unique sequences within RCC2 that could have relevance to glucose metabolism, cell proliferation and cell motility. Additionally, we have established a murine glioma model utilizing a Pten heterozygous mice expressing a GFAP-Cre-recombinase transgene (Gfap-cre;Ptenfl/+). Glioma were induced by stereotaxically injected lentiviral constructs expressing either with HRasV12 oncogene alone or together with RCC2. Neurological symptoms were monitored over a period of 7 months, and histopathological analysis was performed to evaluate the morphological and molecular features of the tumors. We showed that co-expression of HRasV12 and RCC2 exhibited earlier emergence of neurological manifests in both male and female groups (Log-rank test, p<0.05) when compared to HRasV12 alone. Overall, our study provides insights into both the structural mechanism of RCC2 in gliomagenesis through mutational analysis of RCC2 and the functional relevance through a murine model of glioma. (1)Liu, T. et. al. Cancer Lett (2022) 549:215914. Funding: This work is supported by a General Research Fund grant (#14113519) from the University Grants Committee of Hong Kong. Citation Format: Wayne L.H. Ho, Penelope M.Y. Or, Andrew M. Chan. Unraveling the role of RCC2 in glioblastoma by mutational analysis and a murine model of glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3062.

Abstract 6918: Ba/F3-BCR-ABL engineering cell line panel, a useful platform for novel drug discovery

Abstract In the past few years, with the great success of Imatinib, the first kinase inhibitor, Imatinib rapidly became the first-line treatment for CML (Chronic myelogenous leukemia) carrying the BCR-ABL mutation. It opened a new chapter in targeted cancer treatment. Despite the increase in overall survival allowed by imatinib, the onset of drug resistance led scientists to investigate imatinib's fine structural mechanism of action to develop new and more effective compounds against mutated forms of Bcr-Abl. 7 BCR-ABL inhibitors have been approved, they are Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib, Olverembatinib, and Asciminib. However, acquired resistance has been a major challenge in the treatment of CML, and some patients still experience disease progression or even death due to drug resistance. BCR-ABL kinase domain mutations are one of the important mechanisms of acquired resistance, with the T315I mutation being the most common type of drug resistance mutation, accounting for approximately 25% of drug-resistant CML cases. Patients with T315I mutations in CML are resistant to all current first- and second-generation BCR-ABL inhibitors. Asciminib is designed as an allosteric inhibitor combined with an ATP-competitive TKI agent, which may hinder the development of mutation-driven acquired resistance or restore efficacy against highly resistant BCR-ABL mutants. Our group has generated 38 Ba/F3-BCR-ABL engineering cell lines as useful models for novel drug discovery in vitro and in vivo, including wild-type BCR-ABL and inhibitors leading drug resistance mutations, such as T315I, E255, Y253, F317, F359. V299, G250, A337T, V468F, and double mutations. Each cell was validated by cell sequencing and cell efficacy verification using approved BCR-ABL inhibitors. The Ba/F3-BCR-ABL engineering cell line panel can be useful for developing and evaluating next-generation BCR-ABL inhibitors and exploring newly acquired resistance mutations in BCR-ABL. Citation Format: Guoqian Wang, Yao Peng, Yu Wang, Yao Tang, Jingxiao Xu, Jinying Ning, Feng Hao. Ba/F3-BCR-ABL engineering cell line panel, a useful platform for novel drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6918.

Structural mechanisms for VMAT2 inhibition by tetrabenazine

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson’s disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2’s importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington’s chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.

Structural mechanisms for VMAT2 inhibition by tetrabenazine.

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.

Abstract 5609: A WRN screening cascade to facilitate novel drug discovery

Abstract Human RecQ deconjugating enzyme WRN is involved in DNA replication, DNA repair, recombination, transcription and telomere stabilization[1]. It plays a key role in nucleic acid metabolism as well. WRN defects lead to premature aging, type II diabetes, osteoporosis, atherosclerosis and cancer[2]. Hence it is of great interest of both pharmaceutical and academic field to develop the WRN inhibitors. Here we constructed an integrated experimental cascade, which contains both in vitro and in vivo assays, to conduct the high throughput hit-to-lead compound screen. WRN proteins of different length have been successfully purified and utilized to develop multiple biochemical assays such as unwinding assay and ATPase assay. We have also validated different cellular assays, including proliferation and immunofluorescence, to assess the cytotoxicity and the influence of downstream biomarkers of WRN inhibitors. A WRN knock-out cell line has been generated to better appreciate the inhibition mechanism. In addition, we have generated a WRN-HiBiT knock-in cell line to evaluate WRN degraders or target-compound interactions. Lastly, multiple CDX models utilizing different MSI or MSS cell lines have been validated to help determine the efficacy of WRN inhibitors thus shed light on the drug indications. Together our WRN screening cascade can provide comprehensive compound evaluation across in vitro and in vivo platforms, thus serve as an efficient screening platform for new drug discovery. [1] Kitano K. Structural mechanisms of human RecQ helicases WRN and BLM. Front Genet. 2014 Oct 29;5:366. [2]Hussain M, Krishnamurthy S, Patel J, Kim E, Baptiste BA, Croteau DL, Bohr VA. Skin Abnormalities in Disorders with DNA Repair Defects, Premature Aging, and Mitochondrial Dysfunction. J Invest Dermatol. 2021 Apr;141(4S):968-975. Citation Format: Aicheng Wang, Kejun Mao, Tao Li, Lizhao Guan, Yuhong Chen, Haiting Dai, Xian Wu, Jiabao Lv, Xu Wang, Cong Huang, Tiejun Bing. A WRN screening cascade to facilitate novel drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5609.

Active low frequency band expansion mechanism of electromagnetic wave absorber composite structure

Bandwidth expansion of modern antennas and communication systems raises growing demand for electromagnetic wave absorber in compatibility equipment. Single absorption mechanism is hard to reach well-balanced characteristics including wide bandwidth, low frequency absorption and small thickness. Based on the composite structure concept, composite structure for electromagnetic wave absorber’s active low frequency band expansion is proposed, by combining circuit-analog absorber and active absorber to form a superimposed structure. The characteristic of composite structure is better than the single absorber structure, which improves enhancement mechanism brought by the composite structure. Sample fabrication and experiments indicate reflectivity curve envelope reaches −10 dB in 2.15–18 GHz frequency range (relative bandwidth 157.3%), and the tunable absorption frequency range in low-frequency domain is greater than 1.3 GHz. The structure has good adaptation on TE and TM polarizations, as well as good angle insensitivity. This composite structure has application potential in intelligent response system related with electromagnetic compatibility, energy absorption and object security management.

CONSTANS, a HUB for all seasons: How photoperiod pervades plant physiology regulatory circuits.

How does a plant detect the changing seasons and make important developmental decisions accordingly? How do they incorporate daylength information into their routine physiological processes? Photoperiodism, or the capacity to measure the daylength, is a crucial aspect of plant development that helps plants determine the best time of the year to make vital decisions, such as flowering. The protein CONSTANS (CO) constitutes the central regulator of this sensing mechanism, not only activating florigen production in the leaves but also participating in many physiological aspects in which seasonality is important. Recent discoveries place CO in the center of a gene network that can determine the length of the day and confer seasonal input to aspects of plant development and physiology as important as senescence, seed size, or circadian rhythms. In this review, we discuss the importance of CO protein structure, function, and evolutionary mechanisms that embryophytes have developed to incorporate annual information into their physiology.

Crystallization of Ethylene Plant Hormone Receptor-Screening for Structure.

The plant hormone ethylene is a key regulator of plant growth, development, and stress adaptation. Many ethylene-related responses, such as abscission, seed germination, or ripening, are of great importance to global agriculture. Ethylene perception and response are mediated by a family of integral membrane receptors (ETRs), which form dimers and higher-order oligomers in their functional state as determined by the binding of Cu(I), a cofactor to their transmembrane helices in the ER-Golgi endomembrane system. The molecular structure and signaling mechanism of the membrane-integral sensor domain are still unknown. In this article, we report on the crystallization of transmembrane (TM) and membrane-adjacent domains of plant ethylene receptors by Lipidic Cubic Phase (LCP) technology using vapor diffusion in meso crystallization. The TM domain of ethylene receptors ETR1 and ETR2, which is expressed in E. coli in high quantities and purity, was successfully crystallized using the LCP approach with different lipids, lipid mixtures, and additives. From our extensive screening of 9216 conditions, crystals were obtained from identical crystallization conditions for ETR1 (aa 1-316) and ETR2 (aa 1-186), diffracting at a medium-high resolution of 2-4 Å. However, data quality was poor and not sufficient for data processing or further structure determination due to rotational blur and high mosaicity. Metal ion loading and inhibitory peptides were explored to improve crystallization. The addition of Zn(II) increased the number of well-formed crystals, while the addition of ripening inhibitory peptide NIP improved crystal morphology. However, despite these improvements, further optimization of crystallization conditions is needed to obtain well-diffracting, highly-ordered crystals for high-resolution structural determination. Overcoming these challenges will represent a major breakthrough in structurally determining plant ethylene receptors and promote an understanding of the molecular mechanisms of ethylene signaling.

Molecular dynamics simulation of mechanical properties of decagonal quasicrystal approximate phase Al2Fe

By using the molecular dynamics method, the tensile and elastic mechanical properties of Al2Fe (tI6 and oF24) alloys for decagonal quasicrystals approximation are simulated. Structural models for tI6 and oF24 are first established and then the appropriate embedded atom method (EAM) potential function is selected to analyze the effects of temperature and strain rate on the stress-strain relation, atomic structure and deformation mechanism. Furthermore, all the elastic constants Cij of tI6 and oF24 are calculated by the molecular dynamics explicit deformation method, and the crystal structure and stability of tI6 and oF24 are also judged. Besides, the elastic mechanical properties of tI6 and oF24 including bulk modulus, shear modulus, elastic modulus, and Poisson's ratio, are derived by means of both the general formula and the independent crystal system formula. The results show that the elastic modulus and tensile strength of tI6 and oF24 almost decrease linearly with increasing temperature. An increase of strain rate has little effect on the elastic modulus of tI6 and oF24, but it can result in an obvious increase of the tensile strength and ultimate strain. By calculating, tI6 possesses a stable tetragonal crystal structure and oF24 has a stable orthorhombic crystal structure, which are consistent with the previous results derived by the first-principle. The Young's modulus, shear modulus and Poisson's ratio display high anisotropy except for the bulk modulus. The anisotropic of oF24 is higher than that of tI6, while the stiffness and hardness of tI6 are greater than those of oF24. The present work can provide a theoretical reference for analyzing the mechanical properties of the approximate phase of decagonal quasicrystal as well as a novel numerical calculation method for determining the mechanical properties of related materials.

Gallium Trichloride Fluid: Dimer Dissociation Mechanism, Local Structure, and Atomic Dynamics.

Molten gallium trichloride emerges as a promising solvent for oxidative metal recycling. The use of supercritical fluid enhances the performance and kinetics of metal dissolution due to significantly lower viscosity in the reaction media. Additionally, the dual molecular nature of gallium trichloride, existing as edge-sharing ES-Ga2Cl6 dimers at low temperatures and high pressure, or flat trigonal GaCl3 monomers in the vicinity of the critical point and low pressures, creates the possibility to tailor the chemical geometry to a particular metallic species. Nevertheless, the mechanism of dimer dissociation, local structure, and atomic dynamics in supercritical gallium trichloride fluids are not known. Using first-principles molecular dynamics, validated by comparison with our high-energy X-ray diffraction results, we illustrate the elementary steps in dimer dissociation. These include the formation of intermediate corner-sharing CS-Ga2Cl6 dimers, the partial disproportionation of GaCl3 monomers at high temperatures and low pressures, changes in the local environment of molecular entities, and unusual atomic dynamics in supercritical fluids.

Recent advances in clay minerals for groundwater pollution control and remediation.

Clay minerals are abundant on Earth and have been crucial to the advancement of human civilization. The ability of clay minerals to absorb chemicals is frequently utilized to remove hazardous compounds from aquatic environments. Moreover, clay-based adsorbent products are both environmentally acceptable and affordable. This study provides an overview of advances in clay minerals in the field of groundwater remediation and related predictions. The existing literature was examined using data and information aggregation approaches. Keyword clustering analysis of the relevant literature revealed that clay minerals are associated with groundwater utilization and soil pollution remediation. Principal component analysis was used to assess the relationships among clay mineral modification methods, pollutant properties, and the Langmuir adsorption capacity (Qmax). The results demonstrated that pollutant properties affect the Qmax of pollutants adsorbed by clay minerals. Systematic cluster analysis was utilized to classify the collected data and investigate the relationships. The pollution adsorption mechanism of the unique structure of clay minerals was investigated based on the characterization results. Modified clay minerals exhibited changes in surface functional groups, internal structure, and pHpzc. This review provides a summary of recent clay-based materials and their applications in groundwater remediation, as well as discussions of their challenges and future prospects.

Tunable viscoelasticity of bulk fullerene network via high-temperature annealing

Although the experimental transformation of C60 bulk into various functional carbon materials at a certain temperature and pressure has been extensively explored, the understanding of the structural transformation mechanisms and the energy dissipation mechanisms of the derived topologies at the atomic scale is still poor. By using the molecular dynamics (MD) simulations method, the structural transformation of C60 bulk to various carbon materials is studied. Besides, the mechanisms of energy dissipation of three typical structures are revealed and the effects of loading frequency, temperature, loading amplitude, and pre-strain on the storage, loss modulus, and dumping ratio of three typical structures were investigated by dynamic mechanical analysis (DMA). The results show that due to the difference in structural morphology and mechanical behaviors under cyclic loading, three typical structures show different viscoelastic mechanical properties which could also be tuned by changing related parameters. This work systematically investigates the viscoelastic mechanical properties of bulk fullerene network during different annealing processes and corresponding energy dissipation mechanisms and provides important references for further design and application.

Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers

The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this therapeutic challenge are hindered by a poor understanding of how and why cancer mutations specifically amplify ligand-independent EGFR auto-phosphorylation signals to enhance cell survival and how this amplification is related to ligand-dependent cell proliferation. Here we show that drug-resistant EGFR mutations manipulate the assembly of ligand-free, kinase-active oligomers to promote and stabilize the assembly of oligomer-obligate active dimer sub-units and circumvent the need for ligand binding. We reveal the structure and assembly mechanisms of these ligand-free, kinase-active oligomers, uncovering oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Importantly, we find that the active dimer sub-units within ligand-free oligomers are the high affinity binding sites competent to bind physiological ligand concentrations and thus drive tumor growth, revealing a link with tumor proliferation. Our findings provide a framework for future drug discovery directed at tackling oncogenic EGFR mutations by disabling oligomer-assembling interactions.

Seismic Performance and Damage Mechanism of RC Double-Column Pier Structure with Triple Coupling Beams

Seismic Performance and Damage Mechanism of RC Double-Column Pier Structure with Triple Coupling Beams

Multi-Level Structural Enhancement Mechanism of the Excellent Mechanical Properties of Dung Beetle Leg Joint.

The multi-level structure is a strategy to enhance the mechanical properties of dung beetle leg joints. Under external loads, the microstructure facilitates energy dissipation and prevents crack extension. The macrostructure aids in transferring the load to more reliable parts. The connection established by the two hemispheres is present in the dung beetle leg joint. The micron-layered and nanoscale crystal structures further constitute the leg joint with excellent mechanical properties. The maximum compression fracture force is ≈101000 times the weight of the leg. Here, the structural design within the dung beetle leg joints and reveal the resulting mechanical response and enhancement mechanisms is determined. A series of beetle leg joints where the macrostructure and microstructure of the dung beetle leg provide mechanical strength at critical strains while avoiding catastrophic failure by transferring the load from the joint to the exoskeleton of the femur is highlighted. Nanocrystalline structures and fiber layers contribute to crack propagation of the exoskeleton. Based on this, the bionic joint with multi-level structures using resin and conducted a series of tests to verify their effectiveness is prepared. This study provides a new idea for designing and optimizing high-load joints in engineering.

Rheological behavior of particle-filled polymer suspensions and its influence on surface structure of the coated electrodes

Abstract Capacitive deionization electrode prepared by coating was commonly investigated, with polymer solution as binder and active particles as adsorbent. In the coating process, microstructure constituted by the two components was damaged by shear, then rebuilt when shear was removed. The microstructure strongly influenced the surface structure of the coated electrodes, further to performance and cycle life. The discussion of the interaction between the components in the coating process facilitates the identification of structural mechanisms. Rheology bridged the flow regimes in macroscale and interaction in microscale, through which the interaction between the polymer and particles can be investigated in a macroscopic phenomenon. In this study, hydrophilic polymer, poly(vinyl alcohol) (PVA), and poly(ethylene oxide) (PEO) were used as binders to prepare the suspension for coating. The influence of polymer molecular structure to interaction and microstructure was investigated by rheology. Results showed that the flexibility of polymer determined the adsorption morphology, leading to different flocculation structures. For rigid PVA, a 3d-crosslinked network was formed, giving a tough coating. While for flexible PEO, encapsulation structure was formed, leading to a brittle coating. A model based on bridging flocculation was evaluated to describe the formation and destruction of the flocculation structure. And a rheological method for binder selection and coating operation was proposed.

Structural insights into vesicular monoamine storage and drug interactions.

Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions1-5-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled quantal release6,7. Harnessing proton antiport, VMATs enrich monoamines around 10,000-fold and sequester neurotoxicants to protect neurons8-10. VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension and drug addiction1,8,11-16. However, the structural mechanisms underlying these actions remain unclear. Here we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines (dopamine, noradrenaline, serotonin and histamine), the Parkinsonism-inducing MPP+, the psychostimulant amphetamine and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, whereas the other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favoured transition to this lumenal-open state contributes to monoamine accumulation, while protonation facilitates the cytoplasmic-open transition and concurrently prevents monoamine binding to avoid unintended depletion. Monoamines and neurotoxicants share a binding pocket that possesses polar sites for specificity and a wrist-and-fist shape for versatility. Variations in this pocket explain substrate preferences across the SLC18 family. Overall, these structural insights and supporting functional studies elucidate the mechanism of vesicular monoamine transport and provide the basis to develop therapeutics for neurodegenerative diseases and substance abuse.

Highly elastic, fatigue-resistant, antibacterial, conductive, and nanocellulose-enhanced hydrogels with selenium nanoparticles loading as strain sensors

The fabrication of highly elastic, fatigue-resistant and conductive hydrogels with antibacterial properties is highly desirable in the field of wearable devices. However, it remains challenging to simultaneously realize the above properties within one hydrogel without compromising excellent sensing ability. Herein, we fabricated a highly elastic, fatigue-resistant, conductive, antibacterial and cellulose nanocrystal (CNC) enhanced hydrogel as a sensitive strain sensor by the synergistic effect of biosynthesized selenium nanoparticles (BioSeNPs), MXene and nanocellulose. The structure and potential mechanism to generate biologically synthesized SeNPs (BioSeNPs) were systematically investigated, and the role of protease A (PrA) in enhancing the adsorption between proteins and SeNPs was demonstrated. Additionally, owing to the incorporation of BioSeNPs, CNC and MXene, the synthesized hydrogels showed high elasticity, excellent fatigue resistance and antibacterial properties. More importantly, the sensitivity of hydrogels determined by the gauge factor was as high as 6.24 when a high strain was applied (400–700 %). This study provides a new horizon to synthesize high-performance antibacterial and conductive hydrogels for soft electronics applications.

Meta-path-based key node identification in heterogeneous networks

Identifying key nodes in complex networks remains challenging. Whereas previous studies focused on homogeneous networks, real-world systems comprise multiple node and edge types. We propose a meta-path-based key node identification (MKNI) method in heterogeneous networks to better capture complex interconnectivity. Considering that existing studies ignore the differences in propagation probabilities between nodes, MKNI leverages meta-paths to extract semantics and perform node embeddings. Trust probabilities reflecting propagation likelihoods are derived by calculating embedding similarities. Node importance is calculated by using metrics incorporating direct and indirect influence based on trust. The experimental results on three real-world network datasets, DBLP, ACM and Yelp, show that the key nodes identified by MKNI exhibit better information propagation in the Susceptible Infected (SI) and susceptibility-influence model (SIR) model compared to other methods. The proposed method provides a reliable tool for revealing the topological structure and functional mechanisms of the network, which can guide more effective regulation and utilization of the network.

Failure Mechanism and Structural Safety Assessment of the Primary Support Structure of Soft Rock Tunnel: A Case Study

Based on a soft rock tunnel in a mountainous area of northwest Yunnan Province, a refined numerical model of different support forms considering structural interaction is established to comprehensively evaluate the structural failure mechanisms and mechanical responses of different support forms. Research shows that compared to steel rib structures, the axial force and bending moment of sprayed concrete structures is larger under different combinations of support structures. Compared with a single-layer support structure, the stress distribution at each position of the double-layer I-shaped steel structure is more uniform, and the sprayed concrete structure only experiences compression damage at the corner of the side wall. As the strength of sprayed concrete increases, the stress distribution of sprayed concrete at the arch waist becomes more uniform. The stress concentration state of sprayed concrete at the corner of the tunnel wall and the plastic yield state of the steel rib structure have also been improved. The higher the concrete strength, the lower the stress ratio on the steel rib’s inner and outer sides.