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Mechanical metamaterials constitute a nascent category of architected structures comprising arranged periodic components with tailored geometrical features. These materials are now being employed as advanced medical implants due to their extraordinary mechanical properties over traditional devices. Nevertheless, to achieve desired tissue integration and regeneration, it is critical to study how the microarchitecture affects interactions between metamaterial scaffolds and living biological tissues. Based on human induced pluripotent stem cell technology and multiphoton lithography, we report the establishment of an in vitro microtissue model to study the integration and remodeling of human mesenchymal tissues on metamaterial scaffolds with different unit geometries. Microtissues showed distinct tissue morphologies and cellular behaviors between architected octet-truss and bowtie structures. Under the active force generated from mesenchymal tissues, the octet-truss and bowtie metamaterial scaffolds demonstrated unique instability phenomena, significantly different from uniform loading using conventional mechanical testing.

Focal adhesion complexes function as the mediators of cell-extracellular matrix interactions to sense and transmit the extracellular signals. Previous studies have demonstrated that cardiomyocyte focal adhesions can be modulated by surface topographic features. However, the response of focal adhesions to dynamic surface topographic changes remains underexplored. To study this dynamic responsiveness of focal adhesions, we utilized a shape memory polymer-based substrate that can produce a flat-to-wrinkle surface transition triggered by an increase of temperature. Using this dynamic culture system, we analyzed three proteins (paxillin, vinculin and zyxin) from different layers of the focal adhesion complex in response to dynamic extracellular topographic change. Hence, we quantified the dynamic profile of cardiomyocyte focal adhesion in a time-dependent manner, which provides new understanding of dynamic cardiac mechanobiology.

The exploration of magnetism in two-dimensional layered materials has attracted extensive research interest. For the monoclinic phase CrI3 with interlayer antiferromagnetism, finding a static and robust way of realizing the intrinsic interlayer ferromagnetic coupling is desirable. In this work, we study the electronic structure and magnetic properties of the nonmagnetic element (e.g., O, S, Se, N, P, As, and C) doped bi-and triple-layer CrI3 systems via first-principles calculations. Our results demonstrate that O, P, S, As, and Se doped CrI3 bilayer can realize interlayer ferromagnetism. Further analysis shows that the interlayer ferromagnetic coupling in the doped few-layer CrI3 is closely related to the formation of localized spinpolarized state around the doped elements. Further study presents that, for As-doped tri-layer CrI3, it can realize interlayer ferromagnetic coupling. This work proves that nonmagnetic element doping can realize the interlayer ferromagnetically-coupled few-layer CrI3 while maintaining its semiconducting characteristics without introducing additional carriers. [ABSTRACT FROM AUTHOR]

When planned metro disruptions occur, the connectivity of the metro network is severely reduced, impacting the travel of a large number of commuters. The duration of planned metro disruptions varies from a few days to several weeks. To ensure the quality of public transportation services during this period, we propose a bus bridging strategy to address the travel issues of disrupted passengers. This paper introduces a mathematical model for the timetable and bus scheduling of bus bridging when a section of a metro line is planned for disruption, considering two types of buses. In this model, regular buses transfer disrupted passengers whose original destinations are on the disrupted metro section, whereas shuttle buses transfer disrupted passengers whose destinations are on the normal metro line. The model takes into account the impact of metro disruptions on the original passengers of regular buses and aims to minimize passenger transfer waiting time and congestion disutility. The model is solved using a commercial solver and is validated with the case study of Beijing Bus No. 16 and a hypothetical metro line. The results demonstrate that metro disruptions have a significant negative impact on the transfer waiting time and congestion disutility of regular buses. However, the timetable generated by the model effectively mitigates this impact. Additionally, the shuttle bus scheduling solutions generated by the model are not unique, and a specific schedule can be determined based on the shuttle bus costs and service quality. Both the crowding threshold of buses and the maximum number of pickups can reduce the congestion disutility of shuttle buses, but the impact of the crowding threshold is more significant. Practical Applications: This study introduces a model to manage the evacuation of metro commuters during planned service disruptions, such as maintenance closures, announced in advance with a set disruption plan and duration. The model employs a coordinated strategy involving both regular buses and dedicated shuttle buses to evacuate affected passengers efficiently while minimizing disruptions to regular bus passengers. Case study results demonstrate that, although metro disruptions significantly impact regular bus passengers, the optimized timetable developed by the model can alleviate these effects. Passenger waiting time and congestion disutility are developed as key performance indicators. Future applications of this model extend beyond metro disruptions to encompass a wide range of urban transit challenges. For instance, the model can be adapted to manage passenger flow during major city events, natural disasters, or unexpected infrastructure failures. By providing a flexible and scalable framework, this model can support urban planners and transit authorities in enhancing resilience and efficiency in their public transportation systems, ultimately reducing the impact of transit disruptions on daily life. [ABSTRACT FROM AUTHOR]

Most α2-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed virtual screening for human α2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity. Compound P300–2342 and its three analogs significantly decreased the locomotor activity of mice (p < 0.05). Furthermore, P300–2342 and its three analogs inhibited the binding of [3H] Rauwolscine with IC50 values of 7.72 ± 0.76 and 12.23 ± 0.11 μM, respectively, to α2A-AR and α2B-AR. In α2A-AR-HEK293 cells, P300–2342 decreased forskolin-stimulated cAMP production without increasing cAMP production, which indicated that P300–2342 activated α2A-AR with coupling to the Gαi/o pathway but without Gαs coupling. P300–2342 exhibited no agonist but slight antagonist activities in α2B-AR. Similar results were obtained for the analogs of P300–2342. The docking results showed that P300–2342 formed π-hydrogen bonds with Y394, V114 in α2A-AR, and V93 in α2B-AR. Three analogs of P300–2342 formed several π-hydrogen bonds with V114, Y196, F390 in α2A-AR, and V93 in α2B-AR. We believe that these molecules can serve as leads for the further optimization of α2A-AR agonists with potentially few side effects. [ABSTRACT FROM AUTHOR]

The α2A adrenergic receptor (α2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α2A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 μM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the α2A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were −45.93 and −71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics. [ABSTRACT FROM AUTHOR]