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The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.

Timely and accurately identification of the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can greatly contribute to monitoring and controlling the global pandemic. This study gained theoretical insight into a novel phase-modulation plasmonic biosensor working in the near-infrared (NIR) regime, which can be employed for sensitive detection of SARS-CoV-2 and its spike (S) glycoprotein. The proposed plasmonic biosensor was created by integrating two-dimensional (2D) Van der Waals heterostructures, including tellurene and carboxyl-functionalized molybdenum disulfide (MoS2) layers, with transparent indium tin oxide (ITO) film. Excellent biosensing performance can be achieved under the excitation of 1550 nm by optimizing the thickness of ITO film and tellurene-MoS2 heterostructures. For a sensing interface refractive index change as low as 0.0012 RIU (RIU, refractive index unit), the optimized plasmonic configuration of 121 nm ITO film/three-layer tellurene/ten-layer MoS2-COOH can produce the highest detection sensitivity of 8.4069 × 104 degree/RIU. More importantly, MoS2–COOH layer can capture angiotensin-converting enzyme II, which is an ideal adsorption site for specifically binding SARS-CoV-2 S glycoprotein. Then, an excellent linear detection range for S glycoprotein and SARS-CoV-2 specimens is ∼0–301.67 nM and ∼0–67.8762 nM, respectively. This study thus offers an alternative strategy for rapidly performing novel coronavirus diagnosis in clinical applications.

Summary An energy dissipation factor was proposed to quantify the energy dissipation mechanism of particle dampers based on theoretical analysis and was further validated by free vibration tests and wind tunnel tests. The vibration energy of the main structure was consumed by impact and friction between particles and between particles and the container. An elastoplastic collision model and a simplified frictional‐elastic collision model were used to analyze the energy dissipation due to impact and friction, respectively. Then, an energy dissipation factor, reflecting the vibration energy consumption of a particle damper, was defined. Finally, free vibration tests and aero‐elastic wind tunnel tests of a benchmark model unattached or attached with particle dampers were conducted to validate the relationship between the vibration reduction performances and the energy dissipation factors, and the experimental results were in qualitative agreement with the theoretical results. Consequently, the energy dissipation factor indicated the energy dissipation mechanism of particle dampers and can be used to select the proper material of the particles, helping to maximize the vibration control effects from the material's perspective. It was shown that the material of higher kinetic friction coefficient, higher modulus of elasticity, and lower yield strength usually leads to better energy dissipation effects.

Summary A particle tuned mass damper system is an integration of tuned mass damper and particle damper. The damping performance of such device is investigated by an aero‐elastic wind tunnel test on a benchmark high‐rise building. The robustness of the system is studied by comparing the damping performance to that of a traditional tuned mass damper, and the results show that the damper has excellent and steady wind‐induced vibration control effects. Meanwhile, the parameters (filling ratio, mass ratio, and mass ratio of the container to particles), which have great influence on the vibration reduction performance of the system, are also analyzed, and it is found that the particles filling ratio plays the most important role in deciding the damping effects of the dampers. There exists an optimum filling ratio and mass ratios in which the damper can reach the best damping state. Proper parameter selections can greatly improve the damping performance.

In this study, a new type of viscoelastic (VE) damper with strong nonlinear characteristics, showing both softening and hardening, is investigated. Firstly, its performance tests are executed, and its mechanical properties summarized. Then, a shaking table test on a three-story viscoelastically damped structure is designed to investigate the dissipation characteristics and control effect of this type of VE damper. Six VE dampers were installed in pairs at each story and connected vertically to the upper and lower beams. The structure with additional VE dampers and that without additional VE dampers was subjected to three ground motions whose peak ground accelerations varied from 0.1 to 0.6 g. The experimental results indicate that the control effect on the displacements was remarkable, while the effect on accelerations and shear forces was limited, due to the damper's additional stiffness. With the increment of the damper deformation, the additional stiffness decreased, while the additional effective damping ratio increased at first and then declined. Finally, a simplified analytical method is proposed and applied to simulate the shaking table test using OpenSees. The simulating results validate the analytical method of this type of VE damper.

GPCRs are responsible for most cytoplasmic signaling in response to extracellular ligands with different efficacy profiles. Various spectroscopic techniques have identified that agonists exhibiting varying efficacies can selectively stabilize a specific conformation of the receptor. However, the structural basis for activation of the GPCR-G protein complex by ligands with different efficacies is incompletely understood. To better understand the structural basis underlying the mechanisms by which ligands with varying efficacies differentially regulate the conformations of receptors and G proteins, we determined the structures of β2AR-Gαs$\beta $γ bound with partial agonist salbutamol or bound with full agonist isoprenaline using single-particle cryo-electron microscopy at resolutions of 3.26 Å and 3.80 Å, respectively. Structural comparisons between the β2AR-Gs-salbutamol and β2AR-Gs-isoprenaline complexes demonstrated that the decreased binding affinity and efficacy of salbutamol compared with those of isoprenaline might be attributed to the weakened hydrogen bonding interactions, attenuated hydrophobic interactions in the orthosteric binding pocket and different conformational changes in the rotamer toggle switch in TM6. Moreover, the observed stronger interactions between the intracellular loop 2 or 3 (ICL2 or ICL3) of β2AR and Gαs with the binding of salbutamol versus isoprenaline might decrease phosphorylation in the salbutamol-activated β2AR-Gs complex. From the observed structural differences between these complexes of β2AR, a mechanism of β2AR activation by partial and full agonists is proposed to shed structural insights for β2AR desensitization.

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