Conserved class B GPCR activation by a biased intracellular agonist.

Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets1-5. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development6,7. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (Gs) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with Gs. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications.

GPCR activation and GRK2 assembly by a biased intracellular agonist.

Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands1-6. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gαq and the arrestin-biased ligand SBI-5537. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gαq protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR-GRK interactions and GRK2-mediated biased signalling.

Three-directional digital shearography based on SLM using a honeycomb-like pattern.

The possibility of utilizing a honeycomb-like modulation pattern in a spatial light modulator (SLM) for multi-directional synchronous digital shearography measurements has been investigated. Each modulation pixel in the honeycomb-like pattern modulates the shearing amount in different directions, thus avoiding the resolution loss associated with previous methods where a single pixel could only modulate a specific shearing direction. It was demonstrated that high-quality phase maps for different shearing directions can be simultaneously obtained with a single exposure.

AI-driven antibody design with generative diffusion models: current insights and future directions.

Therapeutic antibodies are at the forefront of biotherapeutics, valued for their high target specificity and binding affinity. Despite their potential, optimizing antibodies for superior efficacy presents significant challenges in both monetary and time costs. Recent strides in computational and artificial intelligence (AI), especially generative diffusion models, have begun to address these challenges, offering novel approaches for antibody design. This review delves into specific diffusion-based generative methodologies tailored for antibody design tasks, de novo antibody design, and optimization of complementarity-determining region (CDR) loops, along with their evaluation metrics. We aim to provide an exhaustive overview of this burgeoning field, making it an essential resource for leveraging diffusion-based generative models in antibody design endeavors.

High-temperature thermal disturbance elimination method based on multi-channel extraction and correction.

Digital image correlation (DIC) technology has been widely used in high-temperature measurement fields. However, due to the complexity of high-temperature environments, there are many interference factors that limit the development of high-temperature DIC technology, among which thermal disturbance is one of the most significant factors that severely affects the measurement accuracy of high-temperature DIC. In this paper, a multi-channel separation technique combined with a low-cost laser speckle device is proposed to eliminate thermal disturbance errors in high-temperature DIC measurements. First, a blue laser speckle generation system is independently designed to produce the most suitable speckle particles, and the best laser speckle is determined and projected onto the blue background white spot pattern. Then a green LED illuminates the sample to provide illumination for the sample's own grayscale characteristics. A color camera collects photos, and the obtained images are processed with channel separation to extract and calculate the displacement of different channels. Finally, the displacement fields of the green and blue channels are subtracted to separate the thermal disturbance error and correct the measurement values. In this paper, a laser speckle projection system is first assembled, followed by a comprehensive evaluation of the projected speckle and, finally, a DIC experimental system is constructed for verification experiments at both room temperature and high temperature, and the corrected values are compared with the true values. The results show that the corrected values are highly consistent with the true values, which verifies the reliability of the proposed method.

Application of line-scan CMOS camera in multi-beam heterodyne differential laser Doppler vibration sensor.

The possibility of using a line-scan digital CMOS camera as a photodetector in a multi-beam heterodyne differential laser Doppler vibration sensor has been investigated. Application of the line-scan CMOS camera allows for selection of a different number of beams for a particular application in the sensor design, and for a compact design of the sensor. It was demonstrated that a limitation of the maximum measured velocity caused by the camera limited line rate can be overcome by selecting the beams separation on the object and the value of shear between images on the camera.

Rapid one-shot dual-shearing digital shearography using a spatial light modulator.

Digital shearography is a non-contact, whole-field, and high-accuracy laser-based optical interferometric method. It is widely used in the field of non-destructive testing and material evaluation. Dual-shearing DS, as the state-of-the-art method, can detect defects or measure the derivative of deformation in two sensitive directions. Most existing dual-shearing DS is realized with a bulky Michelson or Mach-Zehnder interferometer; recently, the usage of a spatial light modulator (SLM) in DS offers a new approach to designing a simple and light shearographic system. However, prior proposed SLM-based DS requires multiple shots for the phase map acquisition, with the classic temporal phase-shift (TPS) technique severely limiting its applications. This paper proposes a novel, to our best knowledge, one-shot dual-shearing DS by creating a dual-stripe pattern in the SLM. Two separate phase maps, with different sensitive directions, were acquired simultaneously via the spatial phase-shift technique. The measurement can be easily done within a single shot in its compact and light body. Moreover, the shearing amount of the two sensitive directions can be set independently and precisely. These advantages promote that the proposed system can be applied in various applications, especially for dynamic and complicated composite material testing. A detailed theory and experimental validation are described.

circSKA3 acts as a sponge of miR-6796-5p to be associated with outcomes of ischemic stroke by regulating matrix metalloproteinase 9 expression.

BACKGROUND AND PURPOSE: This study was undertaken to screen the circular RNAs (circRNAs) influencing matrix metalloproteinase 9 (MMP9) through the competing endogenous RNA (ceRNA) network and evaluate the prognostic value of these circRNAs for acute ischemic stroke. METHODS: A total of 220 ischemic stroke patients and 62 healthy subjects were included in this study. RNA was isolated from blood collected in PAXgene tubes. Illumina sequencing, quantitative real-time polymerase chain reaction (qRT-PCR) validation, and luciferase reporter assay were explored to construct and verify the existence of a circRNA-microRNA (miRNA)-matrix metalloproteinase-9 (MMP9) network. The 215 ischemic stroke patients were recruited in a prognostic cohort. They were prospectively followed up for 3 months after stroke onset, and a poor functional outcome was defined as a major disability or death. RESULTS: After Illumina sequencing, six circRNAs were predicted to bind miRNAs and then regulate MMP9 messenger RNA (mRNA). qRT-PCR showed that only circSKA3 was significantly increased in ischemic stroke patients compared to healthy controls and positively associated with MMP9 mRNA expression. Luciferase reporter assay further verified a direct interaction between circSKA3, MMP9, and hsa-miR-6796-5p. Patients in the top tertile of circSKA3 had a 2.672-fold (p < 0.05) risk of poor functional outcome, compared with those in the bottom tertile (p for trend = 0.016). The outcome was predicted by circSKA3 with area under the receiver operating characteristic curve at 0.614 (p = 0.004). CONCLUSIONS: circSKA3 functioned as a ceRNA for hsa-miR-6796-5p to aggravate the progression of ischemic stroke via targeting MMP9. Baseline circSKA3 was positively associated with poor outcomes of ischemic stroke. circSKA3 may be a potential biomarker or therapeutic target in ischemic stroke.

Multi-beam heterodyne laser Doppler vibrometer based on a line-scan CMOS digital camera.

Multi-beam laser Doppler vibrometers (MB-LDVs) have an advantage over scanning single-beam laser Doppler vibrometers (LDVs) due to the reduction in measurement time and their ability to measure non-stationary and transient events. However, the number of simultaneously interrogated points in current MB-LDVs is limited due to the complexity of the electronic hardware, which increases with the number of measurement channels. Recent developments of high-speed line-scan CMOS cameras suggest that their use in MB-LDVs can reduce the hardware complexity and increase the number of measurement channels. We developed a MB-LDV based on a digital line-scan CMOS camera that simultaneously measures vibrations on a linear array of 99 points. The experimental setup and performance of the developed MB-LDV are discussed in this paper.

Exceptional Selectivity to Olefins in the Deoxygenation of Fatty Acids over an Intermetallic Platinum-Zinc Alloy.

Direct deoxygenation of long-chain fatty acids can produce both saturated alkanes (Cn H2n+2 ) and unsaturated olefins (Cn H2n ). However, the selectivity for the production of olefins via the decarbonylation route is relatively low because of the more favorable decarboxylation pathway. We present an atomically ordered intermetallic PtZn alloy on carbon catalyst (PtZn/C) with a record-high total selectivity (97 %) for undecane (C11 H24 ) and undecene (C11 H22 ) in the deoxygenation of lauric acid (C12 H24 O2 ). Interestingly, the selectivity for C11 H22 is as high as 67.0 % on PtZn/C, which is significantly higher than that of 27.5 % obtained on the Pt/C counterpart under the same reaction conditions. Characterization and theoretical calculation results reveal that the intermetallic PtZn alloy not only inhibits the decarboxylation route by increasing the energy barrier of -COO* cleavage, but also facilitates the decarbonylation route by decreasing CO desorption energy, and therefore the major product is switched from alkanes to olefins.

Anisotropic Strain Tuning of L10 Ternary Nanoparticles for Oxygen Reduction.

Tuning the performance of nanoparticle (NP) catalysts by controlling the NP surface strain has evolved as an important strategy to optimize NP catalysis in many energy conversion reactions. Here, we present our new study on using an eigenforce model to predict and experiments to verify the strain-induced catalysis enhancement of the oxygen reduction reaction (ORR) in the presence of L10-CoMPt NPs (M = Mn, Fe, Ni, Cu, Ni). The eigenforce model allowed us to predict anisotropic (that is, two-dimensional) strain levels on distorted Pt(111) surfaces. Experimentally, by preparing a series of 5 nm L10-CoMPt NPs, we could push the ORR catalytic activity of these NPs toward the optimum region of the theoretical two-dimensional volcano plot predicted for L10-CoMPt. The best ORR catalyst in the alloy NP series we studied is L10-CoNiPt, which has a mass activity of 3.1 A/mgPt and a specific activity of 9.3 mA/cm2 at room temperature with only 15.9% loss of mass activity after 30 000 cycles at 60 °C in 0.1 M HClO4.

Intermetallic Nanoparticles: Synthetic Control and Their Enhanced Electrocatalysis.

Intermetallic nanoparticles (NPs) described in this Account are a class of metallic alloy NPs within which metal atoms are bonded via strong d-orbital interaction and ordered anisotropically in a specific crystallographic direction. Compared to the common metallic alloy NPs with solid solution structure, intermetallic NPs are generally more stable against chemical oxidation and etching. The strict stoichiometry requirement, well-defined atom binding environment and layered atomic arrangement also make intermetallic NPs an ideal model for understanding their physical and catalytic properties. This account summarizes the synthetic principles and strategies developed to obtain monodisperse intermetallic NPs, especially tetragonal L10-NPs. The thermodynamics and kinetics involved in the conversion between disordered and ordered structures are briefly discussed. The synthetic methods are grouped into two slightly different categories: solution-phase synthesis followed by solid state annealing and direct solution-phase synthesis. In the former method, high-surface-area supports are often needed to disperse NPs and to prevent them from aggregation, while in the latter method such supports are not required since the structure conversion temperature is lowered to a level that the conversion can proceed in the solution reaction condition. In any of these two synthetic approaches, various factors influencing intermetallic structure formation should be carefully controlled to ensure more complete structural transition within NPs. Using representative synthetic examples, we highlight the strategies explored to facilitate the formation of intermetallic structure, including the introduction of vacancies/defects within NP structures and the control of atom addition rate/seed-mediated diffusion to lower the energy barrier. These strategies illustrate how the concept of thermodynamics and kinetics can be used to design the synthesis of intermetallic NPs. Additionally, to correlate NP structure and catalysis, we introduce briefly the d-band theory to explain how the electronic, strain and ensemble effects can be used to tune NP catalysis. We focus specifically on Pt-, Pd-, and Au-based L10-NPs and demonstrate how these L10-NPs could be prepared to show much enhanced catalysis for electrochemical reactions, including oxygen reduction reaction (ORR), hydrogen evolution reaction (HER), formic acid oxidation reaction (FAOR), and thermo-oxidation reaction of CO. Due to the enhanced metal atom stability in the "sandwich"-type structure, the roles of the first-row transition metal atoms in catalysis are better understood to achieve catalysis optimization. This concept can be extended to other alloy NPs, demonstrating great potentials in using intermetallic structures to control NP reduction and oxidation catalysis for important chemical and energy applications.

Cu3N Nanocubes for Selective Electrochemical Reduction of CO2 to Ethylene.

Understanding the Cu-catalyzed electrochemical CO2 reduction reaction (CO2RR) under ambient conditions is both fundamentally interesting and technologically important for selective CO2RR to hydrocarbons. Current Cu catalysts studied for the CO2RR can show high activity but tend to yield a mixture of different hydrocarbons, posing a serious challenge on using any of these catalysts for selective CO2RR. Here, we report a new perovskite-type copper(I) nitride (Cu3N) nanocube (NC) catalyst for selective CO2RR. The 25 nm Cu3N NCs show high CO2RR selectivity and stability to ethylene (C2H4) at -1.6 V (vs reversible hydrogen electrode (RHE)) with the Faradaic efficiency of 60%, mass activity of 34 A/g, and C2H4/CH4 molar ratio of >2000. More detailed electrochemical characterization, X-ray photon spectroscopy, and density functional theory calculations suggest that the high CO2RR selectivity is likely a result of (100) Cu(I) stabilization by the Cu3N structure, which favors CO-CHO coupling on the (100) Cu3N surface, leading to selective formation of C2H4. Our study presents a good example of utilizing metal nitrides as highly efficient nanocatalysts for selective CO2RR to hydrocarbons that will be important for sustainable chemistry/energy applications.

Chemical Synthesis of Magnetically Hard and Strong Rare Earth Metal Based Nanomagnets.

We report a general chemical approach to synthesize strongly ferromagnetic rare-earth metal (REM) based SmCo and SmFeN nanoparticles (NPs) with ultra-large coercivity. The synthesis started with the preparation of hexagonal CoO+Sm2 O3 (denoted as SmCo-O) multipods via decomposition of Sm(acac)3 and Co(acac)3 in oleylamine. These multipods were further reduced with Ca at 850 °C to form SmCo5 NPs with sizes tunable from 50 to 200 nm. The 200 nm SmCo5 NPs were dispersed in ethanol, and magnetically aligned in polyethylene glycol (PEG) matrix, yielding a PEG-SmCo5 NP composite with the room temperature coercivity (Hc ) of 49.2 kOe, the largest Hc among all ferromagnetic NPs ever reported, and saturated magnetic moment (Ms ) of 88.7 emu g-1 , the highest value reported for SmCo5 NPs. The method was extended to synthesize other ferromagnetic NPs of Sm2 Co17 , and, for the first time, of Sm2 Fe17 N3 NPs with Hc over 15 kOe and Ms reaching 127.9 emu g-1 . These REM based NPs are important magnetic building blocks for fabrication of high-performance permanent magnets, flexible magnets, and printable magnetic inks for energy and sensing applications.

Ternary CoPtAu Nanoparticles as a General Catalyst for Highly Efficient Electro-oxidation of Liquid Fuels.

Efficient electro-oxidation of formic acid, methanol, and ethanol is challenging owing to the multiple chemical reaction steps required to accomplish full oxidation to CO2 . Herein, a ternary CoPtAu nanoparticle catalyst system is reported in which Co and Pt form an intermetallic L10 -structure and Au segregates on the surface to alloy with Pt. The L10 -structure stabilizes Co and significantly enhances the catalysis of the PtAu surface towards electro-oxidation of ethanol, methanol, and formic acid, with mass activities of 1.55 A/mgPt , 1.49 A/mgPt , and 11.97 A/mgPt , respectively in 0.1 m HClO4 . The L10 -CoPtAu catalyst is also stable, with negligible degradation in mass activities and no obvious Co/Pt/Au composition changes after 10 000 potential cycles. The in situ surface-enhanced infrared absorption spectroscopy study indicates that the ternary catalyst activates the C-C bond more efficiently for ethanol oxidation.

Room-Temperature Chemoselective Reduction of 3-Nitrostyrene to 3-Vinylaniline by Ammonia Borane over Cu Nanoparticles.

We report a new strategy of controlling catalytic activity and selectivity of Cu nanoparticles (NPs) for the ammonia borane initiated hydrogenation reaction. Cu NPs are active and selective for chemoselective reduction of nitrostyrene to vinylaniline under ambient conditions. Their activity, selectivity, and more importantly, stability are greatly enhanced by their anchoring on WO2.72 nanorods, providing a room-temperature full conversion of nitrostyrene selectively to vinylaniline (>99% yield). Compared with all other catalysts developed thus far, our new Cu/WO2.72 catalyst shows much enhanced hydrogenation selectivity and stability without the use of pressured hydrogen. The synthetic approach demonstrated here can be extended to prepare various M/WO2.72 catalysts (M = Fe, Co, Ni), with M being stabilized for many chemical reactions.

Fe Stabilization by Intermetallic L10-FePt and Pt Catalysis Enhancement in L10-FePt/Pt Nanoparticles for Efficient Oxygen Reduction Reaction in Fuel Cells.

We report in this article a detailed study on how to stabilize a first-row transition metal (M) in an intermetallic L10-MPt alloy nanoparticle (NP) structure and how to surround the L10-MPt with an atomic layer of Pt to enhance the electrocatalysis of Pt for oxygen reduction reaction (ORR) in fuel cell operation conditions. Using 8 nm FePt NPs as an example, we demonstrate that Fe can be stabilized more efficiently in a core/shell structured L10-FePt/Pt with a 5 Å Pt shell. The presence of Fe in the alloy core induces the desired compression of the thin Pt shell, especially the two atomic layers of Pt shell, further improving the ORR catalysis. This leads to much enhanced Pt catalysis for ORR in 0.1 M HClO4 solution (at both room temperature and 60 °C) and in the membrane electrode assembly (MEA) at 80 °C. The L10-FePt/Pt catalyst has a mass activity of 0.7 A/mgPt from the half-cell ORR test and shows no obvious mass activity loss after 30 000 potential cycles between 0.6 and 0.95 V at 80 °C in the MEA, meeting the DOE 2020 target (<40% loss in mass activity). We are extending the concept and preparing other L10-MPt/Pt NPs, such as L10-CoPt/Pt NPs, with reduced NP size as a highly efficient ORR catalyst for automotive fuel cell applications.

Spatial phase-shift dual-beam speckle interferometry.

The spatial phase-shift technique has been successfully applied to an out-of-plane speckle interferometry system. Its application to a pure in-plane sensitive system has not been reported yet. This paper presents a novel optical configuration that enables the application of the spatial phase-shift technique to pure in-plane sensitive dual-beam speckle interferometry. The new spatial phase-shift dual-beam speckle interferometry (SPS-DBSP) uses a dual-beam in-plane electronic speckle pattern interferometry configuration with individual aperture shears, avoiding the interference in the object plane by the use of a low-coherence source, and different optical paths. The measured object is illuminated by two incoherent beams that are generated by a delay line, which is larger than the coherence length of the laser. The two beams reflected from the object surface interfere with each other at the CCD plane because of different optical paths. A spatial phase shift is introduced by the angle between the two apertures when they are mapped to the same optical axis. The phase of the in-plane deformation can directly be extracted from the speckle patterns by the Fourier transform method. The capability of SPS-DBSI is demonstrated by theoretical discussion as well as experiments.

Pd Nanoparticles Coupled to WO2.72 Nanorods for Enhanced Electrochemical Oxidation of Formic Acid.

We synthesize a new type of hybrid Pd/WO2.72 structure with 5 nm Pd nanoparticles (NPs) anchored on 50 × 5 nm WO2.72 nanorods. The strong Pd/WO2.72 coupling results in the lattice expansion of Pd from 0.23 to 0.27 nm and the decrease of Pd surface electron density. As a result, the Pd/WO2.72 shows much enhanced catalysis toward electrochemical oxidation of formic acid in 0.1 M HClO4; it has a mass activity of ∼1600 mA/mgPd in a broad potential range of 0.4-0.85 V (vs RHE) and shows no obvious activity loss after a 12 h chronoamperometry test at 0.4 V. Our work demonstrates an important strategy to enhance Pd NP catalyst efficiency for energy conversion reactions.

Maximizing the Catalytic Activity of Nanoparticles through Monolayer Assembly on Nitrogen-Doped Graphene.

We report a facile method for assembly of a monolayer array of nitrogen-doped graphene (NG) and nanoparticles (NPs) and the subsequent transfer of two layers onto a solid substrate (S). Using 3 nm NiPd NPs as an example, we demonstrate that NiPd-NG-Si (Si=silicon wafer) can function as a catalyst and show maximum NiPd catalysis for the hydrolysis of ammonia borane (H3 NBH3 , AB) with a turnover frequency (TOF) of 4896.8 h-1 and an activation energy (Ea ) of 18.8 kJ mol-1 . The NiPd-NG-S catalyst is also highly active for catalyzing the transfer hydrogenation from AB to nitro compounds, leading to the green synthesis of quinazolines in water. Our assembly method can be extended to other graphene and NP catalyst materials, providing a new 2D NP catalyst platform for catalyzing multiple reactions in one pot with maximum efficiency.