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Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets 1 – 5 . Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development 6 , 7 . Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G s ) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G s . 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. A study reports an orally available small-molecule agonist that binds between a G protein and its receptor, and characterizes this new binding mode.

High-pressure direct injection diesel/methanol dual-fuel engines exhibit excellent emission reduction potential, but they are still in the initial stage of research and development. The influences of different methanol injection locations, injection duration, and injection pressures on combustion characteristics, mixture homogeneity, and exhaust emissions are investigated to explore appropriate injection strategies and further optimize the engine performance base using CONVERGE software. The results show that the impact of the methanol injection position on the engine is relatively small, especially on combustion characteristics. A larger axial nozzle distance contributes to the formation of the homogeneous mixture, improving the engine economy. However, the engine performance is remarkably affected by methanol injection duration and methanol injection pressure. A shorter combustion duration is achieved with a decrease in the methanol injection duration and an increase in the methanol injection pressure, as a result of which the fuel economy is improved, with the combustion process more concentrated near the top dead center. Simultaneously, the mixture homogeneity is enhanced, which is conducive to a reduction in soot and CO emissions, yet not to a NOX and HC reduction. The lowest overall emissions of NOX, soot, CO, and HC are achieved when the radial nozzle distance and axial nozzle distance are 2.5 mm and 0.5 mm, respectively. Besides, the combustion characteristics and emissions of the engine are affected significantly under different methanol injection locations and injection pressures. The increased injection interval leads to deteriorating combustion characteristics and economy, i.e., a delayed combustion phase (CA50), an extended ignition delay and combustion duration (CA10–CA90), thereby increasing CO and soot emissions, but decreasing NOX emission. Additionally, the optimal economy and exhaust emissions are obtained when adopting an injection duration of 6 °CA and an injection pressure of 44.4 MPa. The ITE is increased in this case compared to the other injection strategies, thereby improving the engine performance significantly. The results provide parametric feedback and theoretical support for the design of high-pressure direct injection diesel/methanol dual-fuel engines from a time and space perspective, which has certain theoretical significance.

Perovskite quantum dots (PQDs) require ligands on their surfaces to passivate defects and prevent aggregation. However, the ligands construct the interface relationship between the PQDs, which may seriously hinder the carrier transport. Hence, we propose a molecular engineering strategy of using 3,4-ethylenedioxythiophene (EDOT) to perfectly solve this problem, benefiting from its high conjugation and passivation ability to CsPbBr 3 PQDs. Furthermore, EDOT on the surface of PQDs can be in-situ polymerized under the photocurrent of the photodetector, thus interconnecting the PQDs which enhanced the performance of the photodetectors up to 178% of its initial performance. We have thoroughly investigated the electropolymerization process of EDOT and its passivation effect on PQDs. The simple lateral photodetector based on EDOT PQDs exhibits a high responsivity of 11.96 A/W, which is 10 4 times higher than that of oleic acid caped PQDs. Due to the protection of poly(3,4-ethylenedioxythiophene) (PEDOT), the photodetector prepared from EDOT PQDs exhibited very high stability, retaining 94% of its performance after six months in air. This strategy provides a solution for the application of PQDs in high performances and stable optoelectronic devices.

On May 12, 2008, a destructive earthquake registering 8.0 on the Richter scale struck Sichuan Province, southwest China. Beichuan County was the epicenter which was one of the areas nearly completely destroyed by the earthquake. In Beichuan, about 15000 people died and 3000 people were missing. Specially, the earthquake took 1587 students' and 214 teachers' lives from the elementary and middle schools there. The main purpose of the study was to provide a better understanding of mental health problems and associated risk factors among children after earthquake. Three hundred and thirty grades 3-5 children completed the questionnaire of disaster -related experience and the Trauma Symptom Checklist for Children-Alternate Version (TSCC-A). The first survey was carried out six months after the earthquake, and the second one was carried out six months later. The measurements and methodology applied in the two sessions were identical. The prevalence rates of the problems at two time-points were 23.3% and 22.7% for anxiety, 14.5% and 16.1% for depression, and 11.2% and 13.4% for PTSD, respectively. Among demographic variables, no significant age difference existed, while it was found that 6 months after the earthquake, symptoms of anxiety, depression and PTSD were significantly more common among students in grades 4 and 5 than those in grade 3, Initial exposure to death, bereavement and extreme fear were significant predictive factors for the occurrence of anxiety, depression and PTSD. Findings of this study suggest that posttraumatic mental health problems after natural disaster in children may have reached epidemic proportions and remain high for a long period. Psychologist and social workers should pay more attention to children who experienced more traumatic stresses and provide appropriate mental health interventions. Implications and limitations of these findings were discussed.

The particle breakage of calcareous sands plays a key role in determining the particle shape and shear strength. This process has been analysed in the current study by employing the ring shear tests on calcareous sands sampled from the South China Sea. In this study, a set of parameters, e.g. roundness and aspect ratio, have been employed to quantify the geometrical properties of calcareous sands pre- and after the breakage. These two parameters have been found to correlate well with the vertical loading stress level, shear strain and shear strength. The particle breakage leads to the change of micro-structure during the shear test, as illustrated by the Scanning Electron Microscopy (SEM) images. It is found that during the shearing deformation, particle breakages can effectively reduce, while particle rearrangements can increase the shear strength of the calcareous sands.

Coral sand is the main filling material for the island–reef foundation. Under tidal actions, the saturation (Sr) of coral sand layers varies with the specific depths in the reclaimed foundation. Studying the Sr effect of coral sand’s mechanical behaviors is crucial for the stability of the reclaimed foundation of island–reefs. In this study, a “quantitative injection method” was designed to prepare coral sand with saturation ranging from 90% to 100%, and unconsolidated–undrained (UU) triaxial shear tests were conducted on coral sand under different effective confining pressures (σ3′). The results indicated that the stress–strain curves of coral sand under various conditions were of the strain-softening type. When σ3′ = 200, 400, 600, and 800 kPa, the shear strength of coral sand decreased exponentially by 13.1, 9.1, 16.8, and 15.2%, respectively, with the increase in Sr from 90% to 100%. As Sr rose, the internal friction angle (φ) dropped by 3.77°. The cohesion (c) was not significantly affected by Sr compared to φ. In consideration of the physical susceptibility of coral sand to breakage, relative breakage ratio (Br) and modified relative breakage index (Br*) were introduced to evaluate the particle breakage behaviors of coral sand samples with different Sr levels in the triaxial shear process. It was found that Br and Br* increase linearly with increasing Sr; the effect of Sr on the particle breakage of coral sand weakens significantly when σ3′ is sufficiently large. The median particle size (d50) of coral sand decreases with increasing Sr, and presents a negative linear correlation with both Br and Br*. Based on comparing the strength and particle breakage characteristics of coral sand samples with varying Sr levels, this study suggests that 92.5% should be considered as the Sr value of coral sand available for testing.

Electrochemical nitrate‐to‐ammonia conversion powered by sustainable green electricity is a promising supplement to the traditional Haber–Bosch process, but it remains limited by low NH3 yield and Faradaic efficiency (FE). Herein, we report the synthesis and performance of a Cu2O/Cu(OH)2@Ni(OH)2 heterostructure catalyst. The interface exploits strong electronic interactions between Cu and Ni species, promoting efficient NO3− adsorption and accelerating in situ water dissociation for hydrogenation steps. In an H‐cell, the catalyst achieved an FE of 99.6 % with an NH3 yield of 1.14 mmol h−1 mg cat−1, while a flow electrolyzer maintained 97.9 % efficiency and 17.13 mmol h−1 mg cat−1 at −600 mA cm−2. Via density functional theory (DFT) calculations and in situ characterization, the interface uses strong Cu–O–Ni electronic interactions to boost efficient NO3− adsorption and accelerate in situ water dissociation for hydrogenation steps. When integrated as a cathode into a Zn‐NO3− hybrid battery, the material served as a high‐performance cathode. The resulting battery's open‐circuit voltage reached 1.45 V, while its power density peaked at 6.47 mW cm−2. The integrated device continuously produced 2.78 mg h−1 cm−2 of NH3 with 93.6 % FE and exhibited robust stability (<2 % voltage decay over 24 h). The strong Cu–O–Ni electronic interaction in the heterostructured catalyst can enhance the effective adsorption of NO3− and accelerate the in situ hydrolysis dissociation of the hydrogenation step. The Zn‐NO3 hybrid battery assembled with this catalyst achieves an open‐circuit voltage of 1.45 V, a peak power density of 6.47 mW cm−2, and can continuously produce NH3 at a rate of 2.78 mg h−1 cm−2 with FE of 93.6 %.

The hypothalamus-pituitary-target gland axis is thought to be linked with insomnia, yet there has been a lack of further systematic studies to prove this. This study included 30 patients with primary insomnia (PI), 30 patients with depression-comorbid insomnia (DCI), and 30 healthy controls for exploring the alterations in the hypothalamus-pituitary-adrenal/thyroid axes' hormones and gonadotropin-releasing hormone (GnRH). The Pittsburgh Sleep Quality Index was used to evaluate sleep quality in all subjects. The serum concentrations of corticotrophin-releasing hormone (CRH), thyrotrophin-releasing hormone (TRH), GnRH, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), cortisol, total triiodothyronine (TT3), and total thyroxine (TT4) in the morning (between 0730 h and 0800 h) were detected. Compared to the controls, all hormonal levels were elevated in the insomniacs, except ACTH and TSH in the PI group. Compared to the DCI patients, the PI patients had higher levels of CRH, cortisol, TT3, and TT4 but lower levels of TRH, GnRH, and ACTH. Spearman's correlation analysis indicated that CRH, TRH, GnRH, TSH, cortisol, TT4, and TT3 were positively correlated with the severity of insomnia. The linear regression analysis showed that only CRH, GnRH, cortisol, and TT3 were affected by the PSQI scores among all subjects, and only CRH was included in the regression model by the \"stepwise\" method in the insomnia patients. Our results indicated that PI patients may have over-activity of the hypothalamus-pituitary-adrenal/thyroid axes and an elevated level of GnRH in the morning.

To further understand the influence of n-heptane on the ignition process of ammonia, an isotope labeling method was applied in the current investigation to decouple the influence of the chemical effect, the thermal effect, and the effect of O radical from the oxidation of n-heptane on the ignition delay times (IDTs) of ammonia. An analysis of the time evolution of fuel, analysis of the time evolution of temperature, rate of consumption and production (ROP) analysis, and sensitivity analysis were conducted to gain a further understanding of the mechanism of the influence of the chemical effect, the thermal effect, and the effect of O radical on the ignition of ammonia. The results showed that the negative temperature coefficient (NTC) behavior of n-heptane is mitigated by the blending of ammonia, and this mitigated effect of ammonia is mainly due to the chemical effect. The IDTs of ammonia under low and medium temperatures are significantly shortened by the chemical effect at a n-heptane mass fraction of 10%. The promoting effect of the chemical effect decreases when the n-heptane mass fraction increases. The time evolution of n-heptane for NC7H16/ND3-G can be classified into three stages at 800 K, and the rapid consumption stage is mitigated by an increase in temperature. The rapid consumption stage is suppressed by the chemical effect of ammonia, while O radical has a promoting effect on the rapid consumption stage. The chemical effect will enhance the sensitivities of reactions associated with ammonia. As the n-heptane mass fraction increases, the sensitivities of reactions associated with n-heptane are enhanced. Correspondingly, the effect of reactions associated with ammonia is weakened. When the n-heptane mass fraction is 30%, only reactions related to n-heptane have a great influence on the ignition of ammonia/n-heptane fuel blends under the thermal effect + the effect of O radical or only the thermal effect.

The role of phosphodiesterase 3 (PDE3), a cyclic AMP (cAMP)-degrading enzyme, in modulating gluconeogenesis remains unknown. Here, linderane, a natural compound, was found to inhibit gluconeogenesis by activating hepatic PDE3 in rat primary hepatocytes. The underlying molecular mechanism and its effects on whole-body glucose and lipid metabolism were investigated. The effect of linderane on gluconeogenesis, cAMP content, phosphorylation of cAMP-response element-binding protein (CREB) and PDE activity were examined in cultured primary hepatocytes and C57BL/6J mice. The precise mechanism by which linderane activates PDE3 and inhibits the cAMP pathway was explored using pharmacological inhibitors. The amelioration of metabolic disorders was observed in mice. Linderane inhibited gluconeogenesis, reduced phosphoenolpyruvate carboxykinase ( ) and glucose-6-phosphatase ( ) gene expression, and decreased intracellular cAMP concentration and CREB phosphorylation in rat primary hepatocytes under both basal and forskolin-stimulated conditions. In rat primary hepatocytes, it also increased total PDE and PDE3 activity but not PDE4 activity. The suppressive effect of linderane on the cAMP pathway and gluconeogenesis was abolished by the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the specific PDE3 inhibitor cilostazol. Linderane indirectly activated PDE3 through extracellular regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) activation. Linderane improved glucose and lipid metabolism after chronic oral administration in mice. Our findings revealed linderane as an indirect PDE3 activator that suppresses gluconeogenesis through cAMP pathway inhibition and has beneficial effects on metabolic syndromes in mice. This investigation highlighted the potential for PDE3 activation in the treatment of type 2 diabetes.