Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine.

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 inhibition in treating neurological disorders, the structural basis of channel inhibition by inhibitor has remained elusive. Here, we present the cryo-electron microscopy structure of human HCN1 channel in complex with inhibitor ivabradine, the drug on the market that acts on HCN channels. Combining electrophysiology, mutagenesis, and molecular dynamics simulations, our findings reveal that ivabradine binds to a previously unidentified pocket formed between the S4, S1, and HCN domain. Furthermore, through structure-based virtual screening, we identify two Food and Drug Administration-approved drugs that can inhibit the HCN1 channel by interacting with the ivabradine-binding site. Our results not only provide insights into the structural intricacies of ivabradine-mediated inhibition, but also offer a potential pharmacological framework for developing novel drugs targeting the HCN1 channel. The elucidation of these molecular interactions serves as a foundational step in advancing therapeutic strategies for modulating HCN1 activity, contributing to the broader landscape of drug discovery and development in this area.

Cryo-EM Structure and Biochemical Analysis of the Human Chemokine Receptor CCR8.

The C-C motif chemokine receptor 8 (CCR8) is a class A G-protein-coupled receptor that has emerged as a promising therapeutic target in cancer and autoimmune diseases. In the present study, we solved the cryo-electron microscopy (cryo-EM) structure of the human CCR8-Gi complex in the absence of a ligand at 2.58 Å. Structural analysis and comparison revealed that our apo CCR8 structure undergoes some conformational changes and is similar to that in the CCL1-CCR8 complex structure, indicating an active state. In addition, the key residues of CCR8 involved in the recognition of LMD-009, a potent nonpeptide agonist, were investigated by mutating CCR8 and testing the calcium flux induced by LMD-009-CCR8 interaction. Three mutants of CCR8, Y1133.32A, Y1724.64A, and E2867.39A, showed a dramatically decreased ability in mediating calcium mobilization, indicating their key interaction with LMD-009 and key roles in activation. These structural and biochemical analyses enrich molecular insights into the agonism and activation of CCR8 and will facilitate CCR8-targeted therapy.

Structural analysis of the human C5a-C5aR1 complex using cryo-electron microscopy.

The complement system is a complex network of proteins that plays a crucial role in the innate immune response. One important component of this system is the C5a-C5aR1 complex, which is critical in the recruitment and activation of immune cells. In-depth investigation of the activation mechanism as well as biased signaling of the C5a-C5aR1 system will facilitate the elucidation of C5a-mediated pathophysiology. In this study, we determined the structure of C5a-C5aR1-Gi complex at a high resolution of 3 Å using cryo-electron microscopy (Cryo-EM). Our results revealed the binding site of C5a, which consists of a polar recognition region on the extracellular side and an amphipathic pocket within the transmembrane domain. Furthermore, we found that C5a binding induces conformational changes of C5aR1, which subsequently leads to the activation of G protein signaling pathways. Notably, a key residue (M265) located on transmembrane helix 6 (TM6) was identified to play a crucial role in regulating the recruitment of ß-arrestin driven by C5a. This study provides more information about the structure and function of the human C5a-C5aR1 complex, which is essential for the proper functioning of the complement system. The findings of this study can also provide a foundation for the design of new pharmaceuticals targeting this receptor with bias or specificity.

Development of a Novel SPME Coating for Efficient Extraction of Organochlorine Pesticides in Liquid Dairy Products.

A sensitive and accurate analysis of organochlorine pesticide (OCP) residues in dairy products poses a significant challenge. Herein, a novel covalent organic polymer, Azo-COP-1, was synthesized for the enhanced extraction of OCPs in dairy products. The solid phase microextraction fiber coated with Azo-COP-1 demonstrated excellent extraction performance for the OCPs via hydrogen bonding, halogen bonding, π-π stacking, and electrostatic interactions. Coupled with gas chromatography-electron capture detection, we developed a facile and reliable method for detecting OCPs in six types of dairy products with low limits of detection (2.0-400 pg g-1) and high method recoveries (82.6-113%). Azo-COP-1 coatings exhibited good stability and durability. The results verified the feasibility of using Azo-COP-1-based SPME to extract OCP residues in dairy product samples, highlighting its potential for routine monitoring of pesticide residues and food safety assessments.

Precise Regulation of Interlayer Stacking Modes in Trinuclear Copper Organic Frameworks for Efficient Photocatalytic Reduction of Uranium(VI).

The interlayer stacking modes of 2D covalent-organic frameworks (COFs) directly influence their structural features, ultimately determining their functional output. However, controllably modulating the interlayer stacking structure in traditional 2D metal-free COFs, based on the same building blocks, remains challenging. Here, two trinuclear copper organic frameworks are synthesized successfully with different interlayer stacking structures: eclipsed AA stacking in Cu3-PA-COF-AA and staggered ABC stacking in Cu3-PA-COF-ABC, using the same monomers. Remarkably, various functionalities, including porosity and electronic and optical properties, can be effectively regulated by interlayer stacking. As a result, Cu3-PA-COF-AA and Cu3-PA-COF-ABC exhibit significantly different activities toward the photoreduction of U(VI), presenting a promising strategy for removing radioactive uranium pollution. Due to its broader visible-light absorption range and superior photogenerated carrier migration and separation efficiency, Cu3-PA-COF-AA achieves a U(VI) removal ratio of 93.6% without additional sacrificial agents in an air atmosphere-≈2.2 times higher than that of Cu3-PA-COF-ABC (42.0%). To the best of the knowledge, this is the first study to elucidate the effect of interlayer stacking in COFs on the photocatalytic activity of U(VI) reduction. This finding may inspire further exploration of the structure-function relationship in COFs as photocatalysts and their potential for photoinduced removal of radionuclides.

Single-Fe-Atom Catalyst for Sensitive Electrochemical Detection of Caffeic Acid.

A single-atom catalyst (Fe SAs/-N-C) with excellent stability and conductivity was strategically fabricated via high-temperature calcination using the NiFe layered double hydroxide (LDH)/ZIF-8 composite as precursors. With the help of Ni as a catalyst, a great number of carbon nanotubes were produced whereby the isolated carbon bulks were interconnected to form an "island-bridge"-like 3D network structure, which greatly enhanced the exposure of active sites and the electron transfer. Accordingly, caffeic acid (CA) with versatile biological and pharmacological activities was chosen as the model analyte. The Fe SAs/-N-C with Fe-N4 as the catalytic active site was employed to establish the electrochemical sensing of CA with satisfactory sensitivity, selectivity, and long-term stability. This work expands the application range of single-atom catalysts and contributes a significant reference for the synthesis of hybrid double-atom catalysts.

Association between Negative Life Events and Somatic Symptoms: A Mediation Model through Self-Esteem and Depression.

The purpose of this study was to investigate the serial multiple mediation of self-esteem and depression in the relationship between negative life events and somatic symptoms in Chinese medical students. We recruited a total of 3383 medical students for this study, and used the Patient Health Questionnaire-15 to assess the somatic symptoms of subjects; the Adolescent Self-Rating Life Events Check List to assess negative life events; the Rosenberg Self-Esteem Scale to assess self-esteem; and the Patient Health Questionnaire for depression. Descriptive analysis and statistical tests were then performed on the collected data. We showed that 39.17% of the medical students had mild somatic symptoms, 24.14% had moderate somatic symptoms, and 5.66% had severe somatic symptoms; we observed significant differences in somatic symptoms among genders, living expenses, and one-child. For negative life events, interpersonal stress was the most important predictor of somatization during the regression analysis. In addition, we observed significance for both the direct and part of the indirect paths from negative life events to somatic symptoms using mediation model analysis. However, we noted that there was no significance for the path through negative life events and self-esteem to somatic symptoms. This study revealed a high prevalence of somatic symptoms among Chinese medical students, and the findings suggested that interventions aimed at reducing somatization in this population should consider the impact of negative life events, particularly those related to interpersonal stress. One potential approach to mitigating the effects of negative life events on somatization is to enhance self-esteem and decrease the level of depression among medical students.

Molecular characterization of a chalcone synthase gene RhCHS from Rhododendron × hybridum Hort.

Chalcone synthase (CHS) plays a vital role in anthocyanin biosynthesis pathway, which is associated with petal color of flower. To date, lots of CHS genes have been obtained from plants, while few were from Rhododendron genus. In this study we got a new CHS gene named RhCHS (MW358095) from Rhododendron × hybridum Hort. It had a 2040 bp coding region consisting of two exons and one intron. By using the deduced RhCHS protein as a query sequence, 15 CHS homologous family genes with sequence similarity from 60% to 98%, designated as RgCHS-D(x), were retrieved from the genome assembly of Rhododendron griersonianum (RGv1.1) by TBlastN. 12 CHS family genes were found locating in No.9 chromosome arranged in clusters, while only 3 of them exhibited in No.1, 2, and 8 chromosomes, respectively. The results revealed gene duplication of CHS in evolutionary process. Multiple alignment of the deduced amino acid sequence of RhCHS showed high similarity of the active site, the catalytic residue, and the signature motif, the conserved characteristics of which were also exhibited in the tertiary structure prediction of the RhCHS, as well as the phylogenetic tree, all these demonstrated the RhCHS belonging to the type III PKS superfamily. HPLC-MS/MS of flower petals detected the total concentration of CC, DC, and PelC. These anthocyanidins showed an overall increasing trend during the flowering period and reached the peak in the full-blooming stage, which was consistence with the changeable rule of RhCHS expression level. The promoter, which was 1507 bp exhibiting high ß-glucuronidase (GUS) staining activity, was predicted containing many cis-acting elements, especially light and transcription factor such as bHLH, MYB, WRKY, Dof, and ERF. In short, this study may provide the help to Rhododendron × hybridum Hort. not only in the mechanism research of petals color exhibition, but also in molecular breeding of CHS practice value.

DFT Modeling of CO2 Adsorption and HCOO• Group Conversion in Anatase Au-TiO2-Based Photocatalysis.

Due to the merits of carbon circulation and hydrocarbon production, solar-assisted photocatalysis has been regarded as an ideal option for securing a sustainable future of energy and environment. In the photocatalytic carbon cycle process, surface reactions including the adsorption of CO2 and the conversion of CO2 into CH4, CH3OH, etc. are crucial to be examined ascribed to their significant influence on the performance of the photocatalysis. Because the conversion reaction starts from the formation of HCOO•, the density functional theory (DFT) model was established in this study to investigate the micromechanism of CO2 adsorption and the conversion of CO2 to HCOO• group in the anatase Au-TiO2 photocatalytic system. The CO2 adsorption bonding in six configurations was simulated, on which basis the effects of the proportion of water molecules and the lattice temperature increase due to the local surface plasmon resonance (LSPR) on the photocatalytic CO2 adsorption and conversion were specifically analyzed. The results show that the experimental conditions that water molecules are released before CO2 are favorable for the formation of the adsorption configuration in which HCOO• tends to be produced without the need of reaction activation energy. This is reasonable since the intermediate C atoms do not participate in bonding under these conditions. Moreover, Au clusters have an insignificant influence on the adsorption behaviors of CO2 including the adsorption sites and configurations on TiO2 surfaces. As a result, the reaction rate is reduced due to the temperature increase caused by the LSPR effect. Nevertheless, the reaction maintains a very high rate. Interestingly, configurations that require activation energy are also possible to be resulted, which exerts a positive influence of temperature on the conversion rate of CO2. It is found that the rate of the reaction can be improved by approximately 1-10 times with a temperature rise of 50 K above the ambient.

Review on LSPR assisted photocatalysis: effects of physical fields and opportunities in multifield decoupling.

Since nano scale local surface plasmon resonance (LSPR) can broaden the visible absorption region, enhance the local electromagnetic field and produce a thermal effect simultaneously, the appropriate utilization of the LSPR effect is a noteworthy research direction towards visible light driven photocatalysts with high efficiency and low cost. In this study, the influence mechanism of the optical, electric, magnetic, and thermal physical fields on the photocatalytic efficiency of the LSPR system is for the first time reviewed, based on which the research bottlenecks of this method including the accurate predesign and regulation of the photocatalyst, the interpretation of electron movement and energy transfer mechanism, are specifically analyzed. Due to the micro-nano localization of LSPR, auxiliary methods are needed to reflect the micro electromagnetic and temperature field distribution which are otherwise formidable to measure experimentally. Alternatively, numerical methods with decoupling calculations of nano-scale physical fields are necessary to develop. Therefore, the development potential of different numerical simulation methods including mainstream FDTD, FEM and DDA is subsequently expounded, providing opportunities in resolving the bottleneck issues associated with photocatalysis. It is worth mentioning that although many important advances have been achieved in the preparation and application of LSPR assisted photocatalysts, the convincing function mechanism of LSPR is still lacking due to its multifield synergistic enhancement effect.