Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Structural basis of amine odorant perception by a mammal olfactory receptor.

Odorants are detected as smell in the nasal epithelium of mammals by two G-protein-coupled receptor families, the odorant receptors and the trace amine-associated receptors1,2 (TAARs). TAARs emerged following the divergence of jawed and jawless fish, and comprise a large monophyletic family of receptors that recognize volatile amine odorants to elicit both intraspecific and interspecific innate behaviours such as attraction and aversion3-5. Here we report cryo-electron microscopy structures of mouse TAAR9 (mTAAR9) and mTAAR9-Gs or mTAAR9-Golf trimers in complex with ß-phenylethylamine, N,N-dimethylcyclohexylamine or spermidine. The mTAAR9 structures contain a deep and tight ligand-binding pocket decorated with a conserved D3.32W6.48Y7.43 motif, which is essential for amine odorant recognition. In the mTAAR9 structure, a unique disulfide bond connecting the N terminus to ECL2 is required for agonist-induced receptor activation. We identify key structural motifs of TAAR family members for detecting monoamines and polyamines and the shared sequence of different TAAR members that are responsible for recognition of the same odour chemical. We elucidate the molecular basis of mTAAR9 coupling to Gs and Golf by structural characterization and mutational analysis. Collectively, our results provide a structural basis for odorant detection, receptor activation and Golf coupling of an amine olfactory receptor.

Wood-inspired anisotropic hydrogel electrolyte with large modulus and low tortuosity realizing durable dendrite-free zinc-ion batteries.

While aqueous zinc-ion batteries exhibit great potential, their performance is impeded by zinc dendrites. Existing literature has proposed the use of hydrogel electrolytes to ameliorate this issue. Nevertheless, the mechanical attributes of hydrogel electrolytes, particularly their modulus, are suboptimal, primarily ascribed to the substantial water content. This drawback would severely restrict the dendrite-inhibiting efficacy, especially under large mass loadings of active materials. Inspired by the structural characteristics of wood, this study endeavors to fabricate the anisotropic carboxymethyl cellulose hydrogel electrolyte through directional freezing, salting-out effect, and compression reinforcement, aiming to maximize the modulus along the direction perpendicular to the electrode surface. The heightened modulus concurrently serves to suppress the vertical deposition of the intermediate product at the cathode. Meanwhile, the oriented channels with low tortuosity enabled by the anisotropic structure are beneficial to the ionic transport between the anode and cathode. Comparative analysis with an isotropic hydrogel sample reveals a marked enhancement in both modulus and ionic conductivity in the anisotropic hydrogel. This enhancement contributes to significantly improved zinc stripping/plating reversibility and mitigated electrochemical polarization. Additionally, a durable quasi-solid-state Zn//MnO2 battery with noteworthy volumetric energy density is realized. This study offers unique perspectives for designing hydrogel electrolytes and augmenting battery performance.

Integrated Manipulation and Addressing of Spin Defect in Diamond.

Scalable and addressable integrated manipulation of qubits is crucial for practical quantum information applications. Different waveguides have been used to transport the optical and electrical driving pulses, which are usually required for qubit manipulation. However, the separated multifields may limit the compactness and efficiency of manipulation and introduce unwanted perturbation. Here, we develop a tapered fiber-nanowire-electrode hybrid structure to realize integrated optical and microwave manipulation of solid-state spins at nanoscale. Visible light and microwave driving pulses are simultaneously transported and concentrated along an Ag nanowire. Studied with spin defects in diamond, the results show that the different driving fields are aligned with high accuracy. The spatially selective spin manipulation is realized. And the frequency-scanning optically detected magnetic resonance (ODMR) of spin qubits is measured, illustrating the potential for portable quantum sensing. Our work provides a new scheme for developing compact, miniaturized quantum sensors and quantum information processing devices.

Catalytic Asymmetric Construction of Chiral Amines with Three Nonadjacent Stereocenters via Trifunctional Catalysis.

Pharmaceuticals and biologically active natural products usually contain multiple stereocenters. The development of catalytic asymmetric reactions for the direct construction of complex motifs containing three nonadjacent stereocenters is a particularly important and formidable challenge. In this paper, we report an unprecedented method for the direct asymmetric construction of complex chiral amines with 1,3,5- or 1,3,4-stereocenters from readily available achiral and racemic starting materials. The reaction was made possible by the development of highly efficient chiral ammonium catalysts that serve three distinct functions: promoting efficient kinetic resolution by chiral recognition of racemic electrophiles, promoting asymmetric C-C bond forming reactions by recognizing enantiotropic faces of achiral nucleophiles, and mediating a highly stereoselective protonation of carbanions. Using these trifunctional catalysts, the reaction of imines and tulipane derivatives proceeded in a highly regio-, chemo-, and stereoselective manner to produce synthetically useful yields of complex chiral amines. We believe that trifunctional catalysis can be applied in a variety of asymmetric transformations for the streamlined asymmetric synthesis of complex chiral molecules with multiple stereocenters.

Synthesis of α-Aminonitriles via Ammonium-Catalyzed Reactions of Aminoacetonitrile.

α-Aminonitriles are not only broadly useful building blocks but also structural motifs in bioactive molecules. The Strecker reaction is one of the most widely used methods for α-aminonitrile synthesis. However, a severe drawback in Strecker reactions is the required use of a stoichiometric amount of toxic cyanation reagents. Thus, the development of a greener and widely applicable method for the synthesis of aminonitriles from readily available starting materials presents an important yet unmet challenge. We developed a general and new method for the synthesis of aminonitriles from readily available aminoacetonitrile. This method utilized off-the-shelf ammonium salts as catalysts, tolerated air and moisture, and avoided the use of cyanation reagents, which rendered it a greener alternative to the widely practiced Strecker reaction approach. We further illustrated that chiral ammonium-catalyzed asymmetric reactions of N-arylidene aminoacetonitriles could provide chiral α-tertiary and α-quaternary aminonitriles and α-aminonitriles bearing two continuous stereocenters.

Room-Temperature Anisotropic Actuation Driven by a Synergistic Order-Disorder and Displacive Phase Transition in a Ferroelectric Crystal.

Actuating materials convert different forms of energy into mechanical responses. To satisfy various application scenarios, they are desired to have rich categories, novel functionalities, clear structure-property relationships, fast responses, and, in particular, giant and reversible shape changes. Herein, we report a phase transition-driven ferroelectric crystal, (rac-3-HOPD)PbI3 (3-HOPD = 3-hydroxypiperidine cation), showing intriguingly large and anisotropic room-temperature actuating behaviors. The crystal consists of rigid one-dimensional [PbI3] anionic chains running along the a-axis and discrete disk-like cations loosely wrapping around the chains, leaving room for anisotropic shape changes in both the b- and c-axes. The shape change is switched by a ferroelectric phase transition occurring at around room temperature (294 K), driven by the exceptionally synergistic order-disorder and displacive phase transition. The rotation of the cations exerts internal pressure on the stacking structure to trigger an exceptionally large displacement of the inorganic chains, corresponding to a crystal lattice transformation with length changes of +24.6% and -17.5% along the b- and c-axis, respectively. Single crystal-based prototype devices of circuit switches and elevators have been fabricated by exploiting the unconventional negative temperature-dependent actuating behaviors. This work provides a new model for the development of multifunctional mechanically responsive materials.

An Azulene-Based Crystalline Porous Covalent Organic Framework for Efficient Photothermal Conversion.

The designed synthesis of a crystalline azulene-based covalent organic framework (COF-Azu-TP) is presented and its photothermal property is investigated. Azulene, a distinctive 5-7 fused ring non-benzenoid aromatic compound with a large intramolecular dipole moment and unique photophysical characteristics, is introduced as the key feature in COF-Azu-TP. The incorporation of azulene moiety imparts COF-Azu-TP with broad-spectrum light absorption capability and interlayer dipole interactions, which makes COF-Azu-TP a highly efficient photothermal conversion material. Its polyurethane (PU) composite exhibits a solar-to-vapor conversion efficiency (97.2%) and displays a water evaporation rate (1.43 kg m-2 h-1) under one sun irradiation, even at a very low dosage of COF-Azu-TP (2.2 wt%). Furthermore, COF-Azu-TP is utilized as a filler in a polylactic acid (PLA)/polycaprolactone (PCL) composited shape memory material, enabling rapid shape recovery under laser stimulation. A comparison study with a naphthalene-based COF isomer further emphasizes the crucial role of azulene in enhancing photothermal conversion efficiency. This study demonstrates the significance of incorporating specific building blocks into COFs for the development of functional porous materials with enhanced properties, paving the way for future applications in diverse fields.

Silicon Nanowire Array Weaved by Carbon Chains for Stretchable Lithium-Ion Battery Anode.

To manufacture flexible batteries, it can be a challenge for silicon base anode materials to maintain structural integrity and electrical connectivity under bending and torsion conditions. In this work, 1D silicon nanowire array structures combined with flexible carbon chains consisting of short carbon nanofibers (CNFs) and long carbon nanotubes (CNTs) are proposed. The CNFs and CNTs serve as chain joints and separate chain units, respectively, weaving the well-ordered Si nanowire array into a robust and integrated configuration. The prepared flexible and stretchable silicon array anode exhibits excellent electrochemical performance during dynamic operation. A high initial specific capacity of 2856 mAh g-1 is achieved. After 1000 cycles, a capacity retention of 60% (1602 mAh g-1) is maintained. Additionally, the capacity attenuation is less than 1% after 100 bending cycles. This excellent cycling stability is obtained with a high Si loading of 6.92 mg cm-2. This novel approach offers great promise for the development of high-loading flexible energy-storage devices.

Characterizing and forecasting neoantigens-resulting from MUC mutations in COAD.

BACKGROUND: The treatment for colon adenocarcinoma (COAD) faces challenges in terms of immunotherapy effectiveness due to multiple factors. Because of the high tumor specificity and immunogenicity, neoantigen has been considered a pivotal target for cancer immunotherapy. Therefore, this study aims to identify and predict the potential tumor antigens of MUC somatic mutations (MUCmut) in COAD. METHODS: Three databases of TCGA, TIMER2.0, and cBioPortal were used for a detailed evaluation of the association between MUCmut and multi-factors like tumor mutation burden (TMB), microsatellite instability (MSI), prognosis, and the tumor microenvironment within the context of total 2242 COAD patients. Next, TSNAdb and the differential agretopicity index (DAI) were utilized to predict high-confidence neopeptides for MUCmut based on 531 COAD patients' genomic information. DAI was calculated by subtraction of its predicted HLA binding affinity of the MUCmut peptide from the corresponding wild-type peptide. RESULTS: The top six mutation frequencies (14 to 2.9%) were from MUC16, MUC17, MUC5B, MUC2, MUC4 and MUC6. COAD patients with MUC16 and MUC4 mutations had longer DFS and PFS. However, patients with MUC13 and MUC20 mutations had shorter OS. Patients with the mutation of MUC16, MUC5B, MUC2, MUC4, and MUC6 exhibited higher TMB and MSI. Moreover, these mutations from the MUC family were associated with the infiltration of diverse lymphocyte cells and the expression of immune checkpoint genes. Through TSNAdb 1.0/NetMHCpan v2.8, 452 single nucleotide variants (SNVs) of MUCmut peptides were identified. Moreover, through TSNAdb2.0/NetMHCpan v4.0, 57 SNVs, 1 Q-frame shift (TS), and 157 short insertions/deletions (INDELs) of MUCmut were identified. Finally, 10 high-confidence neopeptides of MUCmut were predicted by DAI. CONCLUSIONS: Together, our findings establish the immunogenicity and therapeutic potential of mutant MUC family-derived neoantigens. Through combining the tools of TSNAdb and DAI, a group of novel MUCmut neoantigens were identified as potential targets for immunotherapy.

FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

OBJECTIVES: Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator, FTY720, in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. METHODS: The effects of FTY720 in EAV were evaluated by quantifying haematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary haemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analysed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). RESULTS: FTY720 treatment significantly attenuated renal injury and pulmonary haemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1a (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. CONCLUSION: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.

Unveiling Chirality Transfer between Chiral Centers and Metal Halides in Chiral Organic-Inorganic Hybrid Metal Halides.

Chirality transfer refers to the process in which chiral cations compel the crystallization of the inorganic component into the Sohncke group. Enhancing the chirality of the inorganic component in chiral organic-inorganic hybrid metal halides (OIHMHs) through chirality transfer, aimed at improving chiroptical and spintronic properties, remains challenging due to the complexity of the underlying mechanism. To investigate this, we propose a novel concept─chirality transfer coefficient─as a means of quantifying the strength of chirality transfer in OIHMHs. A comparative study of OIHMHs with varying dimensionality, metal ions, and chiral centers was conducted to elucidate this mechanism. By analyzing factors such as hydrogen bonding, the number of chiral centers, dimensionality, helical geometry, and structural distortions, we found that chirality transfer is influenced by a combination of structural dimensions and the number of chiral centers. Importantly, our findings reveal that 0D, and 1D OIHMHs, particularly 1D with a zigzag chain configuration, exhibit stronger chirality transfer than their 2D counterparts. Moreover, in 2D OIHMHs, a reduction in the number of chiral centers enhances chirality transfer. However, no direct correlation was observed between chirality transfer and spin splitting. These insights contribute to a more comprehensive understanding of chirality transfer mechanisms and provide a strategic approach for enhancing the chirality transfer and associated physical properties in OIHMHs.

Constructing a Stable Built-In Electric Field in Bi/Bi2Te3 Nanowires for Electrochemical CO2 Reduction Reaction.

Electrochemically converting carbon dioxide (CO2) into valuable fuels and renewable chemical feedstocks is considered a highly promising approach to achieve carbon neutrality. In this work, a robust interfacial built-in electric field (BEF) has been successfully designed and created in Bi/Bi2Te3 nanowires (NWs). The Bi/Bi2Te3 NWs consistently maintain over 90% Faradaic efficiency (FE) within a wide potential range (-0.8 to -1.2 V), with HCOOH selectivity reaching 97.2% at -1.0 V. Moreover, the FEHCOOH of Bi/Bi2Te3 NWs can still reach 94.3% at a current density of 100 mA cm-2 when it is used as a cathode electrocatalyst in a flow-cell system. Detailed in situ experiments confirm that the presence of interfacial BEF between Bi and Bi/Bi2Te3 promotes the formation of *OHCO intermediates, thus facilitating the production of HCOOH species. DFT calculations show that Bi/Bi2Te3 NWs increase the formation energies of H* and *COOH while reducing the energy barrier for *OCHO formation, thus achieving a bidirectional optimization of intermediate adsorption. This work provides a feasible scheme for exploring electrocatalytic reaction intermediates by using the BEF strategy.

GWAS-based polygenic risk scoring for predicting cerebral artery dissection in the Chinese population.

OBJECTIVE: Cerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital. METHODS: A total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD. RESULTS: Through GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10- 8. Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%. CONCLUSIONS: Our study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation.

Evidence of microbiota-host dysbiosis between periodontitis and cerebral small vessel disease.

OBJECTIVES: To investigate the correlation between periodontitis and cerebral small vessel disease (CSVD) from the clinical and microbiological aspects. SUBJECTS AND METHODS: Periodontitis patients (CP group, n = 31) and CSVD patients (CSVD group, n = 30) were examined for neurological and periodontal condition. Subgingival plaque was collected and performed using 16S rRNA sequencing. Logistic regression and LASSO regression were used to analyze the periodontal parameters and subgingival microbiota related to CSVD, respectively. Inflammatory factors in gingival crevicular fluid (GCF) were also detected and compared between the two groups. RESULTS: Clinical attachment level (CAL), teeth number and plaque index demonstrated a significant difference between CP and CSVD group, meanwhile, CAL was independently associated with CSVD. Besides, the microbial richness and composition were distinct between two groups. Five genera related to periodontal pathogens (Treponema, Prevotella, Streptococcus, Fusobacterium, Porphyromonas) were screened out by LASSO regression, suggesting a potential association with CSVD. Finally, the levels of inflammatory factors in GCF were statistically higher in CSVD group than those in CP group. CONCLUSIONS: Cerebral small vessel disease patients demonstrated worse periodontal condition, meanwhile the interaction between microbiota dysbiosis and host factors (inflammation) leading to a better understanding of the association between periodontitis and CSVD.

An Improved k-Nearest Neighbor Algorithm for Recognition and Classification of Thyroid Nodules.

OBJECTIVES: To complete the task of automatic recognition and classification of thyroid nodules and solve the problem of high classification error rates when the samples are imbalanced. METHODS: An improved k-nearest neighbor (KNN) algorithm is proposed and a method for automatic thyroid nodule classification based on the improved KNN algorithm is established. In the improved KNN algorithm, we consider not only the number of class labels for various classes of data in KNNs, but also the corresponding weights. And we use the Minkowski distance measure instead of the Euclidean distance measure. RESULTS: A total of 508 ultrasound images of thyroid nodules, including 415 benign nodules and 93 malignant nodules, were used in the paper. Experimental results show the improved KNN has 0.872549 accuracy, 0.867347 precision, 1 recall, and 0.928962 F1-score. At the same time, we also considered the influence of different distance weights, the value of k, different distance measures on the classification results. CONCLUSIONS: A comparison result shows that our method has a better performance than the traditional KNN and other classical machine learning methods.

Enantiomer-specific effects of metamifop on serum metabolism in rats.

Metamifop (MET) is a widely used pesticides in paddy field and it has good weed control effect. As a chiral pesticide that may be hazardous to human health through food chain transmission, there could be selective differences in the metabolism and toxicity of its enantiomers, so the study of chiral MET may offer an assessment of MET toxicity and stereoselectivity at the enantiomeric level. A total of 39, 43 and 31 differential metabolites were screened from the data sets of Rac-, R-(-)- and S-(+)-MET, respectively. Metabolic pathway analysis revealed that MET and its enantiomers primarily affected sphingolipid metabolism, glycerophospholipid metabolism, linoleic acid metabolism, α-linolenic acid metabolism and arachidonic acid metabolism. Rac- and S-(+)-MET affected the synthesis of glycosylphosphatidylinositol (GPI)-anchored biomolecules. R-(-)- and S-(+)-MET affected glutathione metabolism. R-(-)-MET affected vitamin B6 metabolism, selenium compound metabolism, and steroid biosynthesis. Pyrimidine metabolism was only affected by Rac-MET. The experimental results indicated that MET and its enantiomers may affect the nervous and immune systems in rats. Further inter-group difference analysis also demonstrated stereoselectivity of MET and its enantiomers on rat serum metabolism. These findings may provide more detailed information on the toxicity of Rac-, S-(+)- and R-(-)-MET in rat, as well as some context for assessing the environmental risk of the three agents to organisms.

11B NMR of the Morphological Evolution of Traditional Chinese Medicine Borax.

This article applies nuclear magnetic resonance technology to the study of boron-containing traditional Chinese medicine, in order to explore the morphological evolution of boron elements in traditional Chinese medicine. Borax is a traditional Chinese medicine with anti-corrosion, anti-inflammatory, antibacterial, and anticonvulsant effects. It is made by boiling, removing stones, and drying borax minerals like borate salts. This article introduces an 11B nuclear magnetic resonance method for identifying and characterizing boron-containing compounds in TCM. We applied this technology to borax aqueous solutions in different chemical environments and found that with boron mixed in the form of SP2 hybridization in equilateral triangles and SP3 hybridization in equilateral tetrahedra, the pH changes in alkaline environments significantly affected the ratio of the two. At the same time, it was found that in addition to the raw material peak, boron signals of other boron-containing compounds were also detected in 20 commercially available boron-containing TCM preparations. These new boron-containing compounds may be true pharmaceutical active ingredients, and adding them directly to the formula can improve quality and safety. This article describes the detection of 11B NMR in boron-containing traditional Chinese medicine preparations. It is simple, non-destructive, and can provide chemical fingerprint studies for boron-containing traditional Chinese medicine.

[Immune mechanism of Daphnes Cortex and its processed products on CIA rats based on B7/CD28/CTLA-4 pathway].

This study investigates the effects of Daphnes Cortex and its processed products on the differentiation of Th17/Treg cells in SD rats with type Ⅱ collagen-induced arthritis(CIA).Sixty-four SD rats were randomly divided into the normal group(normal),model group(model),fried Daphne giraldii Nitsche low-dose and high-dose groups(FDGN-L group, FDGN-H group),raw D. giraldii Nitsche low-dose and high-dose groups(RDGN-L group, RDGN-H group),daphnetin group(DAPH group),and tripterygium glycosides group(GTW group).Except for the normal group, the CIA model was immunized on the seventh day after the first immunization, and was gavaged for 28 days after the second immunization.After sampling, the inflammation of articular synovial membrane in CIA rats was observed by hematoxylin-eosin(HE)staining; the levels of transforming growth factor-ß(TGF-ß),interferon-γ(IFN-γ),interleukin(IL)-2,IL-4,and IL-10 in serum were detected by enzyme-linked immunosorbent assay(ELISA); real-time reverse transcription-PCR(qRT-PCR)and Western blot were used to detect the mRNA and protein expressions of cluster of differentiation(CD) 80(B7-1),CD 86(B7-2),CD28,and cytotoxic T lymphocyte-associated antigen 4(CTLA-4)in the synovial membrane of rats; flow cytometry was used to detect the proportion of Th17 and Treg cells in the synovial membrane of rats.The results showed that compared with the normal group, the joint synovial inflammation of rats in the model group was significantly aggravated, the arthritis index was significantly increased, and the immune organ index was increased(P<0.01).Compared with the model group, each drug administration group could improve the joint inflammation of rats to varying degrees, reduce the arthritis index, inhibit synovial hyperplasia, and reduce the immune organ index; compared with the model group, the serum levels of IL-2 and IFN-γ in each drug administration group were significantly decreased(P<0.01),TGF-ß,IL-4,and IL-10 were significantly increased(P<0.01),the mRNA and protein expressions of B7-1 and CTLA-4 in the synovial membrane were significantly increased(P<0.01),and the proportion of Th17 cells and Treg cells in the joint tissue was significantly decreased(P<0.01).In conclusion, Daphnes Cortex inhibits the expression of Th17 cells in CIA rats and promotes the expression of Treg cells by regulating the B7/CD28/CTLA-4 pathway and the balance of Th17/Treg, thereby treating rheumatoid arthritis.

Shape Shifting and Locking in Mechanically Responsive Organic-Inorganic Hybrid Materials for Thermoelastic Actuators.

The construction of mechanically responsive materials with reversible shape-shifting, shape-locking, and stretchability holds promise for a wide range of applications in fields such as soft robotics and flexible electronics. Here, we report novel thermoelastic one-dimensional organic-inorganic hybrids (R/S-Hmpy)PbI3 (Hmpy=2-hydroxymethyl-pyrrolidinium) to show mechanical responses. The single crystals undergo two phase transitions at 310 K and 380 K. When heated to 380 K, they show shape-shifting and expansion along the b-axis by about 13.4 %, corresponding to a larger deformation than that of thermally activated shape memory alloys (8.5 %), and exhibit a strong actuation force. During the cooling process, the stretched crystal shape maintains and a shape-locking phenomenon occurs, which is lifted when the temperature decreases to 305 K. Meanwhile, due to the introduction of chiral ions, the thermal switching shows a 10-fold second-order nonlinear switching contrast (common values typically below 3-fold). This study presents a thermoelastic actuator based on shape-shifting and -locking of organic-inorganic hybrids for the first time. The dielectric and nonlinear optical switching properties of organic-inorganic hybrids broaden the range of applications of mechanically responsive crystals.