Time-Released Black Phosphorus Hydrogel Accelerates Myocardial Repairing through Antioxidant and Motivates Macrophage Polarization Properties.

The improvement of the myocardial microenvironment largely determines the prognosis of myocardial infarction (MI). After MI, early removal of excessive reactive oxygen species (ROS) in the microenvironment can alleviate oxidative stress injury and promote M2 phenotype polarization of macrophages, which is important for advocating myocardial repair. In this study, we combined traditional natural hydrogel materials chitosan (CS) and gelatin (Gel) to encapsulate polydopamine-modified black phosphorus nanosheets (BP@PDA). We designed an injectable composite gel (CS-Gel-BP@PDA) with a time-released ability to achieve in situ sustained-release BP@PDA in the area of MI. Utilizing the inflammation inhibition ability of CS-Gel itself and the high reactive activity of BP@PDA with ROS, continuous improvement of infarct microenvironment and myocardial repair were achieved. The studies in vivo revealed that, compared with the saline group, CS-Gel-BP@PDA group had alleviated myocardial fibrosis and infarct size and importantly improved cardiac function. Immunofluorescence results showed that the ROS level and inflammatory response in the microenvironment of the CS-Gel-BP@PDA group were decreased. In conclusion, our study demonstrated the time-released ability, antioxidative stress activity and macrophage polarization modulation of the novel composite hydrogel CS-Gel-BP@PDA, which provides inspiration for novel therapeutic modalities for MI.

Prognostic value of postoperative anti-thyroglobulin antibody in patients with differentiated thyroid cancer.

Purpose: Postoperative thyroglobulin (Tg) generally serves as a biomarker to monitor the recurrence or persistence of differentiated thyroid cancer (DTC), whereas it constrains to interference from anti-thyroglobulin antibody (TgAb). This study aimed to determine the value of postoperative TgAb as a surrogate for monitoring tumor status in DTCs with positive TgAb after successful radioactive iodine (RAI) remnant ablation. Methods: We retrospectively enrolled DTC patients with positive (≥40 IU/mL, Roche) postoperative TgAb measurements. An index of TgAb change (ΔTgAb) was defined to describe the TgAb decrease rate. DTC status was defined as either no evidence of disease (NED) or persistent/recurrent disease (PRD). Univariate and multivariate binary logistic analyses were used to identify the independent risk factors of PRD. Receiver operating characteristic (ROC) curves were performed to determine the optimal cutoff values of each risk factor, and DeLong's test was conducted to compare their predictive powers. Kaplan-Meier curves were used to assess the impact of different TgAb trends in the first year on progression-free survival. Results: Of the 232 patients enrolled, the median diagnosis age was 34 years (range, 18-62 years), with a male-to-female ratio of 1:4.66 (41/191). Among them, after a median follow-up of 44 months (range, 4-128 months),183 (78.87%) patients were evaluated as NED, while the other 49 (21.12%) had either persistent (n = 25) or recurrent disease (n = 24). Multivariate regression showed that ΔTgAb (P < 0.001) and lymph node metastasis (LNM) rate (P = 0.009) were independently relevant to the presence of PRD, with optimal cutoff values of 47.0% and 35.1%, respectively. It is important to note that there is a high negative predictive value (96.93%) of ΔTgAb with the cutoff of 47.0%. DeLong's test showed that ΔTgAb alone and the combination of ΔTgAb and LNM rate were significantly greater than the isolated LNM rate (both P < 0.001) in predicting NED, while there was no statistical difference of the predictive power between ΔTgAb and the combination (P = 0.203). Additionally, patients with ΔTgAb >47.0% had longer progression-free survival than those with ΔTgAb ≤47.0% (not reached vs. 50 months, P < 0.001), and those with ΔTgAb >47.0% or negative conversion within the first year after RAI ablation had longer progression-free survival. Conclusion: Our study suggested that ΔTgAb could serve as a valuable indicator of disease status in DTC patients with positive TgAb. A ΔTgAb of >47.0% is conducive to identify those with NED and may help to obviate their overtreatment. The decrease rate and negative conversion of TgAb in the first year were good predictors of disease-free survival in patients.

Dietary kelp meal improves serum antioxidants, intestinal immunity, and lipid metabolism in hybrid snakehead (Channa maculata ♀ × Channa argus ♂).

BACKGROUND: Dietary kelp possesses a variety of useful biological qualities but does not have a toxic effect on the host. In this study, we examine how kelp dietary supplementation enhances the serum biochemistry, intestinal immunity, and metabolism of hybrid snakehead. A total of 810 juvenile hybrid snakeheads (Channa maculata ♀ × Channa argus ♂), with an initial average weight of 11.4 ± 0.15 g, were allocated randomly to three treatment groups (three replicates per group). The fish were fed for 60 days with isonitrogenous and isolipidic diets. The groups were the control group (C) (20% high-gluten flour), the medium replacement group (MR) (10% high-gluten flour and 10% kelp meal), and the full replacement group (FR) (0% high-gluten flour and 15% kelp meal). RESULTS: The results showed that dietary kelp increased the activity of serum antioxidant enzymes significantly and decreased the content of serum malondialdehyde (MDA) in hybrid snakeheads, with significant changes in the FR group (P < 0.05). The intestinal morphology results showed that dietary kelp helped to increase the specific surface area of intestinal villi, which was beneficial for intestinal digestion and absorption. According to transcriptome and quantitative real-time polymerase chain reaction (qRT-PCR) analysis, dietary kelp can improve the expression of intestinal immunity and metabolism-related pathways. Among them, immune-related genes MHC1 and HSPA1 were significantly up-regulated, and IGH, MHC2, and IL-8 were significantly down-regulated (P < 0.05). Lipid metabolism-related genes DGAT2, FABP2, RXRα, and PLPP1 were all significantly up-regulated (P < 0.05). CONCLUSION: Dietary kelp can effectively improve the antioxidant function of hybrid snakeheads, improve intestinal morphology, reduce intestinal inflammation, and promote intestinal lipid synthesis and transportation, thereby improving intestinal immunity and metabolic functions. © 2024 Society of Chemical Industry.

HSP70 positively regulates translation by interacting with the IRES and stabilizes the viral structural proteins VP1 and VP3 to facilitate duck hepatitis A virus type 1 replication.

The maintenance of viral protein homeostasis depends on the interaction between host cell proteins and viral proteins. As a molecular chaperone, heat shock protein 70 (HSP70) has been shown to play an important role in viral infection. Our results showed that HSP70 can affect translation, replication, assembly, and release during the life cycle of duck hepatitis A virus type 1 (DHAV-1). We demonstrated that HSP70 can regulate viral translation by interacting with the DHAV-1 internal ribosome entry site (IRES). In addition, HSP70 interacts with the viral capsid proteins VP1 and VP3 and promotes their stability by inhibiting proteasomal degradation, thereby facilitating the assembly of DHAV-1 virions. This study demonstrates the specific role of HSP70 in regulating DHAV-1 replication, which are helpful for understanding the pathogenesis of DHAV-1 infection and provide additional information about the role of HSP70 in infection by different kinds of picornaviruses, as well as the interaction between picornaviruses and host cells.

The causal relationship between sarcoidosis and autoimmune diseases: a bidirectional Mendelian randomization study in FinnGen.

Background: Sarcoidosis has been considered to be associated with many autoimmune diseases (ADs), but the cause-and-effect relationship between these two diseases has not been fully explored. Therefore, the objective of this study is to explore the possible genetic association between sarcoidosis and ADs. Methods: We conducted a bidirectional Mendelian randomization (MR) study using genetic variants associated with ADs and sarcoidosis (4,041 cases and 371,255 controls) from the FinnGen study. The ADs dataset comprised 96,150 cases and 281,127 controls, encompassing 44 distinct types of autoimmune-related diseases. Subsequently, we identified seven diseases within the ADs dataset with a case size exceeding 3,500 and performed subgroup analyses on these specific diseases. Results: The MR evidence supported the causal association of genetic predictors of ADs with an increased risk of sarcoidosis (OR = 1.79, 95% CI = 1.59 to 2.02, P IVW-FE = 1.01 × 10-21), and no reverse causation (OR = 1.05, 95% CI 0.99 to 1.12, P IVW-MRE = 9.88 × 10-2). Furthermore, subgroup analyses indicated that genetic predictors of type 1 diabetes mellitus (T1DM), celiac disease, and inflammatory bowel disease (IBD) were causally linked to an elevated risk of sarcoidosis (All P < 6.25 × 10-3). Conversely, genetic predictors of sarcoidosis showed causal associations with a higher risk of type 1 diabetes mellitus (P < 6.25 × 10-3). Conclusion: The present study established a positive causal relationship between genetic predictors of ADs (e.g. T1DM, celiac disease, and IBD) and the risk of sarcoidosis, with no evidence of reverse causation.

E-M349E and NS2A/2B-P1(T) are compensatory mutations of rDTMUV-NS2AB-P1P1'(AA), which regain virus proliferation by enhancing the virus package and restoring NS2A/2B cleavage.

Duck Tembusu virus (DTMUV) belongs to the Flaviviridae family and mainly infects ducks. The genome of DTMUV is translated into a polyprotein, which is further cleaved into several protein by viral NS2B3 protease and host proteases. Crucially, the cleavage of the NS2A/2B precursor during this process is essential for the formation of replication complexes and viral packaging. Previous research has demonstrated that alanine mutations in NS2A/2B (P1P1' (AA)) result in an attenuated strain (rDTMUV-NS2A/2B-P1P1' (AA)) by disrupting NS2A/2B cleavage. In this study, we investigate the effects of the P1P1' (AA) mutation on the viral life cycle and explore compensatory mutations in rDTMUV-NS2A/2B-P1P1' (AA). Infected ducklings exhibit similar body weight gain and viral tissue loads to DTMUV-WT. Compensatory mutations E-M349E and P1(T) emerge, restoring proliferation levels to those of rDTMUV-WT. Specifically, E-M349E enhances viral packaging, while P1(T) reinstates NS2A/2B proteolysis in vitro. Thus, our findings reveal novel compensatory sites capable of restoring the attenuated DTMUV during polyprotein cleavage and packaging.

Iron efflux by IetA enhances ß-lactam aztreonam resistance and is linked to oxidative stress through cellular respiration in Riemerella anatipestifer.

BACKGROUND: Riemerella anatipestifer encodes an iron acquisition system, but whether it encodes the iron efflux pump and its role in antibiotic resistance are largely unknown. OBJECTIVES: To screen and identify an iron efflux gene in R. anatipestifer and determine whether and how the iron efflux gene is involved in antibiotic resistance. METHODS: In this study, gene knockout, streptonigrin susceptibility assay and inductively coupled plasma mass spectrometry were used to screen for the iron efflux gene ietA. The MIC measurements, scanning electron microscopy and reactive oxygen species (ROS) detection were used to verify the role of IetA in aztreonam resistance and its mechanism. Mortality and colonization assay were used to investigate the role of IetA in virulence. RESULTS: The deletion mutant ΔietA showed heightened susceptibility to streptonigrin, and prominent intracellular iron accumulation was observed in ΔfurΔietA under excess iron conditions. Additionally, ΔietA exhibited increased sensitivity to H2O2-produced oxidative stress. Under aerobic conditions with abundant iron, ΔietA displayed increased susceptibility to the ß-lactam antibiotic aztreonam due to heightened ROS production. However, the killing efficacy of aztreonam was diminished in both WT and ΔietA under anaerobic or iron restriction conditions. Further experiments demonstrated that the efficiency of aztreonam against ΔietA was dependent on respiratory complexes Ⅰ and Ⅱ. Finally, in a duckling model, ΔietA had reduced virulence compared with the WT. CONCLUSION: Iron efflux is critical to alleviate oxidative stress damage and ß-lactam aztreonam killing in R. anatipestifer, which is linked by cellular respiration.

Inflammation mediates the association between furan exposure and the prevalence and mortality of chronic obstructive pulmonary disease: National Health and Nutrition Examination Survey 2013-2018.

BACKGROUND: Although extensive research has established associations between chronic obstructive pulmonary disease (COPD) and environmental pollutants, the connection between furan and COPD remains unclear. This study aimed to explore the association between furan and COPD while investigating potential mechanisms. METHODS: The study involved 7,482 adults from the National Health and Nutrition Examination Survey 2013-2018. Exposure to furan was assessed using blood furan levels. Participants were categorized into five groups based on quartiles of log10-transformed blood furan levels. Logistic regression and restricted cubic spline regression models were used to assess the association between furan exposure and COPD risk. Mediating analysis was performed to assess the contribution of inflammation to the effects of furan exposure on COPD prevalence. Cox regression was used to assess the association between furan exposure and the prognosis of COPD. RESULTS: Participants with COPD exhibited higher blood furan levels compared to those without COPD (P < 0.001). Log10-transformed blood furan levels were independently associated with an increased COPD risk after adjusting for all covariates (Q5 vs. Q1: OR = 4.47, 95% CI = 1.58-12.66, P = 0.006, P for trend = 0.001). Inflammatory cells such as monocytes, neutrophils, and basophils were identified as mediators in the relationship between furan exposure and COPD prevalence, with mediated proportions of 8.73%, 20.90%, and 10.94%, respectively (all P < 0.05). Moreover, multivariate Cox regression analysis revealed a positive correlation between log10-transformed blood furan levels and respiratory mortality in COPD patients (HR = 41.00, 95% CI = 3.70-460.00, P = 0.003). CONCLUSIONS: Exposure to furan demonstrates a positive correlation with both the prevalence and respiratory mortality of COPD, with inflammation identified as a crucial mediator in this relationship.

Multiple functions of the nonstructural protein 3D in picornavirus infection.

3D polymerase, also known as RNA-dependent RNA polymerase, is encoded by all known picornaviruses, and their structures are highly conserved. In the process of picornavirus replication, 3D polymerase facilitates the assembly of replication complexes and directly catalyzes the synthesis of viral RNA. The nuclear localization signal carried by picornavirus 3D polymerase, combined with its ability to interact with other viral proteins, viral RNA and cellular proteins, indicate that its noncatalytic role is equally important in viral infections. Recent studies have shown that 3D polymerase has multiple effects on host cell biological functions, including inducing cell cycle arrest, regulating host cell translation, inducing autophagy, evading immune responses, and triggering inflammasome formation. Thus, 3D polymerase would be a very valuable target for the development of antiviral therapies. This review summarizes current studies on the structure of 3D polymerase and its regulation of host cell responses, thereby improving the understanding of picornavirus-mediated pathogenesis caused by 3D polymerase.

Chiral Ligand-Concentration Mediating Asymmetric Transformations of Silver Clusters: NIR-II Circularly Polarized Phosphorescence Lighting.

Near infrared (NIR) emitter with circularly polarized phosphorescence (CPP), known as NIR CPP, has emerged as a key part in the research of cutting-edge luminescent materials. However, it remains a challenge to obtain nanoclusters with NIR CPP activity. Here, we propose an asymmetric transformation approach to efficiently synthesize two pairs of chiral silver nanoclusters (R/S-Ag29 and R/S-Ag16) using an achiral Ag10 nanocluster as starting material in the presence of different concentration chiral inducer (R/S)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (R/S-BNP). R/S-Ag29, formed in the low-concentration R/S-BNP, exhibits a unique kernel-shell structure consisting of a distorted Ag13 icosahedron and an integrated cage-like organometallic shell with a C3 symmetry, and possesses a superatomic 6-electron configuration (1S2ǀ1P4). By contrast, R/S-Ag16, formed in the high-concentration R/S-BNP, features a sandwich-like pentagram with AgI-pure kernel. Profiting from the hierarchically chiral structures and superatomic kernel-dominated phosphorescence, R/S-Ag29 exhibits infrequent CPP activity in the second near-infrared (975 nm) region, being the first instance of NIR-II CPP observed among CPL metal nanoclusters. This study presents a new approach to reduce the difficulty of de novo synthesis for chiral silver nanomaterials, and facilitates the design of CPP-active superatomic nanoclusters in NIR region.

Solvent-Mediated Hetero/Homo-Phase Crystallization of Copper Nanoclusters and Superatomic Kernel-Related NIR Phosphorescence.

Atomically precise superatomic copper nanoclusters (Cu NCs) have been the subject of immense interest for their intriguing structures and diverse properties; nonetheless, the variable oxidation state of copper ions and complex solvation effects in wet synthesis systems pose significant challenges for comprehending their synthesis and crystallization mechanism. Herein, we present a solvent-mediated approach for the synthesis of two Cu NCs, namely, superatomic Cu26 and pure-Cu(I) Cu16. They initially formed as a hetero-phase and then separated as a homo-phase via modulating binary solvent composition. In situ UV/vis absorption and electrospray ionization mass spectra revealed that the solvent-mediated assembly was determined to be the underlying mechanism of hetero/homo-phase crystallization. Cu26 is a 2-electron superatom with a kernel-shell structure that includes a [Cu20Se12]4- shell and [Cu6]4+ kernel, containing two 1S jellium electrons. Conversely, Cu16 is a pure-Cu(I) Cu/Se nanocluster that features a [Cu16Se6]4+ core protected by extra dimercaptomaleonitrile ligands. Remarkably, Cu26 exhibits unique near-infrared phosphorescence (NIR PH) at 933 nm due to the presence of a superatomic kernel-related charge transfer state (3MM(Cu)CT). Overall, this work not only showcases the hetero/homo-phase crystallization of Cu NCs driven by a solvent-mediated assembly mechanism but also enables the rare occurrence of NIR PH within the 2-electron copper superatom family.

Single-Nuclei Characterization of Lacrimal Gland in Scopolamine-Induced Dry Eye Disease.

Purpose: The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively characterize LG cellular heterogeneity under normal and DED conditions using single-nucleus RNA sequencing (snRNA-seq). Methods: Single LG nuclei isolated from mice with or without DED induced by scopolamine (SCOP)/desiccating stress (DS) were subjected to snRNA-seq using the 10x Genomics platform. These cells were clustered and annotated using the t-distributed stochastic neighbor embedding (t-SNE) method and unbiased computational informatic analysis. Cluster identification and functional analysis were performed based on marker gene expression and bioinformatic data mining. Results: The snRNA-seq analysis of 30,351 nuclei identified eight major cell types, with acinar cells (∼72.6%) being the most abundant cell type in the LG. Subclustering analysis revealed that the LG mainly contained two acinar cell subtypes, two ductal cell subclusters, three myoepithelial cell (MECs) subtypes, and four immunocyte subclusters. In the SCOP-induced DED model, three major LG parenchymal cell types were significantly altered, characterized by a reduced proportion of acinar cells with a lowered secretion potential and an augmented proportion of ductal cells and MECs. LG immunocytes in DED scenarios showed an intensified inflammatory response and dysregulated intercellular communication with three major LG parenchymal cells. Conclusions: Overall, this study offers a systemic single-nucleus transcriptomic profile of LGs in both normal and DED conditions and an atlas of the complicated interactions of immunocytes with major LG parenchymal cells. The findings also facilitate understanding the pathogenesis of DED.

The topological model of NS4B and its TMD3 in duck TMUV proliferation.

Duck Tembusu virus (DTMUV) belongs to the Flaviviridae family and mainly infects ducks. Duck Tembusu virus genome encodes one polyprotein that undergoes cleavage to produce 10 proteins. Among these, NS4B, the largest transmembrane protein, plays a crucial role in the viral life cycle. In this study, we investigated the localization of NS4B and found that it is located in the endoplasmic reticulum, where it co-localizes with DTMUV dsRNA. Subsequently, we confirmed 5 different transmembrane domains of NS4B and discovered that only its transmembrane domain 3 (TMD3) can traverse ER membrane. Then mutations were introduced in the conserved amino acids of NS4B TMD3 of DTMUV replicon and infectious clone. The results showed that V111G, V117G, and I118G mutations enhanced viral RNA replication, while Q104A, T106A, A113L, M116A, H120A, Y121A, and A122G mutations reduced viral replication. Recombinant viruses with these mutations were rescued and studied in BHK21 cells. The findings demonstrated that A113L and H120A mutations led to higher viral titers than the wild-type strain, while Q104A, T106A, V111G, V117G, and Y121A mutations attenuated viral proliferation. Additionally, H120A, M116A, and A122G mutations enhanced viral proliferation. Furthermore, Q104A, T106A, V111G, M116A, V117G, Y121A, and A122G mutants showed reduced viral virulence to 10-d duck embryos. Animal experiments further indicated that all mutation viruses resulted in lower genome copy numbers in the spleen compared to the WT group 5 days postinfection. Our data provide insights into the topological model of DTMUV NS4B, highlighting the essential role of NS4B TMD3 in viral replication and proliferation.

Guest-Induced Reversible Single-Crystal-to-Single-Crystal Transformation Involving Displacement of 2D Layers and Spin Crossover Behavior Change in a Hofmann-Type Coordination Polymer.

A novel two-dimensional (2D) Hofmann-type coordination polymer, {FeII(PyHbim)2[Pd(CN)4]}·2CH3OH [1·2CH3OH, PyHbim = 2-(4-pyridyl)benzimidazole], has been synthesized, which can undergo a spontaneous guest exchange, transforming to 1·2H2O in a single-crystal-to-single-crystal (SCSC) manner, shifting from orthorhombic Cmmm to monoclinic C2/m involving the displacement of 2D layers. The solvent-induced SCSC transformation process was reversible and verified through powder X-ray diffraction (PXRD) and single-crystal X-ray crystallography analyses. Both 1·2CH3OH and 1·2H2O exhibit complete and abrupt spin crossover (SCO) behaviors in two steps, while their SCO temperature ranges drastically shift by ca.100 K, spanning room temperature, owing to different intermolecular interactions resulting from diverse interlayer packing manners and host-guest interactions. Besides, a structural phase transition is observed in 1·2CH3OH, contributing to the two-step spin transition.

Design and Analysis of a Textured Cu-Encapsulated Ni Tube for Low-Reflection Electromagnetic Interference Shielding Material.

With the frequent increase and update of electromagnetic interference (EMI) shielding materials, a low-resolution material that can absorb most electromagnetic waves, thereby effectively reducing the secondary pollution, is urgently needed. However, the excellent performance, flexibility, and low cost of these methods are usually incompatible with current reports. To address the above dilemma, we reported a facile solution for fabricating a low-reflection and high-performance EMI shielding composite by means of electroless nickel plating (EP-Ni), electroless copper plating (EP-Cu), annealing, and coating with a polydimethylsiloxane (PDMS) polymer with the structure of a Ni@Cu tube encapsulated with PDMS. The results indicate that the active groups on vegetable wool can act as active sites for the absorption of the Pd catalyst, thereby catalyzing the reduction of Ni2+, Cu2+, and the subsequent deposition on the plant fiber surface. Notably, the Ni@Cu-encapsulated plant fibers decreased during annealing at 100 °C. According to the segregated network and synergistic effect of the porous structure, the as-fabricated EMI shielding material demonstrated high absorption and low reflection, in which the power coefficient of the T value was approximately 0.0001, the R value was about 0.1764 (a decrease of 27.5% compared that of EP-Ni cotton), and the A value was approximately 0.8235.

Temperature-Controlled Selective Formation of Silver Nanoclusters and Their Transformation to the Same Product.

Herein, two atomically precise silver nanoclusters, Ag54 and Ag33, directed by inner anion templates (CrO4 2- and/or Cl-), are initially isolated as a mixed phase from identical reactants across a wide temperature range (20-80 °C). Interestingly, fine-tuning the reaction temperature can realize pure phase synthesis of the two nanoclusters; that is, a metastable Ag54 is kinetically formed at a low temperature (20 °C), whereas such a system is steered towards a thermodynamically stable Ag33 at a relatively high temperature (80 °C). Electrospray ionization mass spectrometry illustrates that the stability of Ag33 is superior to that of Ag54, which is further supported by density functional theory calculations. Importantly, the difference in structural stability can influence the pathway of 1,4-bis(pyrid-4-yl)benzene induced transformation reaction starting from Ag54 and Ag33. The former undergoes a dramatic breakage-reorganization process to form an Ag31 dimer (Ag31), while the same product can be also achieved from the latter following a noninvasive ligand exchange process. Both the Ag54 and Ag33 have the potential for further remote laser ignition applications. This work not only demonstrates how temperature controls the isolation of a specific phase, but also sheds light on the structural transformation pathway of nanoclusters with different stability.

Synergistic large segmental bone repair by 3D printed bionic scaffolds and engineered ADSC nanovesicles: Towards an optimized regenerative microenvironment.

Achieving sufficient bone regeneration in large segmental defects is challenging, with the structure of bone repair scaffolds and their loaded bioactive substances crucial for modulating the local osteogenic microenvironment. This study utilized digital laser processing (DLP)-based 3D printing technology to successfully fabricate high-precision methacryloylated polycaprolactone (PCLMA) bionic bone scaffold structures. Adipose-derived stem cell-engineered nanovesicles (ADSC-ENs) were uniformly and stably modified onto the bionic scaffold surface using a perfusion device, constructing a conducive microenvironment for tissue regeneration and long bone defect repair through the scaffold's structural design and the vesicles' biological functions. Scanning electron microscopy (SEM) examination of the scaffold surface confirmed the efficient loading of ADSC-ENs. The material group loaded with vesicles (PCLMA-BAS-ENs) demonstrated good cell compatibility and osteogenic potential when analyzed for the adhesion and osteogenesis of primary rabbit bone marrow mesenchymal stem cells (BMSCs) on the material surface. Tested in a 15 mm critical rabbit radial defect model, the PCLMA-BAS-ENs scaffold facilitated near-complete bone defect repair after 12 weeks. Immunofluorescence and proteomic results indicated that the PCLMA-BAS-ENs scaffold significantly improved the osteogenic microenvironment at the defect site in vivo, promoted angiogenesis, and enhanced the polarization of macrophages towards M2 phenotype, and facilitated the recruitment of BMSCs. Thus, the PCLMA-BAS-ENs scaffold was proven to significantly promote the repair of large segmental bone defects. Overall, this strategy of combining engineered vesicles with highly biomimetic scaffolds to promote large-segment bone tissue regeneration holds great potential in orthopedic and other regenerative medicine applications.

Preparation of limonin monoclonal antibody and establishment of a sensitive icELISA for analyzing limonin in citrus and herbal samples.

Limonin is an intensely bitter and highly oxidized tetracyclic triterpenoid secondary metabolite, which is abundant in the Rutaceae and Meliaceae, especially in Citrus. In order to detect limonin content in complex substrates such as citrus and traditional Chinese medicine, monoclonal antibodies specifically recognizing limonin were prepared and an indirect competitive enzyme-linked immunosorbent assay (icELISA) was established. The median inhibition concentration (IC50) was 5.40 ng/mL and the linear range was 1.25-23.84 ng/mL. The average recoveries from citrus peel and pulp samples were 95.9%-118.8% and 77.5%-113.1%, respectively. Moreover, the contents of limonin in 6 citrus samples and 4 herbal samples were analyzed by icELISA and UPLC-MS, and the results of the two methods were consistent. This validation is sufficient to demonstrate that the developed immunoassay is applicable for the detection of limonin in citrus and herbal samples and has the advantage of high efficiency, sensitivity, and convenience.

Early Structural, Biochemical, and Metabolic Responses to Anlotinib in Patients With Progressive Radioactive Iodine Refractory Differentiated Thyroid Cancer.

OBJECTIVE: We aimed to assess the early efficacy of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer at the structural, biochemical, and metabolic levels. METHODS: Ten eligible patients were prospectively enrolled to receive anlotinib. Their responses were assessed at 6 weeks. Apart from the structural response according to Response Evaluation Criteria in Solid Tumors version 1.1, the biochemical response was assessed by serum thyroglobulin (Tg), and the metabolic response was assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) according to the European Organization for Research and Treatment of Cancer criteria. A safety profile was recorded. RESULTS: Structurally controlled disease (20% partial response + 80% stable disease) was observed in all patients. The median longest diameter of target lesions shrank from 20.8 mm (IQR, 14.9-27.5) to 17.0 mm (IQR, 14.1-23.7) (P < .001), and the average shrinkage rate was -15.1 ± 14.1%. Sharp serum Tg reduction by 72.8 ± 16.4% was observed in 8 measurable patients. The 18F-FDG PET/CT-mapped glucose metabolic response was not quite comparable to the structural response, with 90% of the patients having controlled disease (30% partial metabolic response + 60% stable metabolic disease), whereas 10% presented progressive metabolic disease. The most common treatment-emergent adverse events (AEs) were hypertension (100%) and proteinuria (70%). Most AEs were grade 1 or 2, whereas grade 3 AEs occurred only in hypertension. CONCLUSION: Anlotinib is generally well tolerated and can bring early disease control within the initial 6 weeks of treatment. The sharp biochemical response suggests Tg to be an early sensitive biomarker to anlotinib, whereas the heterogeneous metabolic response might play a complementary role.

Molecular mechanisms underlying the therapeutic effects of Linggui Zhugan decoction in stroke: Insights from network pharmacology and single-cell transcriptomics analysis.

Linggui Zhugan decoction (LZD), a traditional Chinese medicine formula, has demonstrated significant therapeutic effects in managing poststroke cognitive impairment and hemiplegia. However, the precise molecular mechanisms underlying its efficacy remain incompletely elucidated. The active ingredients and target proteins of LZD were retrieved from the traditional Chinese medicine systems pharmacology database and analysis platform database, which is specifically designed for traditional Chinese medicine research. The stroke-related genes were obtained from publicly available databases. Protein-protein interaction, enrichment analysis, and single-cell data analysis were conducted to identify key cells, targets, and pathways. Molecular docking was employed to assess the binding affinity between key components and targets. Network pharmacology analysis identified 190 active ingredients and 248 targets in LZD. These targets were significantly enriched in processes and pathways such as cellular response to lipid, orexin receptor pathway, and were significantly associated with Cerebral infarction and Middle Cerebral Artery Occlusion. Intersection analysis with 2035 stroke-related genes revealed 144 potential targets, which exhibited 2870 interactions and were significantly enriched in signaling pathways such as PI3K-AKT single pathway, MAPK single pathway, and tumor necrosis factor single pathway. Gene set variation analysis showed that the targets of LZD exhibited higher enrichment scores in microglia, M2 macrophages, endothelial cells, and neutrophils, while lower enrichment scores were observed in oligodendrocytes. Furthermore, molecular docking demonstrated a strong binding affinity between key active ingredients and targets. Network pharmacology and single-cell sequencing analysis elucidated the key cells, pathways, targets, and components involved in the therapeutic mechanism of LZD for the treatment of stroke.