A general strategy for the synthesis of taxane diterpenes.

The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties.1As such, taxane diterpenes are one of the most well known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anti-cancer therapeutic for more than 25 years.2-6 In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here, we report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the first total syntheses of taxinine K (2), canataxapropellane (5) and dipropellane C from a single advanced intermediate. The synthetic approach deliberately eschews biomimicry, emphasizing instead the power of stereoelectronic control in orchestrating the interconversion of polycyclic frameworks.

Earth's evolving geodynamic regime recorded by titanium isotopes.

Earth's mantle has a two-layered structure, with the upper and lower mantle domains separated by a seismic discontinuity at about 660 km (refs. 1,2). The extent of mass transfer between these mantle domains throughout Earth's history is, however, poorly understood. Continental crust extraction results in Ti-stable isotopic fractionation, producing isotopically light melting residues3-7. Mantle recycling of these components can impart Ti isotope variability that is trackable in deep time. We report ultrahigh-precision 49Ti/47Ti ratios for chondrites, ancient terrestrial mantle-derived lavas ranging from 3.8 to 2.0 billion years ago (Ga) and modern ocean island basalts (OIBs). Our new Ti bulk silicate Earth (BSE) estimate based on chondrites is 0.052 ± 0.006‰ heavier than the modern upper mantle sampled by normal mid-ocean ridge basalts (N-MORBs). The 49Ti/47Ti ratio of Earth's upper mantle was chondritic before 3.5 Ga and evolved to a N-MORB-like composition between approximately 3.5 and 2.7 Ga, establishing that more continental crust was extracted during this epoch. The +0.052 ± 0.006‰ offset between BSE and N-MORBs requires that <30% of Earth's mantle equilibrated with recycled crustal material, implying limited mass exchange between the upper and lower mantle and, therefore, preservation of a primordial lower-mantle reservoir for most of Earth's geologic history. Modern OIBs record variable 49Ti/47Ti ratios ranging from chondritic to N-MORBs compositions, indicating continuing disruption of Earth's primordial mantle. Thus, modern-style plate tectonics with high mass transfer between the upper and lower mantle only represents a recent feature of Earth's history.

HTCA: a database with an in-depth characterization of the single-cell human transcriptome.

Single-cell RNA-sequencing (scRNA-seq) is one of the most used single-cell omics in recent decades. The exponential growth of single-cell data has immense potential for large-scale integration and in-depth explorations that are more representative of the study population. Efforts have been made to consolidate published data, yet extensive characterization is still lacking. Many focused on raw-data database constructions while others concentrate mainly on gene expression queries. Hereby, we present HTCA (www.htcatlas.org), an interactive database constructed based on ∼2.3 million high-quality cells from ∼3000 scRNA-seq samples and comprised in-depth phenotype profiles of 19 healthy adult and matching fetal tissues. HTCA provides a one-stop interactive query to gene signatures, transcription factor (TF) activities, TF motifs, receptor-ligand interactions, enriched gene ontology (GO) terms, etc. across cell types in adult and fetal tissues. At the same time, HTCA encompasses single-cell splicing variant profiles of 16 adult and fetal tissues, spatial transcriptomics profiles of 11 adult and fetal tissues, and single-cell ATAC-sequencing (scATAC-seq) profiles of 27 adult and fetal tissues. Besides, HTCA provides online analysis tools to perform major steps in a typical scRNA-seq analysis. Altogether, HTCA allows real-time explorations of multi-omics adult and fetal phenotypic profiles and provides tools for a flexible scRNA-seq analysis.

Myelin repair of spinal cord injury in adult mice induced by treadmill training upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha.

Growing evidence has proven the efficacy of physical exercise in remyelination and motor function performance after spinal cord injury (SCI). However, the molecular mechanisms of treadmill training on myelin repair and functional recovery after SCI have not yet been fully studied. Here, we explored the effect of treadmill training on upregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α)-mediated myelin repair and functional recovery in a mouse model of thoracic T10 contusion injury. A 4-week treadmill training scheme was conducted on mice with SCI. The expression levels of oligodendrogenesis-related protein and PGC1α were detected by immunofluorescence, RNA fluorescence in situ hybridization and western blotting. Transmission electron microscopy (TEM) was used to observe myelin structure. The Basso Mouse Scale (BMS) and CatWalk automated gait analysis system were used for motor function recovery evaluation. Motor evoked potentials (MEPs) were also identified. In addition, adeno-associated virus (AAV)-mediated PGC1α knockdown in OLs was used to further unravel the role of PGC1α in exercise-induced remyelination. We found that treadmill training boosts oligodendrocyte precursor cells (OPCs) proliferation, potentiates oligodendrocytes (OLs) maturation, and increases myelin-related protein and myelin sheath thickness, thus impelling myelin repair and hindlimb functional performance as well as the speed and amplitude of nerve conduction after SCI. Additionally, downregulating PGC1α through AAV attenuated these positive effects of treadmill training. Collectively, our results suggest that treadmill training enhances remyelination and functional recovery by upregulating PGC1α, which should provide a step forward in the understanding of the effects of physical exercise on myelin repair.

Ursa: A Comprehensive Multiomics Toolbox for High-Throughput Single-Cell Analysis.

The burgeoning amount of single-cell data has been accompanied by revolutionary changes to computational methods to map, quantify, and analyze the outputs of these cutting-edge technologies. Many are still unable to reap the benefits of these advancements due to the lack of bioinformatics expertise. To address this issue, we present Ursa, an automated single-cell multiomics R package containing 6 automated single-cell omics and spatial transcriptomics workflows. Ursa allows scientists to carry out post-quantification single or multiomics analyses in genomics, transcriptomics, epigenetics, proteomics, and immunomics at the single-cell level. It serves as a 1-stop analytic solution by providing users with outcomes to quality control assessments, multidimensional analyses such as dimension reduction and clustering, and extended analyses such as pseudotime trajectory and gene-set enrichment analyses. Ursa aims bridge the gap between those with bioinformatics expertise and those without by providing an easy-to-use bioinformatics package for scientists in hoping to accelerate their research potential. Ursa is freely available at https://github.com/singlecellomics/ursa.

Genetic and phenotypic links between obesity and extracellular vesicles.

Obesity has a highly complex genetic architecture, making it difficult to understand the genetic mechanisms, despite the large number of discovered loci via genome-wide association studies (GWAS). Omics techniques have provided a better resolution to view this problem. As a proxy of cell-level biology, extracellular vesicles (EVs) are useful for studying cellular regulation of complex phenotypes such as obesity. Here, in a well-established Scottish cohort, we utilized a novel technology to detect surface proteins across millions of single EVs in each individual's plasma sample. Integrating the results with established obesity GWAS, we inferred 78 types of EVs carrying one or two of 12 surface proteins to be associated with adiposity-related traits such as waist circumference. We then verified that particular EVs' abundance is negatively correlated with body adiposity, while no association with lean body mass. We also revealed that genetic variants associated with protein-specific EVs capture 2-4-fold heritability enrichment for blood cholesterol levels. Our findings provide evidence that EVs with specific surface proteins have phenotypic and genetic links to obesity and blood lipids, respectively, guiding future EV biomarker research.

Quantification of eosinophilic area and its potential molecular feature in clear cell renal cell carcinoma.

OBJECTIVE: Previous studies have acknowledged the presence of eosinophilic cytoplasm in clear cell renal cell carcinoma, yet the precise quantification method and potential molecular attributes in clear cell renal cell carcinoma remain elusive. This study endeavours to precisely quantify the eosinophilic attribute and probe into the molecular mechanisms governing its presence in clear cell renal cell carcinoma. METHODS: Data from cohorts of clear cell renal cell carcinoma patients who underwent nephrectomy, comprising The Cancer Genome Atlas cohort (n = 475) and Sun Yat-sen University Cancer Center cohort (n = 480), were aggregated to assess the eosinophilic attribute. Additionally, Omics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) (n = 58) were leveraged to explore the potential molecular features associated with eosinophilic clear cell renal cell carcinoma. Employing receiver operating characteristic curve analysis, the proportion of tumour cells with eosinophilic cytoplasm was determined, leading to the classification of each cohort into distinct groups: a clear group (<5%) and an eosinophilic group (≥5%). RESULTS: In both cohorts, the eosinophilic feature consistently correlated with higher International Society of Urological Pathology (ISUP) grade, elevated tumor stage, and the presence of necrosis. Furthermore, the Kaplan-Meier method demonstrated that patients in the eosinophilic group exhibited shorter overall survival or disease-free survival compared with those in the clear group, a pattern reaffirmed in various stratified survival analyses. Intriguingly, within The Cancer Genome Atlas cohort, the pathological characterization of cell cytoplasm (eosinophilic vs. clear) emerged as an independent risk factor for overall survival (hazard ratio = 2.507 [95% confidence interval: 1.328-4.733], P = 0.005) or disease-free survival (hazard ratio = 1.730 [95% confidence interval: 1.062-2.818], P = 0.028) via Cox regression analysis. Moreover, multi-Omics data unveiled frequent BAP1 mutations and down-regulation of Erythroblast Transformation-Specific-Related Gene associated with the eosinophilic feature in clear cell renal cell carcinoma. Additionally, patients with low expression of Erythroblast Transformation-Specific-Related Gene showed worse overall survival (P < 0.001). CONCLUSIONS: The quantification of the eosinophilic feature serves as a robust predictor of clinical prognosis in clear cell renal cell carcinoma. Furthermore, the manifestation of this feature may be linked to BAP1 mutations and the down-regulation of Erythroblast Transformation-Specific-Related Gene in clear cell renal cell carcinoma. Significantly, the expression levels of Erythroblast Transformation-Specific-Related Gene manifest as an exemplary prognostic marker, providing exceptional predictive accuracy for the clinical prognosis in clear cell renal cell carcinoma.

Isoform-level quantification for single-cell RNA sequencing.

MOTIVATION: RNA expression at isoform level is biologically more informative than at gene level and can potentially reveal cellular subsets and corresponding biomarkers that are not visible at gene level. However, due to the strong 3' bias sequencing protocol, mRNA quantification for high-throughput single-cell RNA sequencing such as Chromium Single Cell 3' 10× Genomics is currently performed at the gene level. RESULTS: We have developed an isoform-level quantification method for high-throughput single-cell RNA sequencing by exploiting the concepts of transcription clusters and isoform paralogs. The method, called Scasa, compares well in simulations against competing approaches including Alevin, Cellranger, Kallisto, Salmon, Terminus and STARsolo at both isoform- and gene-level expression. The reanalysis of a CITE-Seq dataset with isoform-based Scasa reveals a subgroup of CD14 monocytes missed by gene-based methods. AVAILABILITY AND IMPLEMENTATION: Implementation of Scasa including source code, documentation, tutorials and test data supporting this study is available at Github: https://github.com/eudoraleer/scasa and Zenodo: https://doi.org/10.5281/zenodo.5712503. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

IGF-1 Combined with OPN Promotes Neuronal Axon Growth in Vitro Through the IGF-1R/Akt/mTOR Signaling Pathway in Lipid Rafts.

This study aims to investigate the effect of insulin-like growth factor 1 (IGF-1) combined with osteopontin (OPN) on the protein expression levels and growth of neuronal axons and its possible mechanism. In this study, IGF-1 combined with OPN promoted neuronal axon growth through the IGF-1R/Akt/mTOR signaling pathway in lipid rafts, and the effect was better than that of either agent alone. This effect was suppressed when given the mTOR inhibitor rapamycin or the lipid raft cholesterol extraction agent methyl-ß-cyclodextrin (M-ß-CD). Rapamycin could inhibit the expression of phosphorylated ribosomal S6 protein (p-S6) and phosphorylated protein kinase B (p-Akt) and limit axon growth. In addition to the above effects, M-ß-CD significantly downregulated the expression of phosphorylated insulin-like growth factor 1 receptor (p-IR). To further investigate the changes in lipid rafts when stimulated by different recombinant proteins, membrane lipid rafts were isolated to observe the changes by western blot. The expression levels of insulin-like growth factor 1 receptor (IR) and P-IR in the IGF-1 combined with OPN group were the highest. When M-ß-CD was administered to the lipid rafts of neurons, the enrichment of IR by IGF-1 combined with OPN was weakened, and the p-IR was decreased. Our study found that IGF-1 combined with OPN could promote axon growth by activating the IGF-1R/Akt/mTOR signaling pathway in neuronal lipid rafts.

Two-dimensional Janus pentagonal MSeTe (M = Ni, Pd, Pt): promising water-splitting photocatalysts and optoelectronic materials.

Inspired by the interesting and novel properties exhibited by Janus transition metal dichalcogenides (TMDs) and two-dimensional pentagonal structures, we here investigated the structural stability, mechanical, electronic, photocatalytic, and optical properties for a class of two-dimensional (2D) pentagonal Janus TMDs, namely penta-MSeTe (M = Ni, Pd, Pt) monolayers, by using density functional theory (DFT) combined with Hubbard's correction (U). Our results showed that these monolayers exhibit good structural stability, appropriate band structures for photocatalysts, high visible light absorption, and good photocatalytic applicability. The calculated electronic properties reveal that the penta-MSeTe are semiconductors with a bandgap range of 2.06-2.39 eV, and their band edge positions meet the requirements for water-splitting photocatalysts in various environments (pH = 0-13). We used stress engineering to seek higher solar-to-hydrogen (STH) efficiency in acidic (pH = 0), neutral (pH = 7) and alkaline (pH = 13) environments for penta-MSeTe from 0% to +8% biaxial and uniaxial strains. Our results showed that penta-PdSeTe stretched 8% along the y direction and demonstrates an STH efficiency of up to 29.71% when pH = 0, which breaks the theoretical limit of the conventional photocatalytic model. We also calculated the optical properties and found that they exhibit high absorption (13.11%) in the visible light range and possess a diverse range of hyperbolic regions. Hence, it is anticipated that penta-MSeTe materials hold great promise for applications in photocatalytic water splitting and optoelectronic devices.

Role of a DEF/Y motif in histone H2A-H2B recognition and nucleosome editing.

The SWR complex edits the histone composition of nucleosomes at promoters to facilitate transcription by replacing the two nucleosomal H2A-H2B (A-B) dimers with H2A.Z-H2B (Z-B) dimers. Swc5, a subunit of SWR, binds to A-B dimers, but its role in the histone replacement reaction was unclear. In this study, we showed that Swc5 uses a tandem DEF/Y motif within an intrinsically disordered region to engage the A-B dimer. A 2.37-Å X-ray crystal structure of the histone binding domain of Swc5 in complex with an A-B dimer showed that consecutive acidic residues and flanking hydrophobic residues of Swc5 form a cap over the histones, excluding histone-DNA interaction. Mutations in Swc5 DEF/Y inhibited the nucleosome editing function of SWR in vitro. Swc5 DEF/Y interacts with histones in vivo, and the extent of this interaction is dependent on the remodeling ATPase of SWR, supporting a model in which Swc5 acts as a wedge to promote A-B dimer eviction. Given that DEF/Y motifs are found in other evolutionary unrelated chromatin regulators, this work provides the molecular basis for a general strategy used repeatedly during eukaryotic evolution to mobilize histones in various genomic functions.

A Global Survey of the Full-Length Transcriptome of Apis mellifera by Single-Molecule Long-Read Sequencing.

As important pollinators, honey bees play a crucial role in both maintaining the ecological balance and providing products for humans. Although several versions of the western honey bee genome have already been published, its transcriptome information still needs to be refined. In this study, PacBio single-molecule sequencing technology was used to sequence the full-length transcriptome of mixed samples from many developmental time points and tissues of A. mellifera queens, workers and drones. A total of 116,535 transcripts corresponding to 30,045 genes were obtained. Of these, 92,477 transcripts were annotated. Compared to the annotated genes and transcripts on the reference genome, 18,915 gene loci and 96,176 transcripts were newly identified. From these transcripts, 136,554 alternative splicing (AS) events, 23,376 alternative polyadenylation (APA) sites and 21,813 lncRNAs were detected. In addition, based on the full-length transcripts, we identified many differentially expressed transcripts (DETs) between queen, worker and drone. Our results provide a complete set of reference transcripts for A. mellifera that dramatically expand our understanding of the complexity and diversity of the honey bee transcriptome.

Single-Atom or Dual-Atom in TiO2 Nanosheet: Which is the Better Choice for Electrocatalytic Urea Synthesis?

As rising star materials, single-atom and dual-atom catalysts have been widely reported in the electro-catalysis area. To answer the key question: single-atom and dual-atom catalysts, which is better for electrocatalytic urea synthesis? we design two types of catalysts via a vacancy-anchorage strategy: single-atom Pd1 -TiO2 and dual-atom Pd1 Cu1 -TiO2 nanosheets. An ultrahigh urea activity of 166.67 molurea molPd -1 h1 with the corresponding 22.54 % Faradaic efficiency at -0.5 V vs. reversible hydrogen electrode (RHE) is achieved over Pd1 Cu1 -TiO2 , which is much higher than that of Pd1 -TiO2 . Various characterization including an in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and theoretical calculations demonstrate that dual-atom Pd1 Cu1 site in Pd1 Cu1 -TiO2 is more favorable for producing urea, which experiences a C-N coupling pathway with a lower energy barrier compared with Pd1 in Pd1 -TiO2 .

Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin.

BACKGROUND: Metastatic breast carcinoma is commonly considered during differential diagnosis when metastatic disease is detected in females. In addition to the tumor morphology and documented clinical history, sensitive and specific immunohistochemical (IHC) markers such as GCDFP-15, mammaglobin, and GATA3 are helpful for determining breast origin. However, these markers are reported to show lower sensitivity in certain subtypes, such as triple-negative breast cancer (TNBC). MATERIALS AND METHODS: Using bioinformatics analyses, we identified a potential diagnostic panel to determine breast origin: matrix Gla protein (MGP), transcriptional repressor GATA binding 1 (TRPS1), and GATA-binding protein 3 (GATA3). We compared MGP, TRPS1, and GATA3 expression in different subtypes of breast carcinoma of (n = 1201) using IHC. As a newly identified marker, MGP expression was also evaluated in solid tumors (n = 2384) and normal tissues (n = 1351) from different organs. RESULTS: MGP and TRPS1 had comparable positive expression in HER2-positive (91.2% vs. 92.0%, p = 0.79) and TNBC subtypes (87.3% vs. 91.2%, p = 0.18). GATA3 expression was lower than MGP (p < 0.001) or TRPS1 (p < 0.001), especially in HER2-positive (77.0%, p < 0.001) and TNBC (43.3%, p < 0.001) subtypes. TRPS1 had the highest positivity rate (97.9%) in metaplastic TNBCs, followed by MGP (88.6%), while only 47.1% of metaplastic TNBCs were positive for GATA3. When using MGP, GATA3, and TRPS1 as a novel IHC panel, 93.0% of breast carcinomas were positive for at least two markers, and only 9 cases were negative for all three markers. MGP was detected in 36 cases (3.0%) that were negative for both GATA3 and TRPS1. MGP showed mild-to-moderate positive expression in normal hepatocytes, renal tubules, as well as 31.1% (99/318) of hepatocellular carcinomas. Rare cases (0.6-5%) had focal MGP expression in renal, ovarian, lung, urothelial, and cholangiocarcinomas. CONCLUSIONS: Our findings suggest that MGP is a newly identified sensitive IHC marker to support breast origin. MGP, TRPS1, and GATA3 could be applied as a reliable diagnostic panel to determine breast origin in clinical practice.

Ratiometric Luminescence Aptasensor Based on Dual-Emissive Persistent Luminescent Nanoparticles for Autofluorescence- and Exogenous Interference-Free Determination of Trace Aflatoxin B1 in Food Samples.

Sensitive and accurate determination of aflatoxin B1 (AFB1) is of great significance to food safety and human health as it is recognized as the most toxic mycotoxin and carcinogenic. Herein, we report a ratiometric luminescence aptasensor based on dual-emissive persistent luminescent nanoparticles (PLNP) for the accurate determination of trace AFB1 in complex food samples without autofluorescence and exogenous interference. Dual-emissive PLNP ZnGa2O4:Cr0.0001 was prepared first and acted as the donor for energy transfer as well as the signal unit with phosphorescence at 714 and 508 nm (the detection and the reference signal, respectively). AFB1 aptamer was then bonded on the surface of PLNP to offer specific recognition ability. Aptamer complementary DNA modified with Cy5.5 was employed as the acceptor for energy transfer and the quenching group to eventually develop a turn-on ratiometric luminescence aptasensor. The developed ratiometric luminescence aptasensor combined the merits of long-lasting luminescence, in situ excitation and autofluorescence-free of PLNP, exogenous interference-free and self-calibration reading of ratiometric sensor, as well as the high selectivity of aptamer, holding great promise for accurate determination of trace AFB1 in complex matrix. The developed ratiometric aptasensor exhibited excellent linearity (0.05-70 ng mL-1), low limit of detection (0.016 ng mL-1), and good precision (2.3% relative standard deviation for 11 replicate determination of 1 ng mL-1 AFB1). The proposed ratiometric aptasensor was successfully applied for the determination of AFB1 in corn, wheat, peanut, millet, oats, and wheat kernels with recoveries of 95.1-106.5%.

The Chemistry of Nonclassical Taxane Diterpene.

The taxane diterpenes are a pharmaceutically vital family of natural products, consisting of more than 550 congeners. All taxane diterpenes are isolated from slow growing evergreen shrubs (genus Taxus) commonly known as "yews" and have a history of over 50 years as potent anticancer compounds. The most prominent congener, taxol (paclitaxel = PTX), has been used in clinics for more than 25 years and is one of the top-selling anticancer drugs worldwide, with annual sales reaching 1.5 billion USD in 1999. Within the taxane diterpene family 11 different scaffolds originating from rearrangements, fragmentations, or transannular C-C bond formations of the "classical taxane core" are known. Among them, five different scaffolds alone belong to the so-called complex or cyclotaxane subfamily, their signature structural feature bearing different types and numbers of transannular C-C bonds across the classical taxane backbone. For synthetic chemists, these five scaffolds represent by far the most challenging of all and have thus evaded total synthesis as well as detailed pharmaceutical evaluation-the latter due to extremely poor sourcing from natural producers. The cousinship of complex taxanes to taxol renders them potentially interesting compounds for drug research in the fight against cancer.This Account specifically summarizes the work on nonclassical taxanes from a biosynthetic, as well as a synthetic, point and provides a synthetic perspective on complex taxanes. Special attention is given to the biosynthetic relationship of complex taxanes and their biological emergence from classical taxanes. The transannular C-C bond forming events in the biosynthesis leading to the five individual scaffolds within this subfamily are structured on the basis of the exact type and number of these specific C-C bond formations. Since functionalization of the classical taxane core in the "oxidase phase" of the biosynthesis precedes the formation of complex taxanes, and is in part prerequisite for these transannular cyclization events, a detailed discussion of these oxidations of the classical taxane backbone is provided. Synthetic efforts toward nonclassical taxanes are scarce in literature and are thus presented in a comprehensive manner for abeotaxanes and complex taxanes. The last part of this Account deals with a synthetic perspective on the synthesis of complex taxanes (cyclotaxanes) and how these most intricate scaffolds can potentially be obtained via a deconvolution strategy. This discussion involves in part unpublished results by our group and is based upon synthetic studies in the literature. The deconvolution strategy we advocate aims for selective fragmentations of the signature transannular C-C bonds of the most intricate scaffold represented by the natural product canataxpropellane, which has recently been synthesized by our group. This strategy represents the converse process of the biosynthesis of complex taxanes (e.g., transannular cyclizations) and is enabled and feasible due to our approach to the canataxpropellane scaffold. We show that, by following this deconvolution strategy, all five scaffolds of complex taxanes can thereby be accessed.

Preparation and Characterization of Simvastatin-Loaded PCL/PEG Nanofiber Membranes for Drug Sustained Release.

Simvastatin (SIM) particles are liposoluble drugs with large particle sizes, resulting in poor compatibility with electrospun polycaprolactone (PCL)/polyethylene glycol (PEG) nanofibers, so that part of them will be exposed to the electrospun nanofiber surface, which is easy to cause the burst release of drugs. Therefore, in this paper, stearic acid (SA) with good biocompatibility was innovatively added to increase the dispersion uniformity of SIM in the spinning solution, thus improving the performances of SIM-loaded PCL/PEG nanofiber membranes (NFMs). Accordingly, the effects of SA addition on the morphologies, mechanical properties, wettability, and drug release properties of the SIM-loaded NFMs were studied. The results showed that after SIM was dissolved in SA solution, the particle size of SIM was significantly reduced and could be evenly dispersed in the polymer spinning solution, thus obtaining the SIM-loaded composite NFMs with the best morphology and performance.

3,4-Seco-Isopimarane Diterpenes from the Twigs and Leaves of Isodon Flavidus.

Three isopimarane diterpenes [fladins B (1), C (2), and D (3)] were isolated from the twigs and leaves of Chinese folk medicine, Isodon flavidus. The chemical structures were determined by the analysis of the comprehensive spectroscopic data, and the absolute configuration was confirmed by X-ray crystallographic analysis. The structures of 1-3 were formed from isopimaranes through the rearrangement of ring A by the bond break at C-3 and C-4 to form a new δ-lactone ring system between C-3 and C-9. This structure type represents the first discovery of a natural isopimarane diterpene with an unusual lactone moiety at C-9 and C-10. In the crystal of 1, molecules are linked to each other by intermolecular O-H···O bonds, forming chains along the b axis. Compounds 1-3 were evaluated for their bioactivities against different diseases. None of these compounds displayed cytotoxic activities against HCT116 and A549 cancer cell lines, antifungal activities against Trichophyton rubrum and T. mentagrophytes, or antiviral activities against HIV entry at 20 µg/mL (62.9-66.7) µM. Compounds 1 and 3 did not show antiviral activities against Ebola entry at 20 µg/mL either; only 2 was found to show an 81% inhibitory effect against Ebola entry activity at 20 µg/mL (66.7 µM). The bioactivity evidence suggested that this type of compound could be a valuable antiviral lead for further structure modification to improve the antiviral potential.

Dual-Emissive Persistent Luminescence Nanoparticle-Based Charge-Reversible Intelligent Nanoprobe for Persistent Luminescence-Ratio Bioimaging along with Chemo-Photothermal Synergic Therapy.

Persistent luminescence nanoparticles (PLNPs) hold great promise for bioimaging owing to no demand for in situ excitation and negligible tissue autofluorescence interference. Nevertheless, huge challenges remain in the further development of single-emissive PLNPs due to the great variation of luminescence with time after excitation ceases. Herein, we report the controllable fabrication of dual-emissive monodispersed PLNPs (ZnGa2O4:Cr) by a surfactant-assisted hydrothermal method in combination with postcalcination for bioimaging. The prepared PLNPs emit luminescence at 508 and 714 nm with a constant luminescence ratio (I508/I714) for more than 1 h after UV excitation stops. Moreover, the prepared PLNPs give a constant I508/I714 ratio signal after repeated excitation by a LED lamp, allowing luminescence ratio imaging to ensure the long-term accuracy for in vivo imaging. In vivo ratio imaging demonstrates the potential of the prepared PLNPs for precision bioimaging. In addition, the prepared PLNPs have been applied to fabricate a theranostic nanoprobe with intelligent tumor-targeted imaging and chemo-photothermal synergistic therapy to further reveal their unique advantage for imaging guided therapy. We believe that the dual-emissive PLNPs will provide a promising nanoplatform for bioimaging and biomedical applications.

Deficiency in the frequency and function of Tr1 cells in IgAV and the possible role of IL-27.

OBJECTIVE: Type 1 regulatory T (Tr1) cells are involved in the pathogenesis of numerous immune-mediated diseases. However, little is known about whether and how Tr1 cells affect the development of IgA vasculitis (IgAV). We aimed to investigate this question in IgAV patients. METHODS: . Tr1 cells in peripheral blood and kidney tissue of IgAV patients were analysed by multi-parametric flow cytometry and immunofluorescence techniques. An in vitro assay of suppression of T cell proliferation and cytokine release was performed to evaluate the function of Tr1 cells. Real-time PCR and cell stimulation in vitro were used to explore the roles of IL-27 and early growth response gene 2 (EGR2). RESULTS: The frequency of Tr1 cells was decreased in peripheral blood but increased in kidney tissue from IgAV patients. A defective suppressive function of Tr1 cells in IgAV was observed. The frequency of Tr1 cells and the cytokines secreted by them were up-regulated in the presence of recombinant IL-27 in vitro. Moreover, IL-27 also increased the expression of EGR2. Furthermore, lower frequency of Tr1 cells during remission had a higher recurrence rate. CONCLUSION: Tr1 cells are involved in the pathogenesis of IgAV. The low IL-27 in IgAV is responsible for impaired frequency and function of Tr1 cells, and EGR2 may be the specific transcription factor involved in the progression. Tr1 may be a risk factor for IgAV recurrence.