Chiral luminescent lanthanide–organic cages have many potential applications in enantioselective recognition, sensing, and asymmetric catalysis. However, due to the paucity of structures and their ...limited cavities, host–guest chemistry with lanthanide–organic cages has remained elusive so far. Herein, we report a guest-driven self-assembly and chiral induction approach for the construction of otherwise inaccessible Ln4L4-type (Ln = lanthanide ions, i.e., EuIII, TbIII; L = ligand) tetrahedral hosts. Single crystal analyses on a series of host–guest complexes reveal remarkable guest-adaptive cavity breathing on the tetrahedral cages, reflecting the advantage of the variation tolerance on coordination geometry of the f-elements. Meanwhile, noncovalent confinement of pyrene within the lanthanide cage not only leads to diminishment of its excimer emission but also facilitates guest to host energy transfer, opening up a new sensitization window for the lanthanide luminescence on the cage. Moreover, stereoselective self-assembly of either Λ4- or Δ4- type Eu4L4 cages has been realized via chiral induction with R/S-BINOL or R/S-SPOL templates, as confirmed by NMR, circular dichroism (CD), and circularly polarized luminescence (CPL) with high dissymmetry factors (g lum) up to ±0.125.
Mid-infrared (MIR) and near-infrared (NIR) spectroscopy combined with chemometrics were explored to classify Cabernet Sauvignon wines from different countries (Australia, Chile and China). Commercial ...wines (n = 540) were scanned in transmission mode using MIR and NIR, and their characteristic fingerprint bands were extracted at 1750-1000 cm
and 4555-4353 cm
. Through the identification system of Tri-step infrared spectroscopy, the correlation between macroscopic chemical fingerprints and geographical regions was explored more deeply. Furthermore, Principal component analysis (PCA), soft independent modelling of class analogy (SIMCA) and discriminant analysis (DA) based on MIR and NIR spectra were used to visualize or discriminate differences between samples and to realize geographical origin traceability of Cabernet Sauvignon wines. Through "external test set (n = 157)" validation, SIMCA models correctly classified 97%, 97% and 92% of Australian, Chilean and Chinese Cabernet Sauvignon wines, while the DA models correctly classified 86%, 85% and 77%, respectively. Based on unique digital fingerprints of spectroscopy (FT-MIR and FT-NIR) associated with chemometrics, geographical origin traceability was achieved in a more comprehensive, effective and rapid manner. The developed database models based on IR fingerprint spectroscopy with chemometrics could provide scientific basis and reference for geographical origin traceability of Cabernet Sauvignon wines (Australia, Chile and China).
The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among ...Chinese patients and its clinical significance remain unclear.
Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications.
Overall, 16.0% (52 of 325) of TNBC patients harbored at least 1 pathogenic or likely pathogenic germline variant. These germline variants were associated with early onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early onset of breast cancer and elevated HRD. The genes BRCA1 (7.4%), RAD51D (2.8%), and BRCA2 (2.2%) were those most frequently mutated. The RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared with Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD, and sensitivity to PARP inhibitors.
Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help identify TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC.
Somatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent ...homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.
Whole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2
) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.
A new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.
In our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.
The sluggish kinetic in electrode materials is one of the critical challenges in achieving high-power sodium ion storage. We report a coaxial core–shell nanostructure composed of carbon nanotube ...(CNT) as the core and TiO2@MoO2@C as shells for a hierarchically nanoarchitectured anode for improved electrode kinetics. The 1D tubular nanostructure can effectively reduce ion diffusion path, increase electrical conductivity, accommodate the stress due to volume change upon cycling, and provide additional interfacial active sites for enhanced charge storage and transport properties. Significantly, a synergistic effect between TiO2 and MoO2 nanostructures is investigated through ex situ solid-state nuclear magnetic resonance. The electrode exhibits a good rate capability (150 mAh g–1 at 20 A g–1) and superior cycling stability with a reversibly capacity of 175 mAh g–1 at 10 A g–1 for over 8000 cycles.
MicroRNA‐122 (miR‐122) is a liver‐specific microRNA whose expression is specifically turned on in the mouse liver during embryogenesis, thus it is expected to be involved in liver development. ...However, the role of miR‐122 in liver development and its potential underlying mechanism remain unclear. Here, we show that the expression of miR‐122 is closely correlated with four liver‐enriched transcription factors (LETFs)—hepatocyte nuclear factor (HNF) 1α, HNF3β, HNF4α, and CCAAT/enhancer‐binding protein (C/EBP) α—in the livers of developing mouse embryos and in human hepatocellular carcinoma (HCC) cell lines. Correspondingly, promoter analysis revealed that these LETFs are coordinately involved in the transcriptional regulation of miR‐122, and three HNFs directly bind to the miR‐122 promoter as transcriptional activators. Using a luciferase reporter system, we identified a group of miR‐122 targets involved in proliferation and differentiation regulation. Among these targets, the most prominently repressed target was CUTL1, a transcriptional repressor of genes specifying terminal differentiation in multiple cell lineages, including hepatocytes. We show that CUTL1 expression is gradually silenced at the posttranscriptional level during mouse liver development. Overexpression and knockdown studies both showed that miR‐122 repressed CUTL1 protein expression in HCC cell lines. Finally, we show that the stable restoration of miR‐122 in HepG2 cells suppresses cellular proliferation and activates the expression of three hepatocyte functional genes, including the cholesterol‐7α hydroxylase gene (CYP7A1), a known target of CUTL1 in hepatocytes. Conclusion: Our study provides a model in which miR‐122 functions as an effector of LETFs and contributes to liver development by regulating the balance between proliferation and differentiation of hepatocytes, at least by targeting CUTL1. HEPATOLOGY 2010
The role of circulatory proteomics in osteoporosis is unclear. Proteome‐wide profiling holds the potential to offer mechanistic insights into osteoporosis. Serum proteome with 413 proteins was ...profiled by liquid chromatography–tandem mass spectrometry (LC–MS/MS) at baseline, and the 2nd, and 3rd follow‐ups (7704 person‐tests) in the prospective Chinese cohorts with 9.8 follow‐up years: discovery cohort (n = 1785) and internal validation cohort (n = 1630). Bone mineral density (BMD) was measured using dual‐energy X‐ray absorptiometry (DXA) at follow‐ups 1 through 3 at lumbar spine (LS) and femoral neck (FN). We used the Light Gradient Boosting Machine (LightGBM) to identify the osteoporosis (OP)‐related proteomic features. The relationships between serum proteins and BMD in the two cohorts were estimated by linear mixed‐effects model (LMM). Meta‐analysis was then performed to explore the combined associations. We identified 53 proteins associated with osteoporosis using LightGBM, and a meta‐analysis showed that 22 of these proteins illuminated a significant correlation with BMD (p < 0.05). The most common proteins among them were PHLD, SAMP, PEDF, HPTR, APOA1, SHBG, CO6, A2MG, CBPN, RAIN APOD, and THBG. The identified proteins were used to generate the biological age (BA) of bone. Each 1 SD‐year increase in KDM‐Proage was associated with higher risk of LS‐OP (hazard ratio HR, 1.25; 95% CI, 1.14–1.36, p = 4.96 × 10−06), and FN‐OP (HR, 1.13; 95% CI, 1.02–1.23, p = 9.71 × 10−03). The findings uncovered that the apolipoproteins, zymoproteins, complements, and binding proteins presented new mechanistic insights into osteoporosis. Serum proteomics could be a crucial indicator for evaluating bone aging.
Serum proteomics offers potential insight into accelerated aging in osteoporosis. Osteoporosis is commonly referred to as an aging disorder characterized by decreased bone mineral density (BMD) and an elevated risk of fractures. Using longitudinal serum proteomics analyses with 413 protein species covering various protein classes in a population‐based study, we found that the proteins of apolipoproteins, zymoprotein, coagulation, immunoglobulins, complement, and binding proteins may be the potential therapeutic targets for osteoporosis. Serum proteomics could be a crucial indicator for evaluating bone aging.
Lanthanide-containing functional complexes have found a variety of applications in materials science and biomedicine because of their unique electroptical and magnetic properties. However, the poor ...stability and solubility in water of multicomponent lanthanide organic assemblies significantly limit their practical applications. We report here a series of water-stable anionic Ln2n L3n -type (n = 2, 3, 4, and 5) lanthanide organic polyhedra (LOPs) constructed by deprotonation self-assembly of three fully conjugated ligands (H4L1 and H4L2a/b) featuring a 2,6-pyridine bitetrazolate chelating moiety. The outcomes of the LOPs formation reactions were found to be very sensitive toward the reaction conditions including base, metal source, solvents, and concentrations as characterized by a combination of NMR, high-resolution ESI–MS and X-ray crystallography. Ligands H4L2a/b manifested an excellent sensitization toward lanthanide ions (Ln = EuIII and TbIII), with high luminescent quantum yields for Tb8L2a 12 (Φ = 11.2% in water) and Eu8L2b 12 (Φ = 76.8% in DMSO) measured in polar solvents. Furthermore, due to the giant molecular weight and rigidity of the polyhedral skeleton, Gd8L2b 12 showed a very high longitudinal relaxivity (r 1) of 400.53 mM–1S–1. The performance of Gd8L2b 12 as potential magnetic resonance imaging contrast agents (CAs) in vivo was evaluated with much longer retention time in the tumor sites compared with the commercial GdIII-based CAs. Dual-modal imaging potential has also been demonstrated with the mixed Eu/Gd LOPs. Our results not only provide a new design route toward water-stable multinuclear lanthanide organic assemblies but also offer potential candidates of supramolecular-edifices for bioimaging and drug delivery.
Circular RNAs (circRNAs) participate in regulating gene expression in diverse biological and pathological processes. The present study aimed to investigate the mechanism underlying the modulation of ...circRNA_000203 on expressions of fibrosis-associated genes in cardiac fibroblasts. CircRNA_000203 was shown upregulated in the diabetic mouse myocardium and in Ang-II-induced mouse cardiac fibroblasts. Enforced-expression of circRNA_000203 could increase expressions of Col1a2, Col3a1 and α-SMA in mouse cardiac fibroblasts. RNA pull-down and RT-qPCR assay indicated that circRNA_000203 could specifically sponge miR-26b-5p. Dual luciferase reporter assay revealed that miR-26b-5p interacted with 3'UTRs of Col1a2 and CTGF, and circ_000203 could block the interactions of miR-26b-5p and 3'UTRs of Col1a2 and CTGF. Transfection of miR-26b-5p could post-transcriptionaly inhibit expressions of Col1a2 and CTGF, accompanied with the suppressions of Col3a1 and α-SMA in cardiac fibroblasts. Additionally, over-expression of circRNA_000203 could eliminate the anti-fibrosis effect of miR-26b-5p in cardiac fibroblasts. Together, our results reveal that suppressing the function of miR-26b-5p contributes to the pro-fibrosis effect of circRNA_000203 in cardiac fibroblasts.
Genomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine. However, identifying a key driver gene or mutation that can be used for hepatocellular ...carcinoma (HCC) treatment remains difficult. Here, we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S (p. Gly57Ala and p. Lys63Asn). Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious. Further, we observed that wild-type UBE2S, especially in the nucleus, was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC. Functional assays revealed that overexpression of UBE2S promoted the proliferation, invasion, metastasis, and G1/S phase transition of HCC cells in vitro, and promoted the tumor growth significantly in vivo. Mechanistically, UBE2S interacted with TRIM28 in the nucleus, both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression. Most importantly, the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen (HTS) to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo, which may represent a promising strategy for HCC therapy.
PDF
