Synthesis of 12-Connected Three-Dimensional Covalent Organic Framework with lnj Topology.

The structural exploration of three-dimensional covalent organic frameworks (3D COFs) is of great significance to the development of COF materials. Different from structurally diverse MOFs, which have a variety of connectivity (3-24), now the valency of 3D COFs is limited to only 4, 6, and 8. Therefore, the exploration of organic building blocks with higher connectivity is a necessary path to broaden the scope of 3D COF structures. Herein, for the first time, we have designed and synthesized a 12-connected triptycene-based precursor (triptycene-12-CHO) with 12 symmetrical distributions of aldehyde groups, which is also the highest valency reported until now. Based on this unique 12-connected structure, we have successfully prepared a novel 3D COF with lnj topology (termed 3D-lnj-COF). The as-synthesized 3D COF exhibits honeycomb main pores and permanent porosity with a Brunauer-Emmett-Teller surface area of 1159.6 m2 g-1. This work not only provides a strategy for synthesizing precursors with a high connectivity but also provides inspiration for enriching the variety of 3D COFs.

Vibrotactile stimulation at gamma frequency mitigates pathology related to neurodegeneration and improves motor function.

The risk for neurodegenerative diseases increases with aging, with various pathological conditions and functional deficits accompanying these diseases. We have previously demonstrated that non-invasive visual stimulation using 40 Hz light flicker ameliorated pathology and modified cognitive function in mouse models of neurodegeneration, but whether 40 Hz stimulation using another sensory modality can impact neurodegeneration and motor function has not been studied. Here, we show that whole-body vibrotactile stimulation at 40 Hz leads to increased neural activity in the primary somatosensory cortex (SSp) and primary motor cortex (MOp). In two different mouse models of neurodegeneration, Tau P301S and CK-p25 mice, daily exposure to 40 Hz vibrotactile stimulation across multiple weeks also led to decreased brain pathology in SSp and MOp. Furthermore, both Tau P301S and CK-p25 mice showed improved motor performance after multiple weeks of daily 40 Hz vibrotactile stimulation. Vibrotactile stimulation at 40 Hz may thus be considered as a promising therapeutic strategy for neurodegenerative diseases with motor deficits.

Wide identification of chemical constituents in fermented licorice and explore its efficacy of anti-neurodegeneration by combining quasi-targeted metabolomics and in-depth bioinformatics.

Licorice (Gan-Cao in Chinese) is one of the most famous herbal medicines around the world. The fermentation of probiotics and herbs can change the chemical constituents and significantly improve the efficacy. However, it is still unknown whether licorice fermented with probiotics would produce beneficial therapeutic effects. This study aimed to comprehensively analyze the chemical constituents in fermented licorice via quasi-targeted metabolomics, predict the potential efficacy of fermentation products via diverse bioinformatic methods, and further verify the efficacy of fermentation products through in vitro and in vivo experiments. As a result, 1,435 compounds were identified totally. Among them, 424 natural medicinal products were classified with potentially important bioactivities, including 11 anthocyanins, 10 chalcones and dihydrochalcones, 25 flavanones, 45 flavones and flavonols, 117 flavonoids, 34 isoflavonoids, 21 phenols and its derivatives, 20 phenylpropanoids and polyketides, 96 terpenoids and 25 coumarins and derivatives. Interestingly, bioinformatic prediction showed that the targets of some important compounds were related to neurodegeneration, oxidoreductase activity and response to stress. In vitro and in vivo tests further verified that fermented licorice had excellent effects of DPPH clearance, anti-oxidation, anti-neurodegeneration, and anti-stress. Thus, this study would provide a reference method for related research and the development of fermented licorice-related products.

Rh(III)-Catalyzed Double C-H Functionalization of Indoles with Cyclopropenones via Sequential C-H/C-C/C-H Bond Activation.

An unprecedented Rh(III)-catalyzed double C-H functionalization of indoles with cyclopropenones via sequential C-H/C-C/C-H bond activation has been developed. This procedure represents the first example for assembling of cyclopenta[b]indoles utilizing cyclopropenones as 3C synthons. This powerful approach shows excellent chemo- and regioselectivity, wide functional group tolerance, and good reaction yields.

Large-Scale and Highly Efficient Production of Ultrafine PVA Fibers by Electro-Centrifugal Spinning for NH3 Adsorption.

Ultrafine Polyvinyl alcohol (PVA) fibers have an outstanding potential in various applications, especially in absorbing fields. In this manuscript, an electrostatic-field-assisted centrifugal spinning system was designed to improve the production efficiency of ultrafine PVA fibers from PVA aqueous solution for NH3 adsorption. It was established that the fiber production efficiency using this self-designed system could be about 1000 times higher over traditional electrospinning system. The produced PVA fibers establish high morphology homogeneity. The impact of processing variables of the constructed spinning system including rotation speed, needle size, liquid feeding rate, and voltage on fiber morphology and diameter was systematically investigated by SEM studies. To acquire homogeneous ultrafine PVA fiber membranes, the orthogonal experiment was also conducted to optimize the spinning process parameters. The impact weight of different studied parameters on the spinning performance was thus provided. The experimental results showed that the morphology of micro/nano-fibers can be well controlled by adjusting the spinning process parameters. Ultrafine PVA fibers with the diameter of 2.55 µm were successfully obtained applying the parameters, including rotation speed (6500 rpm), needle size (0.51 mm), feeding rate (3000 mL h-1), and voltage (20 kV). Furthermore, the obtained ultrafine PVA fiber mat was demonstrated to be capable of selectively adsorbing NH3 gas relative to CO2, thus making it promising for NH3 storage and other environmental purification applications.

CEMIP, acting as a scaffold protein for bridging GRAF1 and MIB1, promotes colorectal cancer metastasis via activating CDC42/MAPK pathway.

Metastasis is the leading cause of treatment failure and tumor-related death in colorectal cancer (CRC). Our previous studies report that CEMIP functionally promotes CRC metastasis and is closely related to poor outcomes. However, the molecular network of CEMIP promoting CRC metastasis is still not fully understood. In the current study, we identify CEMIP interacting with GRAF1, and the combination of high-CEMIP and low-GRAF1 predicts poor survival of patients. Mechanistically, we elucidate that CEMIP interacts with the SH3 domain of GRAF1 through the 295-819aa domain, and negatively regulates the stability of GRAF1. Moreover, we identify MIB1 to be an E3 ubiquitin ligase for GRAF1. Importantly, we uncover that CEMIP acts as a scaffold protein in bridging MIB1 and GRAF1, which is critical to GRAF1 degradation and CEMIP-mediated CRC metastasis. Furthermore, we found that CEMIP activates CDC42/MAPK pathway-regulated EMT by enhancing the degradation of GRAF1, which is indispensable to CEMIP-mediated migration and invasion of CRC cells. Subsequently, we prove that CDC42 inhibitor suppresses CEMIP-mediated CRC metastasis in vitro and in vivo. Collectively, our results reveal that CEMIP promotes CRC metastasis through GRAF1/CDC42/MAPK pathway-regulated EMT, and suggest that CDC42 inhibitor could be a novel therapeutic strategy for CEMIP-mediated CRC metastasis.

A nitric oxide responsive AIE probe for detecting the progression of osteoarthritis.

Nitric oxide (NO) is reported to be elevated in osteoarthritis (OA) both in vitro and in vivo and may be adopted to develop fluorescent probes for detecting the progression of OA. Here we report a nitric oxide responsive aggregation induced emission (AIE) probe TPE-2NHCOCH2CH2-(PEG)24-NH-Diacerein, which is derived from tetraphenylethene (TPE) modified with the hydrophilic group long poly(ethylene glycol) chain and an anti-inflammatory drug diacerein. o-Phenylenediamine within its structure can react with NO to form benzotriazole and emit fluorescence. The results show that the NO-responsive AIE probe can smartly monitor the progression of OA with the change of fluorescence intensity in vitro and in vivo. This study may provide a new development direction for early OA monitoring in clinics.

Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation.

BACKGROUND: Loss of major histocompatibility complex class I (MHC-I) in tumor cells limits the use of immune checkpoint blockade (ICB) in colorectal cancer. Nevertheless, the regulatory mechanism of MHC-I downregulation in tumor cells has not been fully elucidated. Overexpression of CEMIP in tumor tissues is associated with a poor prognosis in colorectal cancer. Here, in this research, we aim to address the role of CEMIP in mediating MHC-I expression in tumor cells and investigate the underlying regulatory mechanisms. METHOD: Protein levels were analyzed by western blotting. Flow cytometry analysis was used to examine immune cells. Protein-protein interactions were investigated by co-immunoprecipitation and proximity ligation assays. The intracellular trafficking of MHC-I was revealed by an immunofluorescent technique. In addition, the effect of CEMIP on tumor growth and the antitumor efficacy of targeting CEMIP in combination with ICB therapy were evaluated in murine models of colorectal cancer. RESULTS: We reported that CEMIP specifically downregulated the expression of MHC-I on the surface of murine and human colon cancer cells, hindering the cytotoxicity of CD8+ T cells. We also demonstrated that CEMIP restricted CD8+ T-cell antitumor activities both in vitro and in vivo due to impaired MHC-I-mediated antigen presentation. Correspondingly, the combination of CEMIP inhibition and ICB impeded tumor growth and enhanced therapeutic efficacy. Mechanistically, CEMIP acted as an adaptor for the interaction betweenMHC-I and clathrin, which drove MHC-I internalization via clathrin-dependent endocytosis. Furthermore, CEMIP anchored internalized MHC-I to lysosomes for degradation, disrupting the recycling of MHC-I to the cell surface. CONCLUSION: Overall, our study unveils a novel regulatory mechanism of MHC-I on tumor cell surfaces by CEMIP-mediated internalization and degradation. Furthermore, targeting CEMIP provides an effective strategy for colorectal cancer immunotherapy.

Research on the Mechanism of Multi-Domain Coupling Centrifugal Electrostatic Blowing Flying Deposition.

The centrifugal electrostatic blowing process proposed in this paper solves the difficult continuous and stable deposition problem in the traditional centrifugal electrostatic spinning process. By establishing a flight deposition model of the centrifugal electrostatic spraying process, CFD is used to simulate and analyze the electrohydrodynamic effect of centrifugal jets, and the driving mechanism is explored. Subsequently, MATLAB is used to obtain the optimal solution conditions, and finally, the establishment of a two-dimensional flight trajectory model is completed and experimentally verified. In addition, the deposition model of the jet is established to clarify the flight trajectory under the multi-field coupling, the stable draft area of the jet is found according to this, and the optimal drafting station is clarified. This research provides new ideas and references for the exploration of the deposition mechanism of the centrifugal electrostatic blowing and electrostatic spinning process.

KIAA1199 drives immune suppression to promote colorectal cancer liver metastasis by modulating neutrophil infiltration.

BACKGROUND AND AIMS: Metastasis is the primary cause of cancer mortality, and colorectal cancer (CRC) frequently metastasizes to the liver. Our previous studies demonstrated the critical role of KIAA1199 in tumor invasion and metastasis in CRC. In the present study, we described an immune regulatory effect of KIAA1199 that creates a permissive environment for metastasis. APPROACH AND RESULTS: Flow cytometry was used to examine the effects of KIAA1199 on the infiltration of tumor immune cells. Neutrophils and T cells were isolated, stimulated, and/or cultured for in vitro function assays. In the patients with CRC, high expression levels of KIAA1199 were associated with an increased neutrophil infiltration into the liver. This result was further validated in mouse metastasis models. The increased influx of neutrophils contributed to the KIAA1199-driven CRC liver metastasis. Mechanistically, KIAA1199 activated the TGFß signaling pathway by interacting with the TGFBR1/2 to stimulate CXCL1 and CXCL3 production, thereby driving the aggregation of immunosuppressive neutrophils. Genetic blockade or pharmacologic inhibition of KIAA1199 restored tumor immune infiltration, impeded tumor progression, and potentiated response to immune checkpoint blockade (ICB). CONCLUSIONS: These findings indicated that KIAA1199 could facilitate the liver infiltration of immunosuppressive neutrophils via the TGFß-chemokine (C-X-C motif) ligand (CXCL)3/1-CXCR2 axis, which might be clinically targeted for the treatment of hepatic metastasis.

CEMIP, a novel adaptor protein of OGT, promotes colorectal cancer metastasis through glutamine metabolic reprogramming via reciprocal regulation of ß-catenin.

Metastasis is the leading cause of colorectal cancer (CRC)-induced death. However, the underlying molecular mechanisms of CRC metastasis are poorly understood. Metabolic reprogramming is an intrinsic feature of cancer, which have complicated effects on cancer metastasis. Here, we find that a novel metastasis-related protein, cell migration-inducing and hyaluronan-binding protein (CEMIP), can act as a novel adaptor protein of O-GlcNAc transferase (OGT) to promote CRC metastasis through glutamine metabolic reprogramming. Mechanistically, CEMIP interacts with OGT and ß-catenin, which leads to elevated O-GlcNAcylation of ß-catenin and enhanced ß-catenin nuclear translocation from cytomembrane. Furthermore, accumulated ß-catenin in nucleus enhances the transcription of CEMIP to reciprocally regulate ß-catenin and contributes to over-expression of glutaminase 1 and glutamine transporters (SLC1A5 and SLC38A2). Combinational inhibition of CEMIP and glutamine metabolism could dramatically attenuate the metastasis of CRC in vivo. Collectively, this study reveals the importance of glutamine metabolic reprogramming in CEMIP-induced CRC metastasis, indicating the great potential of CEMIP and glutamine metabolism for CRC metastasis prevention.

Distributions of water-soluble ions in size-aggregated aerosols over the Southern Ocean and coastal Antarctica.

To investigate mass size distributions of water-soluble ions in aerosols in the marine boundary layer (MBL) over the Southern Ocean, size-segregated (0.056-18 µm in aerodynamic diameter) aerosols were collected on the 28th Chinese National Antarctic Research Expedition (CHINARE) cruise from November 2011 to March 2012. Major water-soluble inorganic and organic species in aerosols were analyzed by ion chromatography (IC). Results showed that high loadings of aerosol mass were observed over the western sector of the Southern Ocean, attributed to the high mass loadings of Na+ and Cl- in the particles >1.0 µm in diameter and high mass loadings of non-sea-salt (nss) SO42- and methanesulfonate (MSA) in the particles <1.0 µm in diameter. Nss-SO42- and MSA accounted for ∼40% of the total mass in aerosols with particle size <0.56 µm over the eastern sector of the Southern Ocean, while it was elevated to more than 60% over the western sector of the Southern Ocean that could be linked with high marine productivity reflected by high chlorophyll-a occurrence in surface waters in that region. MSA/nss-SO42- ratios showed an increasing trend as latitude increased in the southern hemisphere with a dramatic increase south of 60 °S and the variation of MSA may shape the spatial distribution of the ratios. High MSA concentration and MSA/nss-SO42- ratios were observed in west Antarctica, especially in the supermicron particles. A bimodal mass size distribution of total Ca2+ with a small peak in the 0.18-0.32 µm size range was observed, suggesting different sea spray aerosol (SSA) production mechanisms. Nss-SO42-, MSA was mainly enriched in the particle size range of 0.18 µm to 0.56 µm. The concentrations of formate and oxalate were low and detected only in certain size particles, mainly in the range <0.56-1.8 µm. Further studies should be conducted over the remote Southern Ocean to reveal marine ecosystem-aerosol-climate interactions.

NUMB suppression by miR-9-5P enhances CD44+ prostate cancer stem cell growth and metastasis.

Experimental and clinical studies over the past two decades have provided overwhelming evidence that human cancers, including prostate cancer (PCa), harbor cancer stem cells (CSCs) that sustain tumor growth, drive tumor progression and mediate therapy resistance and tumor relapse. Recent studies have also implicated NUMB as a PCa suppressor and an inhibitor of PCa stem cells (PCSCs); however, exactly how NUMB functions in these contexts remains unclear. Here, by employing bioinformatics analysis and luciferase assays and by conducting rescue experiments, we first show that NUMB is directly targeted by microRNA-9-5p (miR-9-5p), an oncogenic miR associated with poor prognosis in many malignancies. We further show that miR-9-5p levels are inversely correlated with NUMB expression in CD44+ PCSCs. miR-9-5p reduced NUMB expression and inhibited numerous PCSC properties including proliferation, migration, invasion as well as self-renewal. Strikingly, overexpression of NUMB in CD44+ PCSCs overcame all of the above PCSC properties enforced by miR-9-5p. Taken together, our results suggest that inhibiting the expression of the oncomiR miR-9-5p and overexpressing NUMB may represent novel therapeutic strategies to target PCSCs and PCa metastasis.

Comparison of first line chemotherapy regimens for advanced soft tissue sarcoma: a network meta-analysis.

The best first line chemotherapy regimen for advanced soft tissue sarcoma (ASTS) remains inconclusive. Here, we aimed to find the best first line chemotherapy regimen by performing a network meta-analysis. Regimens were compared in terms of overall survival (OS), overall response rate(ORR), progression free survival (PFS), and toxicity. Twenty-eight eligible trials with a total of 6928 patients were included. EC (epirubicin + cisplatin) was considered as the better regimen for advanced STS with probability of 61.9% in terms of OS. However, this regimen only have been evaluated in a single small trial and tend to have more hematological toxicities than doxorubicin. No regimen was superior to doxorubicin with significant statistical difference in terms of PFS and ORR, even aldoxorubicin behaved better than doxorubicin in the network analysis. Collectively, doxorubicin still can be selected preferentially for the first line chemotherapy for patients.

Erratum: Role of (-)-epigallocatechin-3-gallate in the osteogenic differentiation of human bone marrow mesenchymal stem cells: An enhancer or an inducer?

[This corrects the article DOI: 10.3892/etm.2015.2579.].

Effect of anthracyclines/ifosfamide-based adjuvant chemotherapy for soft tissue sarcoma: a conventional and network Meta-analysis.

The objective of this study is to assess the effect of anthracyclines/ifosfamide-based adjuvant chemotherapy for soft tissue sarcoma (STS) and provide a relative ranking of regimens for STS. We pooled the hazard ratios of overall survival (OS) and relapse free survival (RFS) by conventional meta-analysis to appraise whether adjuvant chemotherapy benefits STS and performed a network meta-analysis using a Bayesian model to establish the relative ranking of regimens. Nine studies were included in our meta-analysis. The pooled hazard ratios were 0.68 (95%CI: 0.53-0.86) and 0.65 (95%CI: 0.52-0.83) for OS and RFS, respectively. Doxorubicin was indicated as best regimen to benefit OS (probability: 30.2%), while cyclophosphamide + vincristine + doxorubicin + dactinomycin was indicated as the best regimen for RFS (probability: 37.1%). This meta-analysis confirms the positive effect of anthracyclines/ifosfamide-based adjuvant chemotherapy in STS for both OS and RFS.

MMP-13 enzyme and pH responsive theranostic nanoplatform for osteoarthritis.

Stimulus-responsive therapy permits precise control of therapeutic effect only at lesion of interest, which determines it a promising method for diagnosis and imaging-guided precision therapy. The acid environment and overexpressed matrix metalloproteinases-13 (MMP-13) are typical markers in osteoarthritis (OA), which enables the development of stimulus-responsive drug delivery system with high specificity for OA. We herein demonstrate a nano-micelle based stimuli-responsive theranostic strategy with reporting and drug release controlled by acidic pH and MMP-13 for OA therapy. Such nanoplatform is incorporated with a motif specifically targeting on cartilage, a motif responsive to matrix metalloproteinases-13 to specifically report OA condition and biodynamics of nano-micelles, an anti-inflammatory drug (e.g., psoralidin (PSO)) from traditional Chinese medicine, and a biocompatible polymeric skeleton for sustainable drug release in response to the acidic OA condition. The high effectiveness of this targeted precision therapy is demonstrated comprehensively by both in vitro and vivo evidences.

Long noncoding RNA TCL6 binds to miR-106a-5p to regulate hepatocellular carcinoma cells through PI3K/AKT signaling pathway.

Long noncoding RNAs (lncRNAs) have been reported to dysregulate and involve in the pathology of hepatocellular carcinoma (HCC). Nonetheless, the functional role of lncRNA T cell leukemia/lymphoma 6 (TCL6) and its underlying mechanism in HCC remain unclear. Herein, we analyzed the expression of TCL6 and elucidated its mechanistic involvement in HCC. Bioinformatics analyses indicated TCL6 was evidently downregulated in HCC tissues compared with normal controls. TCL6 was downregulated while microRNA-106a-5p (miR-106a-5p) was upregulated in HCC cell lines. Moreover, knockdown or overexpression of TCL6 significantly raised or diminished the expression level of miR-106a-5p in HCC cells, similar to the effect of miR-106a-5p on TCL6 expression. Functionally, TCL6 inhibited the proliferative, migratory, and invasive potentials of HCC cells as analyzed by cell counting kit-8, scratch wound healing, and transwell assays, respectively. Conversely, miR-106a-5p exerted an opposite effect on the proliferative, migratory, and invasive potentials of HCC. RNA immune precipitation and luciferase reporter assays revealed TCL6 directly bound to miR-106a-5p and luciferase reporter assay verified phosphatase and tensin homolog (PTEN) was a target gene of miR-106a-5p. Mechanistically, TCL6 knockdown evidently reduced PTEN expression at both messenger RNA and protein levels, and miR-106a-5p inhibitor partially rescued this reduction effect in HCC cells. Additionally, western blot assays demonstrated miR-106a-5p downregulation or TCL6 overexpression promoted the protein level of PTEN, and suppressed the phosphorylation level of AKT, the protein level of phosphatidylinositol 3-kinase (PI3K). Collectively, these results revealed TCL6 as a tumor-suppressive lncRNA regulates PI3K/AKT signaling pathway via directly binding to miR-106a-5p in HCC. This mechanism provides a theoretical basis for HCC pathogenesis and a potential therapeutic strategy for HCC treatment.