Fang Wang

Background Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. Methods In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. Findings The analysis included 105 872 participants (730 577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1 128 310 participants (4 732 110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1·73 m2 and 105 mL/min/1·73 m2 and increased at lower eGFRs. Compared with eGFR 95 mL/min/1·73 m2, adjusted HRs for all-cause mortality were 1·18 (95% CI 1·05–1·32) for eGFR 60 mL/min/1·73 m2, 1·57 (1·39–1·78) for 45 mL/min/1·73 m2, and 3·14 (2·39–4·13) for 15 mL/min/1·73 m2. ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0·6 mg/mmol, adjusted HRs for all-cause mortality were 1·20 (1·15–1·26) for ACR 1·1 mg/mmol, 1·63 (1·50–1·77) for 3·4 mg/mmol, and 2·22 (1·97–2·51) for 33·9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. Interpretation eGFR less than 60 mL/min/1·73 m2 and ACR 1·1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. Funding Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTFluorescent Chemosensors Based on Spiroring-Opening of Xanthenes and Related DerivativesXiaoqiang Chen†‡, Tuhin Pradhan§, Fang Wang†, Jong Seung Kim*§, and Juyoung Yoon*†View Author Information† Departments of Chemistry and Nano Science and of Bioinspired Science (WCU), Ewha Womans University, Seoul 120-750, Korea‡ State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering, Nanjing University of Technology, Nanjing 210009, China§ Department of Chemistry, Korea University, Seoul 136-701, Korea*Phone: 82-2-3277-2400 (J.Y.); 82-2-3290-3143 (J.S.K.). Fax: 82-2-3277-2384 (J.Y.); 82-2-3290-3121 (J.S.K.). E-mail: [email protected] (J.Y.); [email protected] (J.S.K.).Cite this: Chem. Rev. 2012, 112, 3, 1910–1956Publication Date (Web):October 31, 2011Publication History Received5 June 2011Published online31 October 2011Published inissue 14 March 2012https://doi.org/10.1021/cr200201zCopyright © 2011 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views22134Altmetric-Citations1661LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (9 MB) Get e-AlertsSUBJECTS:Fluorescence,Heterocyclic compounds,Ions,Mercury,Sensors Get e-Alerts

IDHology Among the most exciting drug targets to emerge from cancer genome sequencing projects are two related metabolic enzymes, isocitrate dehydrogenases 1 and 2 (IDH1, IDH2). Mutations in the IDH1 and IDH2 genes are common in certain types of human cancer. Whether inhibition of mutant IDH activity might offer therapeutic benefits is unclear (see the Perspective by Kim and DeBerardinis ). F. Wang et al. (p. 622 , published online 4 April) isolated a small molecule that selectively inhibits mutant IDH2, describe the structural details of its binding to the mutant enzyme, and show that this compound suppresses the growth of patient-derived leukemia cells harboring the IDH2 mutation. Rohle et al. (p. 626 , published online 4 April) show that a small molecule inhibitor of IDH1 selectively slows the growth of patient-derived brain tumor cells with the IDH1 mutation.

Monkeys serve as important model species for studying human diseases and developing therapeutic strategies, yet the application of monkeys in biomedical researches has been significantly hindered by the difficulties in producing animals genetically modified at the desired target sites. Here, we first applied the CRISPR/Cas9 system, a versatile tool for editing the genes of different organisms, to target monkey genomes. By coinjection of Cas9 mRNA and sgRNAs into one-cell-stage embryos, we successfully achieve precise gene targeting in cynomolgus monkeys. We also show that this system enables simultaneous disruption of two target genes (Ppar-γ and Rag1) in one step, and no off-target mutagenesis was detected by comprehensive analysis. Thus, coinjection of one-cell-stage embryos with Cas9 mRNA and sgRNAs is an efficient and reliable approach for gene-modified cynomolgus monkey generation.

High quality carbon nanodots (C-dots) with high purity were synthesized through a mild, one-step electrochemical approach, without the assistance of any chemicals but only pure water. This high productivity method makes the synthetic process of C-dots synthesis both economical as well as environment-friendly. The as prepared C-dots are predominantly multi-layer graphene oxide, with luminescence and high up-conversion photoluminescence (emission of light at shorter wavelengths than the excitation wavelength). Meanwhile, C-dots showed peroxidise mimetic function and visible-light-sensitive photocatalytic activity for methyl orange degradation. In addition, a novel photocatalyst (TiO2/C-dots) was obtained by combining C-dots with TiO2 through an easy hydrothermal method. Remarkably, TiO2/C-dots exhibited an excellent visible-light photocatalytic activity.

A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.

Language model pre-training, such as BERT, has significantly improved the performances of many natural language processing tasks.However, pre-trained language models are usually computationally expensive, so it is difficult to efficiently execute them on resourcerestricted devices.To accelerate inference and reduce model size while maintaining accuracy, we first propose a novel Transformer distillation method that is specially designed for knowledge distillation (KD) of the Transformer-based models.By leveraging this new KD method, the plenty of knowledge encoded in a large "teacher" BERT can be effectively transferred to a small "student" Tiny-BERT.Then, we introduce a new two-stage learning framework for TinyBERT, which performs Transformer distillation at both the pretraining and task-specific learning stages.This framework ensures that TinyBERT can capture the general-domain as well as the task-specific knowledge in BERT. TinyBERT 41 with 4 layers is empirically effective and achieves more than 96.8% the performance of its teacher BERT BASE on GLUE benchmark, while being 7.5x smaller and 9.4x faster on inference.TinyBERT 4 is also significantly better than 4-layer state-of-the-art baselines on BERT distillation, with only ∼28% parameters and ∼31% inference time of them.Moreover, TinyBERT 6 with 6 layers performs on-par with its teacher BERT BASE .

N 6 ‐Methyladenosine (m 6 A) modification has been implicated in many biological processes. However, its role in cancer has not been well studied. Here, we demonstrate that m 6 A modifications are decreased in hepatocellular carcinoma, especially in metastatic hepatocellular carcinoma, and that methyltransferase‐like 14 (METTL14) is the main factor involved in aberrant m 6 A modification. Moreover, METTL14 down‐regulation acts as an adverse prognosis factor for recurrence‐free survival of hepatocellular carcinoma and is significantly associated with tumor metastasis in vitro and in vivo . We confirm that METTL14 interacts with the microprocessor protein DGCR8 and positively modulates the primary microRNA 126 process in an m 6 A‐dependent manner. Further experiments show that microRNA 126 inhibits the repressing effect of METTL14 in tumor metastasis. Conclusion : These studies reveal an important role of METTL14 in tumor metastasis and provide a fresh view on m 6 A modification in tumor progression. (H epatology 2017;65:529‐543).

Abstract The INDUCER OF CBF EXPRESSION (ICE)–C-REPEAT BINDING FACTOR/DRE BINDING FACTOR1 (CBF/DREB1) transcriptional pathway plays a critical role in modulating cold stress responses in Arabidopsis thaliana. Dissecting crucial upstream regulatory signals or components of the ICE-CBF/DREB1 cascade will enhance our understanding of plant cold-tolerance mechanisms. Here, we show that jasmonate positively regulates plant responses to freezing stress in Arabidopsis. Exogenous application of jasmonate significantly enhanced plant freezing tolerance with or without cold acclimation. By contrast, blocking endogenous jasmonate biosynthesis and signaling rendered plants hypersensitive to freezing stress. Consistent with the positive role of jasmonate in freezing stress, production of endogenous jasmonate was triggered by cold treatment. In addition, cold induction of genes acting in the CBF/DREB1 signaling pathway was upregulated by jasmonate. Further investigation revealed that several JASMONATE ZIM-DOMAIN (JAZ) proteins, the repressors of jasmonate signaling, physically interact with ICE1 and ICE2 transcription factors. JAZ1 and JAZ4 repress the transcriptional function of ICE1, thereby attenuating the expression of its regulon. Consistent with this, overexpression of JAZ1 or JAZ4 represses freezing stress responses of Arabidopsis. Taken together, our study provides evidence that jasmonate functions as a critical upstream signal of the ICE-CBF/DREB1 pathway to positively regulate Arabidopsis freezing tolerance.

In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain largely unknown. Differentially expressed lncRNAs between HBV-related HCC and paired peritumoral tissues were identified by microarray and validated using quantitative real-time polymerase chain reaction. Liver samples from patients with HBV-related HCC were analyzed for levels of a specific differentially expressed lncRNA High Expression In HCC (termed lncRNA-HEIH); data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. The effects of lncRNA-HEIH were assessed by silencing and overexpressing the lncRNA in vitro and in vivo. The expression level of lncRNA-HEIH in HBV-related HCC is significantly associated with recurrence and is an independent prognostic factor for survival. We also found that lncRNA-HEIH plays a key role in G0/G1 arrest, and further demonstrated that lncRNA-HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of EZH2 target genes. Conclusions: Together, these results indicate that lncRNA-HEIH is an oncogenic lncRNA that promotes tumor progression and leads us to propose that lncRNAs may serve as key regulatory hubs in HCC progression. (HEPATOLOGY 2011

Fatty acid alkyl esters, also called biodiesel, are environmentally friendly and show great potential as an alternative liquid fuel. Biodiesel is produced by transesterification of oils or fats with chemical catalysts or lipase. Immobilized lipase as the biocatalyst draws high attention because that process is "greener". This article reviews the current status of biodiesel production with immobilized lipase, including various lipases, immobilization methods, various feedstocks, lipase inactivation caused by short chain alcohols and large scale industrialization. Adsorption is still the most widely employed method for lipase immobilization. There are two kinds of lipase used most frequently especially for large scale industrialization. One is Candida antartica lipase immobilized on acrylic resin, and the other is Candida sp. 99-125 lipase immobilized on inexpensive textile membranes. However, to further reduce the cost of biodiesel production, new immobilization techniques with higher activity and stability still need to be explored.

•Carbon neutrality may be achieved by reforming current global development systems to minimize greenhouse gas emissions and increase CO2 capture•Harnessing the power of renewable and carbon-neutral resources to produce energy and other fossil-based alternatives may eliminate our dependence on fossil fuels•Protecting natural carbon sinks and promoting CO2 capture, utilization, and storage are conducive to mitigating climate change•This review presents the current state, opportunities, challenges, and perspectives of technologies related to achieving carbon neutrality Global development has been heavily reliant on the overexploitation of natural resources since the Industrial Revolution. With the extensive use of fossil fuels, deforestation, and other forms of land-use change, anthropogenic activities have contributed to the ever-increasing concentrations of greenhouse gases (GHGs) in the atmosphere, causing global climate change. In response to the worsening global climate change, achieving carbon neutrality by 2050 is the most pressing task on the planet. To this end, it is of utmost importance and a significant challenge to reform the current production systems to reduce GHG emissions and promote the capture of CO2 from the atmosphere. Herein, we review innovative technologies that offer solutions achieving carbon (C) neutrality and sustainable development, including those for renewable energy production, food system transformation, waste valorization, C sink conservation, and C-negative manufacturing. The wealth of knowledge disseminated in this review could inspire the global community and drive the further development of innovative technologies to mitigate climate change and sustainably support human activities. Global development has been heavily reliant on the overexploitation of natural resources since the Industrial Revolution. With the extensive use of fossil fuels, deforestation, and other forms of land-use change, anthropogenic activities have contributed to the ever-increasing concentrations of greenhouse gases (GHGs) in the atmosphere, causing global climate change. In response to the worsening global climate change, achieving carbon neutrality by 2050 is the most pressing task on the planet. To this end, it is of utmost importance and a significant challenge to reform the current production systems to reduce GHG emissions and promote the capture of CO2 from the atmosphere. Herein, we review innovative technologies that offer solutions achieving carbon (C) neutrality and sustainable development, including those for renewable energy production, food system transformation, waste valorization, C sink conservation, and C-negative manufacturing. The wealth of knowledge disseminated in this review could inspire the global community and drive the further development of innovative technologies to mitigate climate change and sustainably support human activities.

The presence of cyanide ions in surface water is not only caused by industrial waste but also by biological processes. Owing to the extreme toxicity of cyanide in physiological systems and its widespread presence in the environment, considerable attention has been given to the development of methods for the detection of cyanide. Among the most simple, inexpensive and rapid methods to detect cyanide ions are chemosensors that rely on fluorometric and colorimetric responses. This review, which focuses on CN(-) fluorescence and colorimetric chemosensors that have been developed since 2010, follows a format in which the sensors are classified according to their structural features and reaction mechanisms. Finally, a general overview of the design of fluorometric and colorimetric chemosensors for CN(-) is provided.

[reaction: see text] A new sensing mechanism based on C=N isomerization, which shows a very significant fluorescence enhancement to the metal cations in a simple and efficient way, is demonstrated. A coumarin derivative (L) containing a C=N group was designed as an example for illustration. The free ligand L is almost nonfluorescent due to the isomerization of C=N double bond in the excited state. However, the solution of ligand shows about a 200-fold increase of fluorescence quantum yield (about 30%) upon addition of Zn(ClO4)2.

Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1α (HIF1α)-mediated transcription activation, and c-Myc-heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1α/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.

Plasma, the soluble component of the human blood, is believed to harbor thousands of distinct proteins, which originate from a variety of cells and tissues through either active secretion or leakage from blood cells or tissues. The dynamic range of plasma protein concentrations comprises at least nine orders of magnitude. Proteins involved in coagulation, immune defense, small molecule transport, and protease inhibition, many of them present in high abundance in this body fluid, have been functionally characterized and associated with disease processes. For example, protein sequence mutations in coagulation factors cause various serious disease states. Diagnosing and monitoring such diseases in blood plasma of affected individuals has typically been conducted by use of enzyme-linked immunosorbent assays, which using a specific antibody quantitatively measure only the affected protein in the tested plasma samples. The discovery of protein biomarkers in plasma for diseases with no known correlations to genetic mutations is challenging. It requires a highly parallel display and quantitation strategy for proteins. We fractionated blood serum proteins prior to display on two-dimensional electrophoresis (2-DE) gels using immunoaffinity chromatography to remove the most abundant serum proteins, followed by sequential anion-exchange and size-exclusion chromatography. Serum proteins from 74 fractions were displayed on 2-DE gels. This approach succeeded in resolving approximately 3700 distinct protein spots, many of them post-translationally modified variants of plasma proteins. About 1800 distinct serum protein spots were identified by mass spectrometry. They collapsed into 325 distinct proteins, after sequence homology and similarity searches were carried out to eliminate redundant protein annotations. Although a relatively insensitive dye, Coomassie Brilliant Blue G-250, was used to visualize protein spots, several proteins known to be present in serum in < 10 ng/mL concentrations were identified such as interleukin-6, cathepsins, and peptide hormones. Considering that our strategy allows highly parallel protein quantitation on 2-DE gels, it holds promise to accelerate the discovery of novel serum protein biomarkers.

Forkhead transcription factors FOXO1 (FKHR), FOXO3a (FKHRL1), and FOXO4 (AFX) play a pivotal role in tumor suppression by inducing growth arrest and apoptosis. Loss of function of these factors due to phosphorylation and proteasomal degradation has been implicated in cell transformation and malignancy. However, the ubiquitin ligase necessary for the ubiquitination of the FOXO factors and the relevance of this regulation to tumorigenesis have not been characterized. Here we demonstrate that Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, interacts with, ubiquitinates, and promotes the degradation of FOXO1. This effect of Skp2 requires Akt-specific phosphorylation of FOXO1 at Ser-256. Moreover, expression of Skp2 inhibits transactivation of FOXO1 and abolishes the inhibitory effect of FOXO1 on cell proliferation and survival. Furthermore, expression of the FOXO1 protein is lost in a mouse lymphoma model, where Skp2 is overexpressed. These data suggest that the Skp2-promoted proteolysis of FOXO1 plays a key role in tumorigenesis.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.

Recently, long noncoding RNAs (lncRNAs) were found to be dysregulated in a variety of tumors. However, it remains unknown how and through what molecular mechanisms the expression of lncRNAs is controlled. In this study, we found that the lncRNA Low Expression in Tumor (lncRNA-LET) was generally downregulated in hepatocellular carcinomas, colorectal cancers, and squamous-cell lung carcinomas. We demonstrated that hypoxia-induced histone deacetylase 3 repressed lncRNA-LET by reducing the histone acetylation-mediated modulation of the lncRNA-LET promoter region. Interestingly, the downregulation of lncRNA-LET was found to be a key step in the stabilization of nuclear factor 90 protein, which leads to hypoxia-induced cancer cell invasion. Moreover, the relationship among hypoxia, histone acetylation disorder, low lncRNA-LET expression level, and metastasis was found in clinical hepatocellular carcinoma samples. These results advance our understanding of the role of lncRNA-LET as a regulator of hypoxia signaling and offer new avenues for therapeutic intervention against cancer progression.

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

In modern society, traffic and transportation and the manufacturing industry and construction industries continuously release large amounts of dust and particles into the atmosphere, which can cause heavy air pollution, leading to health hazards. The haze disaster, a serious problem in developing countries such as China and India, has become one of the main issues of global environmental pollution in recent decades. Many air filtration technologies have been developed. Air filtration using electrospun fibers that intercept fine particles/volatile organic gases/bacterium is a relatively new, but highly promising, technique. Due to their interconnected nanoscale pore structures, highly specific surface areas, fine diameters, and porous structure as well as their ability to incorporate active chemistry on a nanoscale surface, electrospun fibers are becoming a promising versatile platform for air filtration. In this review, following a short introduction concerning the need for air filtration and filtration theory and mechanism, electrospun nanofibers membranes for air filtration have been highlighted, including the preparation (electrospinning process) and the parameters relevant to filtration efficacy. Additionally, various types (function) of the electrospun air filtration membranes have been classified in detail. Furthermore, their potential in the filtration of fine particles and chemical pollutants has been discussed. Finally, the challenges of their practical application and the future prospects have been summarized. Given that some advanced electrospun air filtration nanofibrous membranes exist for treating different contaminants from various types of polluted atmosphere, it is believed that they should make a significant contribution in protection against air pollution.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte–macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy. The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E2.

A new rhodamine-based derivative bearing a pyrene group (PRC) was synthesized as a ratiometric and “off−on” chemosensor for Cu2+. PRC displayed a selective and chelation enhanced ratiometric fluorescence change and colorimetric change with Cu2+ among the metal ions examined.

Antibody drug conjugates (ADCs) are a therapeutic class offering promise for cancer therapy. The attachment of cytotoxic drugs to antibodies can result in an effective therapy with better safety potential than nontargeted cytotoxics. To understand the role of conjugation site, we developed an enzymatic method for site-specific antibody drug conjugation using microbial transglutaminase. This allowed us to attach diverse compounds at multiple positions and investigate how the site influences stability, toxicity, and efficacy. We show that the conjugation site has significant impact on ADC stability and pharmacokinetics in a species-dependent manner. These differences can be directly attributed to the position of the linkage rather than the chemical instability, as was observed with a maleimide linkage. With this method, it is possible to produce homogeneous ADCs and tune their properties to maximize the therapeutic window.

Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein we examined the expression profiles of long noncoding RNAs (lncRNAs) found in fetal and adult liver in mice. Many fetal hepatic lncRNAs were identified; one of these, lncRNA-mPvt1, is an oncofetal RNA that was found to promote cell proliferation, cell cycling, and the expression of stem cell-like properties of murine cells. Interestingly, we found that human lncRNA-hPVT1 was up-regulated in HCC tissues and that patients with higher lncRNA-hPVT1 expression had a poor clinical prognosis. The protumorigenic effects of lncRNA-hPVT1 on cell proliferation, cell cycling, and stem cell-like properties of HCC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Moreover, mRNA expression profile data showed that lncRNA-hPVT1 up-regulated a series of cell cycle genes in SMMC-7721 cells. By RNA pulldown and mass spectrum experiments, we identified NOP2 as an RNA-binding protein that binds to lncRNA-hPVT1. We confirmed that lncRNA-hPVT1 up-regulated NOP2 by enhancing the stability of NOP2 proteins and that lncRNA-hPVT1 function depends on the presence of NOP2. Conclusion: Our study demonstrates that the expression of many lncRNAs is up-regulated in early liver development and that the fetal liver can be used to search for new diagnostic markers for HCC. LncRNA-hPVT1 promotes cell proliferation, cell cycling, and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects on the treatment of HCC. (Hepatology 2014;60:1278–1290)

This paper investigates the mechanisms of penetration induced thermal runaway (TR) propagation process within a large format lithium ion battery pack. A 6-battery module is built with 47 thermocouples installed at critical positions to record the temperature profiles. The first battery of the module is penetrated to trigger a TR propagation process. The temperature responses, the voltage responses and the heat transfer through different paths are analyzed and discussed to characterize the underlying physical behavior. The temperature responses show that: 1) Compared with the results of TR tests using accelerating rate calorimetry (ARC) with uniform heating, a lower onset temperature and a shorter TR triggering time are observed in a penetration induced TR propagation test due to side heating. 2) The maximum temperature difference within a battery can be as high as 791.8 °C in a penetration induced TR propagation test. The voltage responses have a 5-stage feature, indicating that the TR happens in sequence for the two pouch cells packed inside a battery. The heat transfer analysis shows that: 1) 12% of the total heat released in TR of a battery is enough to trigger the adjacent battery to TR. 2) The heat transferred through the pole connector is only about 1/10 of that through the battery shell. 3) The fire has little influence on the TR propagation, but may cause significant damage on the accessories located above the battery. The results can enhance our understandings of the mechanisms of TR propagation, and provide important guidelines in pack design for large format lithium ion battery.

Organic-inorganic hybrid perovskite (OIHP) photodetectors that simultaneously achieve an ultrafast response and high sensitivity in the near-infrared (NIR) region are prerequisites for expanding current monitoring, imaging, and optical communication capbilities. Herein, we demonstrate photodetectors constructed by OIHP and an organic bulk heterojunction (BHJ) consisting of a low-bandgap nonfullerene and polymer, which achieve broadband response spectra up to 1 μm with a highest external quantum efficiency of approximately 54% at 850 nm, an ultrafast response speed of 5.6 ns and a linear dynamic range (LDR) of 191 dB. High sensitivity, ultrafast speed and a large LDR are preeminent prerequisites for the practical application of photodetectors. Encouragingly, due to the high-dynamic-range imaging capacity, high-quality visible-NIR actual imaging is achieved by employing the OIHP photodetectors. We believe that state-of-the-art OIHP photodetectors can accelerate the translation of solution-processed photodetector applications from the laboratory to the imaging market.

Populations of certain unicellular organisms, such as suspensions of yeast in nutrient solutions, undergo transitions to coordinated activity with increasing cell density. The collective behavior is believed to arise through communication by chemical signaling via the extracellular solution. We studied large, heterogeneous populations of discrete chemical oscillators (approximately 100,000) with well-defined kinetics to characterize two different types of density-dependent transitions to synchronized oscillatory behavior. For different chemical exchange rates between the oscillators and the surrounding solution, increasing oscillator density led to (i) the gradual synchronization of oscillatory activity, or (ii) the sudden "switching on" of synchronized oscillatory activity. We analyze the roles of oscillator density and exchange rate of signaling species in these transitions with a mathematical model of the interacting chemical oscillators.

Sphingosine 1-phosphate (SPP) has been shown to inhibit chemotaxis of a variety of cells, in some cases through intracellular actions, while in others through receptor-mediated effects. Surprisingly, we found that low concentrations of SPP (10–100 nm) increased chemotaxis of HEK293 cells overexpressing the G protein-coupled SPP receptor EDG-1. In agreement with previous findings in human breast cancer cells (Wang, F., Nohara, K., Olivera, O., Thompson, E. W., and Spiegel, S. (1999) <i>Exp. Cell Res.</i> 247, 17–28), SPP, at micromolar concentrations, inhibited chemotaxis of both vector- and EDG-1-overexpressing HEK293 cells. Nanomolar concentrations of SPP also induced a marked increase in chemotaxis of human umbilical vein endothelial cells (HUVEC) and bovine aortic endothelial cells (BAEC), which express the SPP receptors EDG-1 and EDG-3, while higher concentrations of SPP were less effective. Treatment with pertussis toxin, which ADP-ribosylates and inactivates G_i-coupled receptors, blocked SPP-induced chemotaxis. Checkerboard analysis indicated that SPP stimulates both chemotaxis and chemokinesis. Taken together, these data suggest that SPP stimulates cell migration by binding to EDG-1. Similar to SPP, sphinganine 1-phosphate (dihydro-SPP), which also binds to this family of SPP receptors, enhanced chemotaxis; whereas, another structurally related lysophospholipid, lysophosphatidic acid, did not compete with SPP for binding nor did it have significant effects on chemotaxis of endothelial cells. Furthermore, SPP increased proliferation of HUVEC and BAEC in a pertussis toxin-sensitive manner. SPP and dihydro-SPP also stimulated tube formation of BAEC grown on collagen gels (<i>in vitro</i> angiogenesis), and potentiated tube formation induced by basic fibroblast growth factor. Pertussis toxin treatment blocked SPP-, but not bFGF-stimulated <i>in vitro</i> angiogenesis. Our results suggest that SPP may play a role in angiogenesis through binding to endothelial cell G_i-coupled SPP receptors.

This paper addresses the finite-time tracking problem of nonlinear pure-feedback systems. Unlike the literature on traditional finite-time stabilization, in this paper the nonlinear system functions, including the bounding functions, are all totally unknown. Fuzzy logic systems are used to model those unknown functions. To present a finite-time control strategy, a criterion of semiglobal practical stability in finite time is first developed. Based on this criterion, a novel adaptive fuzzy control scheme is proposed by a backstepping technique. It is shown that the presented controller can guarantee that the tracking error converges to a small neighborhood of the origin in a finite time, and the other closed-loop signals remain bounded. Finally, two examples are used to test the effectiveness of proposed control strategy.

The durability and degradation behavior of the Nafion NR111 proton exchange membranes (PEMs) is investigated in detail under various mechanical, chemical and polarization conditions. It was found that the fatigue strength or the safety limit of the cyclic stress for Nafion NR111 membrane is ∼1.5 MPa that is 1/10 of the tensile strength of the membrane. The cyclic stress and dimensional change (or strain) induced by the water uptake can be substantial and are the main causes for the mechanical degradation and failure of the membrane. For example, in the case of RH cycling of water soaked state to 25% RH state, the cyclic stress of the Nafion membrane was as high as 2.23 MPa and the dimensional change was ∼11%. Both FTIR and NMR analysis indicate that the decomposition of the Nafion polymer in the H2O2 solution in the presence of trace Fe, Cr and Ni ions started from the ends of the main chain, resulting in the loss of the repeat units and the formation of voids and pinholes in the membrane. The high degradation rate of the membrane at the open circuit voltage most likely results from the attack of H2O2 formed between O2 and H2 crossovered through the membrane.

(Cell 173, 371–385.e1–e9; April 5, 2018) It has come to our attention that we made two errors in preparation of this manuscript. First, in the STAR Methods, under the subheading of “Hypermutators and Immune Infiltrates” within the “Quantification and Statistical Analysis” section, we inadvertently referred to Figures S7A–S7C for data corresponding to sample stratification by hypermutator status alone in the last sentence. It should have referred to Figure S6A–S6C. Second, the lists of highly frequent missense mutations for COAD (colon adenocarcinoma) and READ (rectum adenocarcinoma) displayed in Figure S7 were incorrect because when we ordered the mutations in the initial analysis, we mistakenly combined the two cancer types COAD and READ for analysis, despite the fact that they were listed as two separate cancer types in the x-axis of the figure. After re-ordering the mutations by frequency for COAD and READ independently, information on highly frequent missense mutations for each of these cancer types is different and updated now in the revised Figure S7. These errors don’t change the major conclusions of the paper and have been corrected online. We apologize for any confusion they may have caused.Figure S7On-Label/Off-Label Calculations for Druggable Mutations in Cancer (original)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Comprehensive Characterization of Cancer Driver Genes and MutationsBailey et al.CellApril 05, 2018In BriefA comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples. Full-Text PDF Open Access

Survival of patients with hepatocellular carcinoma (HCC) remains poor, which is largely attributed to active angiogenesis. However, the mechanisms underlying angiogenesis in HCC remain to be discovered. In this study, we found that long noncoding RNA associated with microvascular invasion in HCC (lncRNA MVIH) (lncRNA associated with microvascular invasion in HCC) was generally overexpressed in HCC. In a cohort of 215 HCC patients, the overexpression of MVIH was associated with frequent microvascular invasion (P = 0.016) and a higher tumor node metastasis stage (P = 0.009) as well as decreased recurrence-free survival (RFS) (P < 0.001) and overall survival (P = 0.007). Moreover, the up-regulation of MVIH served as an independent risk factor to predict poor RFS. We also found that MVIH could promote tumor growth and intrahepatic metastasis by activating angiogenesis in mouse models. Subsequent investigations indicated that MVIH could activate tumor-inducing angiogenesis by inhibiting the secretion of phosphoglycerate kinase 1 (PGK1). Additionally, in 65 HCC samples, MVIH expression was inversely correlated with the serum level of PGK1 and positively correlated with the microvessel density.Deregulation of lncRNA MVIH is a predictor for poor RFS of HCC patients after hepatectomy and could be utilized as a potential target for new adjuvant therapies against active angiogenesis.

Abstract Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate–dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation–positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation–positive advanced hematologic malignancies. Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478–93. ©2017 AACR. See related commentary by Thomas and Majeti, p. 459. See related article by Shih et al., p. 494. This article is highlighted in the In This Issue feature, p. 443

Single-cell transcriptomic analysis is widely used to study human tumors. However, it remains challenging to distinguish normal cell types in the tumor microenvironment from malignant cells and to resolve clonal substructure within the tumor. To address these challenges, we developed an integrative Bayesian segmentation approach called copy number karyotyping of aneuploid tumors (CopyKAT) to estimate genomic copy number profiles at an average genomic resolution of 5 Mb from read depth in high-throughput single-cell RNA sequencing (scRNA-seq) data. We applied CopyKAT to analyze 46,501 single cells from 21 tumors, including triple-negative breast cancer, pancreatic ductal adenocarcinoma, anaplastic thyroid cancer, invasive ductal carcinoma and glioblastoma, to accurately (98%) distinguish cancer cells from normal cell types. In three breast tumors, CopyKAT resolved clonal subpopulations that differed in the expression of cancer genes, such as KRAS, and signatures, including epithelial-to-mesenchymal transition, DNA repair, apoptosis and hypoxia. These data show that CopyKAT can aid in the analysis of scRNA-seq data in a variety of solid human tumors.

The SIR2 family of nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases modulates diverse biological functions in different species, including longevity, apoptosis, cell cycle exit, and cellular differentiation. SIRT1, the closest mammalian ortholog of the yeast <i>SIR2</i> (silent information regulator 2) gene, represses several transcription factors, including p53, NFκB and forkhead proteins. The p300 protein serves as a rate-limiting transcriptional cointegrator of diverse transcription factors either to activate or to repress transcription through modular subdomains. Herein, SIRT1 physically interacted with and repressed p300 transactivation, requiring the NAD-dependent deacetylase activity of SIRT1. SIRT1 repression involved the CRD1 transcriptional repression domain of p300. Two residues within the CRD1 domain (Lys-1020 and Lys-1024) were required for SIRT1 repression and served as substrates for SIRT1 deacetylation. These residues also serve as acceptor lysines for modification by the ubiquitin-like SUMO protein. The SUMO-specific protease SSP3 relieved SIRT1 repression of p300. SSP3 antagonism of SIRT1 required the SUMO-deconjugating function of SSP3. Thus, p300 serves as a deacetylase substrate for SIRT1 through a conserved SUMO consensus motif. Because p300 is a limiting transcriptional cofactor, deacetylation and repression of p300 by SIRT1 may serve an important integration point during metabolism and cellular differentiation.

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

Among Caucasians, it is well known that 75-95% of primary glaucoma is due to open-angle glaucoma (POAG), with angle-closure (PACG) comprising only a very small minority of cases. These figures are reversed among other groups such as Asians and Eskimos, where PACG makes up 80-90% of primary glaucoma. Among Eskimos, the prevalence of PACG has been reported as 2-8%, as compared to 0.1% among Caucasians. It appears that a population tendency toward shallow anterior chambers may explain the excess burden of PACG morbidity. Among Asians, the prevalence of PACG is intermediate between Caucasians and Eskimos. Existing biometrical data do not show a clear tendency toward shallower anterior chambers among Asians. PACG may be screened for on a population basis by means of various techniques that estimate axial or limbal anterior chamber depth, measure intraocular pressure, or evaluate the optic disc or visual fields. Demographic information and medical and family history will also be of great importance in screening for PACG in large populations. Groups at increased risk for the disease include women, individuals over 50, first-degree relatives of PACG probands, and hyperopes.

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD‐L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose‐regulated protein 78, activating transcription factor 6, protein kinase R–like ER kinase, and inositol‐requiring enzyme 1α) was up‐regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress–related proteins positively correlated with CD68 + macrophage recruitment and PD‐L1 expression in HCC tissues. High‐throughput sequencing analysis identified miR‐23a‐3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)‐treated HCC cells (Exo‐TMs). miR‐23a‐3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo‐TMs up‐regulated the expression of PD‐L1 in macrophages in vitro and in vivo . Bioinformatics analysis suggests that miR‐23a‐3p regulates PD‐L1 expression through the phosphatase and tensin homolog (PTEN)–phosphatidylinositol 3‐kinase–protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR‐23a‐3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD‐L1 expression in macrophages. Finally, coculture of T cells with Exo‐TM–stimulated macrophages decreased CD8 + T‐cell ratio and interleukin‐2 production but increased T‐cell apoptosis in vitro . Conclusion : ER‐stressed HCC cells release exosomes to up‐regulate PD‐L1 expression in macrophages, which subsequently inhibits T‐cell function through an exosome miR‐23a–PTEN–AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

A lipase from Candida sp., suitable for transesterification of fats and oils to produce fatty acid methyl ester (FAME), was immobilized on a cheap cotton membrane, in this paper. The conversion ratio of salad oil to biodiesel could reach up to 96% with the optimal reaction conditions. Continuous reaction in a fixed bed reactor was also investigated. A three-step transesterification with methanol (methanolysis) of oil was conducted by using a series of nine columns packed with immobilized Candida sp. 99–125 lipase. As substrate of the first reaction step, plant or waste oil was used together with 1/3 molar equivalent of methanol against total fatty acids in the oil. Mixtures of the first- and second-step eluates and 1/3 molar equivalent of methanol were used for the second- and third-reaction steps. A hydrocyclone was used in order to on-line separate the by-product glycerol after every 1/3 molar equivalent of methanol was added. Petroleum ether was used as solvent (3/2, v/v of oil) and the pump was operated with a flow rate of 15 L/h giving an annual throughput of 100 t. The final conversion ratio of the FAME from plant oil and waste oil under the optimal condition was 90% and 92%, respectively. The life of the immobilized lipase was more than 10 days. This new technique has many strongpoints such as low pollution, environmentally friendly, and low energy costs.

Abstract Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non–small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [125I]iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal–regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs. Cancer Res; 70(20); 7981–91. ©2010 AACR.

Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.

3D printing techniques are being researched extensively in the construction sector. However, the key issue lies in the development of cementitious materials with both favorable printability and enough mechanical capability by means of high strength and ductility. In this study, an optimal basalt fiber content was determined basing firstly on suitable printability and then on mechanical performance. A self-developed 3D printer was used for extrusion of the cementitious material and also for mechanical enhancement of fiber alignment along the print direction by keeping the nozzle diameter smaller than the length of the basalt fiber. The printing process deposits directional filaments, intrinsically resulting in laminated structures and mechanical anisotropy. Anisotropic performances of the printed material were evaluated by direction-based mechanical performance testing and confirmed by ultrasonic pulse velocity testing. The mechanical behaviors of 3D printed samples exposed to compressive, tensile, flexural and shearing loadings were experimentally investigated. The mesoscale structures of printed samples were detected through the advanced CT scanning technique. Both mechanical and acoustic indexes were proposed to evaluate the anisotropic properties of printed materials. In particular, empirical relationships between the mechanical anisotropic properties and ultrasonic signals were established. On the microstructural level, mechanical enhancement of fiber alignment, fiber pullout and fiber fracture were all probed through scanning electron microscope (SEM) imaging.

MicroRNAs (miRNAs) play an important role in diverse physiological and developmental processes by negatively regulating expression of target genes at the post-transcriptional level. Here, we globally analyzed the genomic organization of all registered 326 human miRNA genes in miRNA registry 7.1 and found that 148 human miRNA genes appeared in a total of 51 clusters. Alignment of the miRNA sequences in different clusters revealed a significant number of miRNA paralogs among the clusters, implying an evolution process targeting the potentially conserved roles of these molecules. Then we performed Northern blot analysis for expression profiling of all clustered miRNAs in several human leukemia cell lines. Consistent expression of the miRNAs in a single cluster was revealed in 39 clusters, while inconsistent expression of members in a single cluster was detected in the other 12 clusters. Meanwhile, we identified several hematopoietic lineage-specific or -enriched miRNA clusters (e.g., the mir-29c, mir-302, mir-98, mir-29a, and let-7a-1 clusters) and individual miRNAs (e.g., mir-181c, mir-181d, mir-191, and mir-136). These findings may suggest vital roles of these miRNA clusters or miRNAs in human hematopoiesis and oncogenesis, and provide clues for understanding the function and mechanism of miRNAs in various biological processes.

TiO2 nanotube arrays loaded with carbon quantum dots were used as a photoanode for efficient hydrogen generation under visible light.

In this paper, a fuzzy adaptive approach for stochastic strict-feedback nonlinear systems with quantized input signal is developed. Compared with the existing research on quantized input problem, the existing works focus on quantized stabilization, while this paper considers the quantized tracking problem, which recovers stabilization as a special case. In addition, uncertain nonlinearity and the unknown stochastic disturbances are simultaneously considered in the quantized feedback control systems. By putting forward a new nonlinear decomposition of the quantized input, the relationship between the control signal and the quantized signal is established, as a result, the major technique difficulty arising from the piece-wise quantized input is overcome. Based on fuzzy logic systems' universal approximation capability, a novel fuzzy adaptive tracking controller is constructed via backstepping technique. The proposed controller guarantees that the tracking error converges to a neighborhood of the origin in the sense of probability and all the signals in the closed-loop system remain bounded in probability. Finally, an example illustrates the effectiveness of the proposed control approach.

Summary The WRKY transcription factors have been demonstrated to play crucial roles in regulating stress responses; however, the exact mechanisms underlying their involvement in stress responses are not fully understood. A rabidopsis WRKY8 was predominantly expressed in roots and was highly upregulated by salt treatment. Disruption of WRKY 8 rendered plants hypersensitive to salt, showing delayed germination, inhibited post‐germination development and accelerated chlorosis. Further investigation revealed that WRKY 8 interacted with VQ 9, and their interaction decreased the DNA ‐binding activity of WRKY 8. The VQ 9 protein was exclusively localized in the nucleus, and VQ9 expression was strongly responsive to N a Cl treatment. Mutation of VQ9 enhanced tolerance to salt stress, indicating that VQ 9 acts antagonistically with WRKY 8 to mediate responses to salt stress. The antagonist functions of WRKY 8 and VQ 9 were consistent with an increased or reduced N a + / K + concentration ratio, as well as contrasting expression patterns of downstream stress‐responsive genes in salt‐stressed wrky8 and vq9 mutants. Moreover, chromatin immunoprecipitation ( C h IP ) assays showed that WRKY 8 directly bound the promoter of RD29A under salt conditions. These results provided strong evidence that the VQ 9 protein acts as a repressor of the WRKY 8 factor to maintain an appropriate balance of WRKY 8‐mediated signaling pathways to establish salinity stress tolerance.

Chronic kidney disease (CKD) is considered a serious worldwide public health problem, but data from developing countries are extremely limited.Cross-sectional study.A representative sample of 13,925 adults in Beijing, China.Age (18 to 39, 40 to 59, 60 to 69, and >70 years), sex, urban or rural area, history of chronic respiratory infection and cardiovascular disease, hepatitis B virus infection, smoking, family history (diabetes, hypertension, and CKD), nephrotoxic medications, central obesity, diabetic and hypertension status, and dyslipidemia.CKD was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) or markers of kidney damage. Glomerular filtration rate was estimated by using calibrated serum creatinine level and a formula specific for China. Persistent albuminuria and hematuria were considered markers of kidney damage.The prevalence of CKD in adults in Beijing was 13.0% (95% confidence interval [CI], 11.9 to 14.2). It therefore was estimated that the number of adults in Beijing with CKD was 1.43 million. In subjects aged 18 to 39, 40 to 59, 60 to 69, and older than 70 years, prevalences of CKD were 10.0% (95% CI, 8.9 to 11.3), 14.2% (95% CI, 13.0 to 15.4), 20.8% (95% CI, 18.1 to 23.9), and 30.5% (95% CI, 26.6 to 34.7), respectively. Factors independently associated with decreased kidney function included older age (odds ratio [OR], 1.83; 95% CI, 1.51 to 2.22 per 10-year increase), nephrotoxic medications (OR, 2.19; 95% CI, 1.21 to 3.97), rural area (versus urban area; OR, 0.47; 95% CI, 0.28 to 0.78), history of cardiovascular disease (OR, 2.04; 95% CI, 1.24 to 3.38), high-density lipoprotein cholesterol level less than 40 mg/dL (OR, 3.00; 95% CI, 1.39 to 6.51), and hypertension status (with duration > 10 years; OR, 1.85; 95% CI, 1.19 to 2.88).Kidney function and indicators of kidney damage were based on single measurements.CKD is a public health burden in Beijing.

Abstract Next-generation polarized mid-infrared imaging systems generally requires miniaturization, integration, flexibility, good workability at room temperature and in severe environments, etc. Emerging two-dimensional materials provide another route to meet these demands, due to the ease of integrating on complex structures, their native in-plane anisotropy crystal structure for high polarization photosensitivity, and strong quantum confinement for excellent photodetecting performances at room temperature. However, polarized infrared imaging under scattering based on 2D materials has yet to be realized. Here we report the systematic investigation of polarized infrared imaging for a designed target obscured by scattering media using an anisotropic tellurium photodetector. Broadband sensitive photoresponse is realized at room temperature, with excellent stability without degradation under ambient atmospheric conditions. Significantly, a large anisotropic ratio of tellurium ensures polarized imaging in a scattering environment, with the degree of linear polarization over 0.8, opening up possibilities for developing next-generation polarized mid-infrared imaging technology.

Unlocking retinal regeneration in mice Zebrafish can regenerate damaged retinal tissue, but mice cannot. Hoang et al. found that tracking changes in gene expression and chromatin accessibility upon injury revealed clues as to why retinal glial cells in zebrafish could generate new neurons but the same cell type in mice could not. In zebrafish, activated Müller glial cells shift into a proliferative phase, whereas in mice, a genetic network returns the glial cells to quiescence. A few transcription factors enforce quiescence in the mouse, and disruption of these allowed Müller glia to proliferate and generate new neurons after retinal injury. Science , this issue p. eabb8598

The antagonistic interaction between iron (Fe) and phosphorus (P) has been noted in the area of plant nutrition. To understand the physiology and molecular mechanisms of this interaction, we studied the growth performance, nutrient concentration, and gene expression profiles of root and shoot segments derived from 10-d-old rice (Oryza sativa) seedlings under four different nutrient conditions: (1) full strength of Fe and P (+Fe+P); (2) full strength of P and no Fe (-Fe+P); (3) full strength of Fe and no P (+Fe-P); and (4) without both Fe and P (-Fe-P). While removal of Fe in the growth medium resulted in very low shoot and root Fe concentrations, the chlorotic symptoms and retarded seedling growth were only observed on seedlings grown in the presence of P. Microarray data showed that in roots, 7,628 transcripts were significantly changed in abundance in the absence of Fe alone. Interestingly, many of these changes were reversed if P was also absent (-Fe-P), with only approximately 15% overlapping with -Fe alone (-Fe+P). Analysis of the soluble Fe concentration in rice seedling shoots showed that P deficiency resulted in significantly increased Fe availability within the plants. The soluble Fe concentration under -Fe-P conditions was similar to that under +Fe+P conditions. These results provide evidence that the presence of P can affect Fe availability and in turn can influence the regulation of Fe-responsive genes.

Long noncoding RNAs (lncRNAs) have recently emerged as important regulators in governing fundamental biological processes, and many of which are likely to have functional roles in tumorigenesis. Maternally expressed gene 3 (MEG3) gene encodes a lncRNA whose expression is lost in an expanding list of primary human tumors and tumor cell lines, however its biological role and regulatory mechanism in gastric cancer (GC) development and progression are poorly defined. Quantitative RT-PCR analysis was used to determine whether aberrant MEG3 expression was associated with GC patients pTNM stage and pM state. Furthermore, the effect of ectopic expression of MEG3 on cell proliferation, migration, invasion and cell apoptosis was assessed by using CCK-8, wound healing, transwell invasion assays and flow cytometric analysis, respectively, in GC cell lines HGC-27 and MGC-803. Moreover, the competing endogenous RNA (ceRNA) activity of MEG3 on miR-181a was investigated via luciferase reporter assay and immunoblot analysis. MEG3 is decreased in GC patients and cell lines, and its expression was associated with metastatic GC. Furthermore, ectopic expression of MEG3 in HGC-27 and MGC-803 cells inhibited cell proliferation, migration, invasion, and promoted cell apoptosis, which might be due to MEG3 sequestering oncogenic miR-181 s in GC cells. Furthermore, MEG3 could up-regulated Bcl-2 via its competing endogenous RNA (ceRNA) activity on miR-181a. These findings suggest that lncRNA MEG3, a ceRNA of miR-181 s, could regulate gastric carcinogenesis and may serve as a potential target for antineoplastic therapies.

We investigate the hypothesis that oxidative damage of the cerebral vascular barrier interface (the blood–brain barrier, BBB) causes the development of mild traumatic brain injury (TBI) during a primary blast-wave spectrum. The underlying biochemical and cellular mechanisms of this vascular layer-structure injury are examined in a novel animal model of shock tube. We first established that low-frequency (123 kPa) single or repeated shock wave causes BBB/brain injury through biochemical activation by an acute mechanical force that occurs 6–24 h after the exposure. This biochemical damage of the cerebral vasculature is initiated by the induction of the free radical-generating enzymes NADPH oxidase 1 and inducible nitric oxide synthase. Induction of these enzymes by shock-wave exposure paralleled the signatures of oxidative and nitrosative damage (4-HNE/3-NT) and reduction of the BBB tight-junction (TJ) proteins occludin, claudin-5, and zonula occluden 1 in the brain microvessels. In parallel with TJ protein disruption, the perivascular unit was significantly diminished by single or repeated shock-wave exposure coinciding with the kinetic profile. Loosening of the vasculature and perivascular unit was mediated by oxidative stress-induced activation of matrix metalloproteinases and fluid channel aquaporin-4, promoting vascular fluid cavitation/edema, enhanced leakiness of the BBB, and progression of neuroinflammation. The BBB leakiness and neuroinflammation were functionally demonstrated in an in vivo model by enhanced permeativity of Evans blue and sodium fluorescein low-molecular-weight tracers and the infiltration of immune cells across the BBB. The detection of brain cell proteins neuron-specific enolase and S100β in the blood samples validated the neuroastroglial injury in shock-wave TBI. Our hypothesis that cerebral vascular injury occurs before the development of neurological disorders in mild TBI was further confirmed by the activation of caspase-3 and cell apoptosis mostly around the perivascular region. Thus, induction of oxidative stress and activation of matrix metalloproteinases by shock wave underlie the mechanisms of cerebral vascular BBB leakage and neuroinflammation.

Abstract The paper examines terrestrial and oceanic carbon budgets from preindustrial time to present day in the version of Beijing Climate Center Climate System Model (BCC_CSM1.1) which is a global fully coupled climate‐carbon cycle model. Atmospheric CO 2 concentration is calculated from a prognostic equation taking into account global anthropogenic CO 2 emissions and the interactive CO 2 exchanges of land‐atmosphere and ocean‐atmosphere. When forced by prescribed historical emissions of CO 2 from combustion of fossil fuels and land use change, BCC_CSM1.1 can reproduce the trends of observed atmospheric CO 2 concentration and global surface air temperature from 1850 to 2005. Simulated interannual variability and long‐term trend of global carbon sources and sinks and their spatial patterns generally agree with other model estimates and observations, which shows the following: (1) Both land and ocean in the last century act as net carbon sinks. The ability of carbon uptake by land and ocean is enhanced at the end of last century. (2) Interannual variability of the global atmospheric CO 2 concentration is closely correlated with the El Niño‐Southern Oscillation cycle, in agreement with observations. (3) Interannual variation of the land‐to‐atmosphere net carbon flux is positively correlated with surface air temperature while negatively correlated with soil moisture over low and midlatitudes. The relative contribution of soil moisture to the interannual variation of land‐atmosphere CO 2 exchange is more important than that of air temperature over tropical regions, while surface air temperature is more important than soil moisture over other regions of the globe.

Due to their properties such as superparamagnetism, high surface area, large surface-to-volume ratio, easy separation under external magnetic fields, iron magnetic nanoparticles have attracted much attention in the past few decades. Various modification methods have been developed to produce biocompatible magnetic nanoparticles for protein immobilization. This review provides an updated and integrated focus on the fabrication and characterization of suitable magnetic iron nanoparticle-based nano-active materials for protein immobilization.

Highly stable zirconium metal-organic frameworks (UiO-66 and UiO-66(NH2)) had been synthesized and investigated to remove arsenic (As) from contaminated water. The As(III, V) removal performance was studied by batch experiments and adsorption kinetics. At the pH of 9.2 ± 0.1, UiO-66 had exceptional removal capacities of 205.0 and 68.21 mg/g for As(III) and As(V), respectively. The As removal processes were exothermic and verified as chemisorption reactions according to the calculation of Gibbs free energy and Dubinin-Radushkevich (D-R) isotherm model. Fixed-bed reactor removal experiments indicated that the number of effective treatment volumes reached 2270 and 1775 BVs for As(III) and As(V), respectively, until the most stringent As regulation level of 10 μg/L (initial As concentration at 100 μg/L) was reached. FTIR and XPS study indicated that ZrO bonds of zirconium metal-organic frameworks played a vital role in As adsorption. XANES revealed the As adsorption on UiO-66 without the change of oxidation state. More intriguingly, EXAFS spectra demonstrated the main formation of bidentate mononuclear complexes for As(V), and bidentate binuclear complexes for As(III) on the hexanuclear Zr cluster of UiO-66. The advantages of nontoxicity, high stability, high As adsorption capacity, low-cost and easy availability confirm the highly promising application of zirconium metal-organic frameworks in As-contaminated wastewater remediation.

The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.

Fibrous carbon materials have been attracted many researchers' attentions. Carbon fibers have been developed as one of the most important industrial materials for modern science and technology since 1960s [1]. Due to the superior mechanical properties including high-specific strength and modulus, low density and thermal expansion, heat resistance, and chemical stability, carbon fibers as reinforcement materials have provided the impetus for researchers in developing high-performance composite materials. Nowadays, carbon fiber reinforced plastics (CFRP) are widely applied in the industries of aeronautic, aerospace, sporting goods, as well as new energy. The region between the fibers and matrix, contains unique micromechanical properties, is characteristically called the interphase and influence the bulk composite properties. Interface between fibers (reinforcements) and matrix is an important component for CFRP which may govern the CFRP performances [2]. For example, the interphase determines the off-axis strength and impact toughness of CFRP, environmental stability of CFRP and functional performance of CFRP. The effect of interface on composite can be achieved by regulating the composition, structure and distribution of the interface [3]. It has been proved that there has an optical interface for polymer based composite through the match of composite interface, reinforcement and polymer matrix. However, in terms of the smooth surface and chemical inertness of carbon fiber, the interface between carbon fiber and resin matrix is unsatisfactory. The interface should be modified and carefully controlled, which can be through by increasing the surface polarity of carbon fiber, improving the wettability between carbon fiber and resin, as well as promoting the chemical reaction. Obey these principles, the interfacial modification methods have been well developed. The universality of carbon fiber and polymer matrix, and the variability of the composite material forming process result in the complexity of polymer-based composites interface problems. Meanwhile the scale of the interface region is very small, it has great difficulty in characterizing the chemical structure, physical properties and mechanical characteristics. Recently, a series of effective characterization methods have been developed and initial interface characterization system is always being improved. With interface characterization techniques, the interfacial composition, structure morphology and micro-mechanical characteristics of interface can be researched easily, which can provide the basis for studying the interface physical and chemical properties. Hence interface characterization techniques not only are theory researches, but also have important practical significance for solving practical application problems of carbon fiber composites. Interface characterization techniques have become an important research direction of interface engineering research. In this paper, the researches in this field of carbon fiber interface were described, such as carbon fiber composite material characterization methods, interface control, and interfacial modification methods. With reference to the research achievements of a large number of scholars at present, so their current development trend were systemic concluded.

Biochars produced from biomass residues have been recognized as effective sorbents to hydrophobic compounds, but knowledge on sorption of antibiotics to biochar and its mechanisms are still inadequate. Sorption of oxytetracycline (OTC) in aqueous solution to maize-straw-derived biochar, and the effect of pH and metal ions, was investigated in batch experiments, and the main sorption mechanisms were elucidated using FTIR and zeta potential measurements. The results showed that sorption of OTC on biochar was highly pH-dependant. The amount of sorbed OTC first increased and then decreased with increasing pH, and maximum sorption was achieved at pH 5.5. Cu(2+) enhanced the sorption of OTC, while Pb(2+) slightly reduced the sorption under acidic conditions. Other metal ions had no significant effect on the sorption of OTC to biochar. Surface complexation, through π-π interaction and metal bridging, was the most important sorption mechanism although cation exchange might have played a role.

LPS-activated macrophages undergo a metabolic shift from dependence on mitochondria-produced ATP to reliance on aerobic glycolysis, where PKM2 is a critical determinant. Here, we show that PKM2 is a physiological substrate of SIRT5 and that SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. Moreover, a succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. Furthermore, we show that SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1α is formed at the promoter of IL-1β gene in LPS-stimulated macrophages. Activation of PKM2 using TEPP-46 attenuates Sirt5-deficiency-mediated IL-1β upregulation in LPS-stimulated macrophages. Finally, we find that Sirt5-deficient mice are more susceptible to DSS-induced colitis, which is associated with Sirt5 deficiency prompted PKM2 hypersuccinylation and boosted IL-1β production. In conclusion, our findings reveal a mechanism by which SIRT5 suppresses the pro-inflammatory response in macrophages at least in part by regulating PKM2 succinylation, activity, and function.

Hepatocellular carcinoma (HCC) is a common and deadly cancer. Most cases of HCC arise in a cirrhotic/fibrotic liver, indicating that environment may play a paramount role in cancer genesis. Previous studies from our group and others have shown that, in desmoplastic cancers, there is a rich intercellular communication between activated, cancer‐associated fibroblasts and cancer cells. Moreover, extracellular vesicles (EVs), or exosomes, have been identified as an important arm of this intercellular communication platform. Finally, these studies have shown that EVs can carry microRNA (miR) species in vivo and deliver them to desmoplastic cancers. The precise role played by activated liver fibroblasts/stellate cells in HCC development is insufficiently known. Based on previous studies, it appears plausible that activated fibroblasts produce signals carried by EVs that promote HCC genesis. In the current study, we first hypothesized and then demonstrated that stellate cell‐derived EVs 1) can be loaded with an miR species of choice (miR‐335‐5p); 2) are taken up by HCC cells in vitro and more importantly in vivo ; 3) can supply the miR‐335‐5p cargo to recipient HCC cells in vitro as well as in vivo ; and 4) inhibit HCC cell proliferation and invasion in vitro as well as induce HCC tumor shrinkage in vivo . Finally, we identified messenger RNA targets for miR‐335 that are down‐regulated after treatment with EV‐miR‐335‐5p. This study informs potential therapeutic strategies in HCC, whereby stellate cell‐derived EVs are loaded with therapeutic nucleic acids and delivered in vivo . (H epatology 2018;67:940–954)

BACKGROUND AND PURPOSE Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients of Panax ginseng with little toxicity and has been shown to have neuroprotective effects. In this study, we investigated the antidepressant‐like effect of Rg1 in models of depression in mice. EXPERIMENTAL APPROACH The effects of Rg1 were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Rg1 was also investigated in the chronic mild stress (CMS) mouse model of depression with imipramine as the positive control. Changes in hippocampal neurogenesis and spine density, the brain‐derived neurotrophic factor (BDNF) signalling pathway, and serum corticosterone level after chronic stress and Rg1 treatment were then investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressive mechanisms of Rg1. KEY RESULTS Ginsenoside Rg1 exhibited antidepressant‐like activity in the FST and TST in mice without affecting locomotor activity. It was also effective in the CMS model of depression. Furthermore, Rg1 up‐regulated the BDNF signalling pathway in the hippocampus and down‐regulated serum corticosterone level during the CMS procedure. In addition, Rg1 was able to reverse the decrease in dendritic spine density and hippocampal neurogenesis caused by CMS. However, Rg1 had no discernable effect on the monoaminergic system. CONCLUSIONS AND IMPLICATIONS Our results provide the first evidence that Rg1 has antidepressant activity via activation of the BDNF signalling pathway and up‐regulation of hippocampal neurogenesis.

Polyaniline (PANI)-decorated {001} facets of Bi2O2CO3 nanosheets were synthesized by a low-temperature chemical method. We demonstrate that the strong interfacial interactions between Bi2O2CO3 {001} facets and PANI could promote in situ formation of oxygen vacancy at the interface confirmed by both density functional theory calculations and electron spin resonance experiments, which is due to the high oxygen density characteristic of Bi2O2CO3 {001} facets. In addition, such interfacial interaction also leads to a 0.38 eV positive shifting of the valence band of Bi2O2CO3. Importantly, the decorated PANI can stabilize these interfacial oxygen vacancies. Therefore, the migration and separation of photogenerated carriers have been improved significantly evidenced by electrochemical impedance spectroscopy, photoluminescence, and nanosecond time-resolved fluorescence-decay spectra, resulting in a 4.5 times higher activity toward photodegradation of Rhodamine B and a 6 times higher photocurrent density compared to their corresponding bare Bi2O2CO3. The finding of the in situ oxygen vacancy formation at the interface could provide some hints for the deep understanding of the interactions between PANI and crystal facets of semiconductors to develop highly efficient photocatalysts.

Abstract Colorectal cancer (CRC) is a common human gastrointestinal cancer, and recent studies indicate that circular RNA (circRNA) may regulate cancer development. In this study, we assess the role of circRNA specifically in colorectal cancer. Our quantitative PCR assays demonstrate an upregulation of the circRNA has_circ_0020397 and a downregulation of miR‐138 in CRC cells, as well as a negative correlation between these two. Using a dual‐luciferase reporter assay, we show evidence of miR‐138‐binding sites on hsa_circ_0020397, and that overexpression of hsa_circ_0020397 could inhibit the downregulation of luciferase activity by miR‐138. Although hsa_circ_0020397 did not influence miR‐138 expression per se, has_circ_0020397 did inhibit miR‐138 activity, as examined via the expression of miR‐138 targets telomerase reverse transcriptase (TERT) and programmed death‐ligand 1 (PD‐L1). Control treatments with plasmids overexpressing linear hsa_circ_0020397 did not have these effects. Hsa_circ_0020397 promoted cell viability and invasion of CRC cells and inhibited their apoptosis, whereas miR‐138 had the opposite effect. Nevertheless, hsa_circ_0020397 antagonized miR‐138 suppression of cell growth. When TERT or PD‐L1 expression was suppressed with siRNAs, the above functions of hsa_circ_0020397 were attenuated, suggesting that hsa_circ_0020397 can regulate CRC cell viability, apoptosis and invasion by promoting the expression of miR‐138 target genes. These findings support the role of circRNA in CRC pathogenesis.

Uncontrolled growth of abdominal aortic aneurysms (AAAs) is a life-threatening vascular disease without an effective pharmaceutical treatment. AAA incidence dramatically increases with advancing age in men. However, the molecular mechanisms by which aging predisposes individuals to AAAs remain unknown.In this study, we investigated the role of SIRT1 (Sirtuin 1), a class III histone deacetylase, in AAA formation and the underlying mechanisms linking vascular senescence and inflammation.The expression and activity of SIRT1 were significantly decreased in human AAA samples. SIRT1 in vascular smooth muscle cells was remarkably downregulated in the suprarenal aortas of aged mice, in which AAAs induced by angiotensin II infusion were significantly elevated. Moreover, vascular smooth muscle cell-specific knockout of SIRT1 accelerated angiotensin II-induced formation and rupture of AAAs and AAA-related pathological changes, whereas vascular smooth muscle cell-specific overexpression of SIRT1 suppressed angiotensin II-induced AAA formation and progression in Apoe-/- mice. Furthermore, the inhibitory effect of SIRT1 on AAA formation was also proved in a calcium chloride (CaCl2)-induced AAA model. Mechanistically, the reduction of SIRT1 was shown to increase vascular cell senescence and upregulate p21 expression, as well as enhance vascular inflammation. Notably, inhibition of p21-dependent vascular cell senescence by SIRT1 blocked angiotensin II-induced nuclear factor-κB binding on the promoter of monocyte chemoattractant protein-1 and inhibited its expression.These findings provide evidence that SIRT1 reduction links vascular senescence and inflammation to AAAs and that SIRT1 in vascular smooth muscle cells provides a therapeutic target for the prevention of AAA formation.

Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5-dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation.

It have been recognized that the coupling of graphene quantum dots (GQDs) with semiconductor photocatalysts endow the resulting nanocomposites with enhanced photocatalytic performances, however, the essential roles of GQDs have not been clearly revealed yet. Herein, we report that a high efficiency of the photocatalytic H2 evolution was achieved using strongly coupled nanohybrids of CdS with GQDs (CdS/GQDs) as visible-light-driven photocatalysts. CdS/GQDs nanohybrids were synthesized by a facile hydrothermal method in which the crystallization of CdS precursor and coupling of GQDs could be accomplished in one-step. GQDs are firmly decorated on the surface of CdS nanoparticles, forming “dot-on-particle” heterodimer structures. GQDs have no significant influence on the crystallite structure of CdS but render the nanohybrids with strong light absorption at the wavelength beyond the band edge of CdS. Under visible light irradiation (≥420 nm), CdS/GQDs nanohybrids reach the highest H2 production rate of 95.4 μmol·h−1, about 2.7 times higher than that of pure CdS nanoparticles, at GQDs content of 1.0 wt%, and the apparent quantum efficiency (AQE) was determined to be 4.2% at 420 nm. Incident light-wavelength dependent experiments reveal that the light absorption of CdS dominated the performance of nanohybrids, and the excess light absorption coming from GQDs hardly contributes to the observed higher activity. Photocurrent response, steady-state and time-resolved PL, and EIS measurements suggest that the high activity of CdS/GQDs is attributed predominantly to the graphene-like nature of GQDs, which can act as an efficient electron acceptor to induce an efficient charge separation. This work clearly reveals that GQDs mainly played a role of electron acceptor instead of a photosensitizer in enhancing the photocatalytic H2 evolution performances of CdS/GQDs nanohybrids, which offers a new insight to understand the essential roles of GQDs in semiconductor/GQDs nanohybrids for efficient solar energy conversion applications.

MicroRNAs act as tumor suppressors or oncogenes. The pathological roles of miRNAs in gastric tumorigenesis are largely unknown. Although miR-10b was identified as an miRNA deregulator expressed in gastric cancer (GC), there also exists some debate on whether miR-10b is acting as tumor suppressor or oncogene in GC. Quantitative RT-PCR was employed to investigate the level of miR-10b in GC tissues and matched adjacent normal tissues (n = 100). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate the biological effects of miR-10b. Because silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorigenesis, GC cells were treated with 5-aza-2′-deoxycytidine and trichostatin A, and expression changes of miR-10b were subsequently examined by quantitative RT-PCR. Furthermore, the methylation status of the CpG island upstream of miR-10b was analyzed by methylation-specific PCR in GC tissues (n = 29). We showed here that miR-10b was significantly downregulated in GC cell lines and tissues as demonstrated by quantitative real-time PCR. Overexpression of miR-10b in MGC-803 and HGC-27 dramatically suppressed cell proliferation, migration, invasion, and induced apoptosis. Moreover, we demonstrated that T-cell lymphoma invasion and metastasis (Tiam1) was a target of miR-10b. Furthermore, 5-aza-2′-deoxycytidine and trichostain A increased miR-10b expression, and the methylation level was high in the CpG islands upstream of miR-10b gene. Taken together, these findings suggest that miR-10b may function as a novel tumor suppressor and is partially silenced by DNA hypermethylation in GC.

Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.

Article8 September 2017free access Source DataTransparent process LncRNA-PAGBC acts as a microRNA sponge and promotes gallbladder tumorigenesis Xiang-Song Wu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Fang Wang Department of Medical Genetics, Second Military Medical University, Shanghai, China Search for more papers by this author Huai-Feng Li Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yun-Ping Hu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Lin Jiang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Fei Zhang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Mao-Lan Li Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Xu-An Wang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yun-Peng Jin Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi-Jian Zhang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wei Lu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wen-Guang Wu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi-Jun Shu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Hao Weng Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yang Cao Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Run-Fa Bao Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Hai-Bin Liang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Zheng Wang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi-Chi Zhang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wei Gong Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Lei Zheng Corresponding Author [email protected] orcid.org/0000-0003-4163-2541 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USAThese authors share co-corresponding authorship Search for more papers by this author Shu-Han Sun Corresponding Author [email protected] orcid.org/0000-0001-6641-6197 Department of Medical Genetics, Second Military Medical University, Shanghai, ChinaThese authors share co-corresponding authorship Search for more papers by this author Ying-Bin Liu Corresponding Author [email protected] orcid.org/0000-0002-1075-1890 Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaThese authors share co-corresponding authorship Search for more papers by this author Xiang-Song Wu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Fang Wang Department of Medical Genetics, Second Military Medical University, Shanghai, China Search for more papers by this author Huai-Feng Li Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yun-Ping Hu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Lin Jiang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Fei Zhang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Mao-Lan Li Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Xu-An Wang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yun-Peng Jin Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi-Jian Zhang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wei Lu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wen-Guang Wu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi-Jun Shu Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Hao Weng Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yang Cao Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Run-Fa Bao Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Hai-Bin Liang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Zheng Wang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi-Chi Zhang Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wei Gong Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Lei Zheng Corresponding Author [email protected] orcid.org/0000-0003-4163-2541 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USAThese authors share co-corresponding authorship Search for more papers by this author Shu-Han Sun Corresponding Author [email protected] orcid.org/0000-0001-6641-6197 Department of Medical Genetics, Second Military Medical University, Shanghai, ChinaThese authors share co-corresponding authorship Search for more papers by this author Ying-Bin Liu Corresponding Author [email protected] orcid.org/0000-0002-1075-1890 Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Research Center of Biliary Tract Disease, Shanghai, China Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaThese authors share co-corresponding authorship Search for more papers by this author Author Information Xiang-Song Wu1,2,3,‡, Fang Wang4,‡, Huai-Feng Li1,2,3,‡, Yun-Ping Hu1,2,3,‡, Lin Jiang1,2,3, Fei Zhang1,2,3, Mao-Lan Li1,2,3, Xu-An Wang1,2,3, Yun-Peng Jin1,2,3, Yi-Jian Zhang1,2,3, Wei Lu1,2,3, Wen-Guang Wu1,2,3, Yi-Jun Shu1,2,3, Hao Weng1,2,3, Yang Cao1,2,3, Run-Fa Bao1,2,3, Hai-Bin Liang1,2,3, Zheng Wang1,2,3, Yi-Chi Zhang1,2,3, Wei Gong1,2,3, Lei Zheng *,5, Shu-Han Sun *,4 and Ying-Bin Liu *,1,2,3 1Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Shanghai Research Center of Biliary Tract Disease, Shanghai, China 3Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China 4Department of Medical Genetics, Second Military Medical University, Shanghai, China 5Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA ‡These authors contributed equally to this work *Corresponding author. Tel: +1 410 5026241; E-mail: [email protected] *Corresponding author. Tel: +86 021 81871053; Fax: +86 021 81871053; E-mail: [email protected] *Corresponding author. Tel/Fax: +86 021 25077880; E-mail: [email protected] EMBO Rep (2017)18:1837-1853https://doi.org/10.15252/embr.201744147 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis-associated gallbladder cancer lncRNA (lncRNA-PAGBC), which we find to be an independent prognostic marker in GBC. Functional analysis indicates that lncRNA-PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA-PAGBC competitively binds to the tumour suppressive microRNAs miR-133b and miR-511. This competitive role of lncRNA-PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA-PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC. Synopsis Long noncoding RNAs play roles in the development and progression of many cancers. In this study the lncRNA PAGBC is identified as promoting tumorigenesis in human gallbladder cancer by competitive binding to the tumour suppressive microRNAs miR-133b and miR-511. LncRNA-PAGBC is up-regulated in GBC and increased levels associate with poor prognosis. LncRNA-PAGBC promotes tumour growth and metastasis, and activates AKT/mTOR signaling by competitively binding to mirR-133b and mirR-511. LncRNA-PAGBC interacts with and is stabilized by the polyadenylate binding protein PABPC1. Introduction Gallbladder carcinoma (GBC) is the most common cancer of the biliary tract and the sixth most common type of gastrointestinal cancer worldwide 1. Because of its non-specific symptoms and highly invasive character, GBC is often detected at an advanced stage 2. Hence, only a minority of GBC patients are candidates for curative resection, and this cancer therefore carries an extremely poor prognosis. The reported mean survival for this malignancy ranges from 13.2 months to 19 months 34. Although various aberrantly expressed or mutated protein-coding genes have been identified in GBC, none have been useful for early diagnosis or for the development of targeted clinical therapies 56. Therefore, an understanding of the molecular changes in GBC will be important for early diagnosis and the development of effective targeted therapies, which together will improve the prognosis of GBC patients. In recent years, studies from different institutions have shown that long noncoding RNAs (lncRNAs) are involved in numerous physiological and pathological processes through various mechanisms 78, especially in the development and progression of different carcinomas 910. Thus, the investigation of the role of lncRNAs in GBC could help with the understanding of tumorigenesis and the identification of novel diagnostic and therapeutic targets. The lncRNAs work in a complicated way as critical regulators of epigenetic modulation, transcription and translation in a spatiotemporal manner 78. Recently, a role of competing endogenous RNAs (ceRNAs) has been proposed. In this model, lncRNA can affect other mRNA or lncRNA transcripts by competitively binding to a miRNA response element (MRE) to influence post-transcriptional regulation 1112. Until now, several lncRNAs, such as MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), have been identified in GBC 13. However, the overall functions of most lncRNAs in GBC and the detailed mechanism still remain unknown. In this study, we identified the profile of differentially expressed lncRNAs and mRNAs in GBCs relative to paired peritumoural tissues. Among the deregulated lncRNAs, we characterized a lncRNA-PAGBC (prognosis-associated gallbladder cancer lncRNA) which plays a critical role in the GBC development. As a ceRNA, lncRNA-PAGBC competitively binds to tumour suppressors, microRNA-133b and microRNA-511. This competitive role of lncRNA-PAGBC is required for its ability to activate the AKT/mTOR pathway and thus promote tumour growth and metastasis. Moreover, lncRNA-PAGBC interacts with and is stabilized by PABPC1. Our results provide novel insight into the disease mechanism of GBC and a potential therapeutic target for this malignancy. Results Expression profiles of lncRNAs in GBC A total of 7,798 lncRNAs and 7,290 protein-coding RNAs were identified as differentially expressed between nine pairs of GBC and non-tumour samples. Hierarchical clustering demonstrated systematic variations in the expression levels of the lncRNAs and mRNAs between GBC and the paired non-tumour samples (Fig EV1A and B, and Dataset EV1). The heatmaps of the top 60 lncRNAs and mRNAs that are differentially expressed in GBC were shown in Fig 1A. To validate the reliability of the microarray results, the expression of four randomly selected lncRNAs and lncRNA-MALAT1 (an lncRNA reported to be highly expressed in GBC 13) was analysed in 26 additional pairs of GBCs and corresponding non-tumour samples. The results confirmed that BC010117, NR_038835 and MALAT1 were highly expressed in the GBC samples, whereas AC240664.3 and ENST00000415656 were deregulated in non-tumour samples (Fig 1B). Click here to expand this figure. Figure EV1. Expanded information for differential expression of lncRNAs in GBC A, B. Hierarchical clustering analysis of lncRNAs (A) and protein-coding RNAs (B) that were differentially expressed between GBC samples (c, cancer tissues) and non-tumour samples (n, non-tumour samples). The colour scale shown on the right illustrates the relative expression level of RNA; red represents high expression and green represents low expression. C. Coexpression network in GBC tissues. Red nodes represent lncRNAs, and green nodes represent protein-coding genes. D. Coexpression network in non-tumour tissues. Red nodes represent lncRNAs, and green nodes represent protein-coding genes. Source data are available online for this figure. Download figure Download PowerPoint Figure 1. Differential expression of lncRNAs in GBC Heatmaps of the top 60 lncRNAs (left) and protein-coding RNAs (right) that were differentially expressed between GBC samples (c, cancer tissues) and non-tumour samples (n, non-tumour samples). The colour scale shown on the left illustrates the relative expression level of RNA; red represents high expression and green represents low expression. The differential expression of four randomly selected lncRNAs and MALAT1 in 26 paired GBC and non-tumour samples was determined via qRT–PCR. lncRNA expression is expressed as the lncRNA/GAPDH expression ratio (i.e. 2−ΔCt). Data are mean ± SD (n = 26). lncRNA-PAGBC subnetwork in the GBC coexpression network. This subnetwork consists of 17 lncRNAs (red) and 30 protein-coding genes (green) with fold change ≥ 10.0 and a P-value ≤ 0.05. lncRNA-PAGBC expression in human GBC tissues and paired non-tumour tissues was analysed via qRT–PCR. The results are shown by box plots (left) and bar charts (right). In the box plot, horizontal lines in the box plots represent the median, the boxes represent the interquartile range, and whiskers represent the 2.5th and 97.5th percentiles (n = 60). Upper panel: The survival rates of 77 HCC patients who underwent surgery were compared between the high- and low-lncRNA-PAGBC expression groups. Lower panel: Kaplan–Meier survival curves of gallbladder cancer patients with different expression levels of PAGBC stratified by the TNM stage of the tumour. P-value was obtained by log-rank test. Stage I and II gallbladder cancers with low expression level of PAGBC versus high expression level of PAGBC, P < 0.01; Stage III and IV gallbladder cancers with low expression level of PAGBC versus high expression level of PAGBC, P < 0.05; Stage I and II gallbladder cancers with high expression level of PAGBC versus Stage III and IV gallbladder cancers with low expression level of PAGBC, P > 0.05. Northern blot analysis of lncRNA-PAGBC in GBC tissues and cells shows the length of the lncRNA-PAGBC fragment. Molecular weight markers are indicated on the right. β-actin was used as an internal control. qRT–PCR analysis of lncRNA-PAGBC expression in NOZ cells. The total, nuclear and cytoplasmic RNA fractions were extracted. β-actin, GAPDH, U2 and U6 were used as endogenous controls. Data are mean ± SD (n = 3). Localization of lncRNA-PAGBC by RNA-FISH in GBC-SD and NOZ cells transfected with negative control siRNA(siNC) or PAGBC siRNA. Nuclei are stained blue (DAPI), and lncRNA-PAGBC is stained green. Scale bars represent 25 μm. Data information: *P < 0.05, **P < 0.01, ***P < 0.001 (Student's t-test). Source data are available online for this figure. Source Data for Figure 1 [embr201744147-sup-0005-SDataFig1.pdf] Download figure Download PowerPoint A newly identified lncRNA serves as an independent prognostic factor for the overall survival of GBC patients A gene-coexpression network was used to cluster various transcripts into phenotypically relevant coexpression modules 101415. The structural differences in the coexpression networks for the GBC and non-tumour samples indicated the variance in lncRNA and mRNA expression levels in the GBC and non-tumour samples (Fig EV1C and D). Considering that biologically related gene groups tend to show similar patterns of change during cancer development 1014, we focused on the lncRNAs with a high rate of coexpressed protein-coding RNAs. In particular, lncRNA-LINC01133 (NR_038849.1) caught our attention and was designated as the prognosis-associated gallbladder cancer lncRNA (lncRNA-PAGBC). lncRNA-PAGBC was highly expressed in GBC tissues and was associated with 17 lncRNAs and 30 protein-coding genes with fold change ≥ 10.0 and a P-value ≤ 0.05 involved in tumour growth and metastasis in the coexpression network (Fig 1C, Appendix Table S1). qRT–PCR was performed on 60 pairs of human GBC tissues and corresponding non-tumour tissues, and the results indicated that the levels of the lncRNA-PAGBC transcript were significantly increased in GBC tissues compared with the corresponding non-tumour tissues (P < 0.01, Fig 1D). We further examined lncRNA-PAGBC expression in 77 human GBC tissues. Based on the clinical and pathological data, we found that higher levels of lncRNA-PAGBC expression were associated with more advanced tumour stages (Appendix Table S2). Kaplan-Meier analysis indicated that GBC patients with higher lncRNA-PAGBC expression levels exhibited significantly reduced overall survival (OS) (P < 0.001, Fig 1E, upper panel). Multivariate analyses showed that the lncRNA-PAGBC expression level was an independent prognostic factor for overall patient survival (P < 0.01). When stratified by TNM stage, patients with a low expression level of PABGC had significantly better overall survival results than those with a high expression level of PABGC (P < 0.01 and P < 0.05, respectively; Fig 1E, lower panel). The full length of lncRNA-PAGBC was confirmed by rapid amplification of cDNA ends (RACE) analysis (Fig EV2A and B), its existence and expected size was further testified by northern blot assay (Fig 1F). Fluorescence in situ hybridization and RT–PCR results suggested that this lncRNA mainly located in the cytoplasm (Fig 1G and H). Analysis of the sequences using the Open Reading Frame (ORF) Finder of the National Center for Biotechnology Information and codon substitution frequency (CSF) analysis with PhyloCSF indicated that lncRNA-PAGBC had little potential to code proteins (Fig EV2C and D). An in vitro translation analysis failed to identify an extra band compared with the non-template group (Fig EV2E), which further supported the notion that the lncRNA-PAGBC transcript showed no protein-coding potential. Click here to expand this figure. Figure EV2. Expanded information for lncRNA-PAGBC The nucleotide sequence of full-length human lncRNA-PAGBC. A representative image of the PCR products of the 5′-RACE and 3′-RACE procedures. Putative proteins that may be encoded by lncRNA-PAGBC, as predicted by ORF Finder. Codon substitution frequency scores (CSF) of lncRNA-PAGBC. PAGBC translation reactions with PSPT19 backbone vector constructs: Molecular weight marker (M), TNT® SP6 Quick master mix control (Ctrl), 5 μl of the 50 μl in vitro translation reaction mixture with PSPT19-PAGBC (PAGBC). Source data are available online for this figure. Download figure Download PowerPoint Collectively, these data suggest that lncRNA-PAGBC could represent a role in carcinogenesis of GBC. lncRNA-PAGBC regulates tumour growth and metastasis in GBC cells To determine the biological function of lncRNA-PAGBC in GBC cell lines, we stably knocked down lncRNA-PAGBC in NOZ and GBC-SD cells for their relatively high expression levels of lncRNA-PAGBC; on the opposite, lncRNA-PAGBC was overexpressed in SGC996 and EH-GB1 cells (Fig EV3A–E). Cell-counting kit-8 (CCK-8) assays and colony formation assays demonstrated that the proliferation of NOZ and GBC-SD cells was significantly inhibited after lncRNA-PAGBC silencing (Fig 2A and B). Furthermore, a subcutaneous xenog

Recent advances in gene editing technology have introduced the potential for application of mutagenesis approaches in nonhuman primates to model human development and disease. Here we report successful TALEN-mediated mutagenesis of an X-linked, Rett syndrome (RTT) gene, methyl-CpG binding protein 2 (MECP2), in both rhesus and cynomolgus monkeys. Microinjection of MECP2-targeting TALEN plasmids into rhesus and cynomolgus zygotes leads to effective gene editing of MECP2 with no detected off-target mutagenesis. Male rhesus (2) and cynomolgous (1) fetuses carrying MECP2 mutations in various tissues including testes were miscarried during midgestation, consistent with RTT-linked male embryonic lethality in humans. One live delivery of a female cynomolgus monkey occurred after 162 days of gestation, with abundant MECP2 mutations in peripheral tissues. We conclude that TALEN-mediated mutagenesis can be an effective tool for genetic modeling of human disease in nonhuman primates.

Retrieving 3D models from 2D human sketches has received considerable attention in the areas of graphics, image retrieval, and computer vision. Almost always in state of the art approaches a large amount of “best views” are computed for 3D models, with the hope that the query sketch matches one of these 2D projections of 3D models using predefined features. We argue that this two stage approach (view selection - matching) is pragmatic but also problematic because the “best views” are subjective and ambiguous, which makes the matching inputs obscure. This imprecise nature of matching further makes it challenging to choose features manually. Instead of relying on the elusive concept of “best views” and the hand-crafted features, we propose to define our views using a minimalism approach and learn features for both sketches and views. Specifically, we drastically reduce the number of views to only two predefined directions for the whole dataset. Then, we learn two Siamese Convolutional Neural Networks (CNNs), one for the views and one for the sketches. The loss function is defined on the within-domain as well as the cross-domain similarities. Our experiments on three benchmark datasets demonstrate that our method is significantly better than state of the art approaches, and outperforms them in all conventional metrics.

Elucidating the tumorigenic mechanism of R-2-hydroxyglutarate (R-2HG) is critical for determining how NADP(+)-IDH mutations cause cancer. Here we report that R-2HG induces cancerous metabolism and apoptosis resistance through promoting hypersuccinylation. By competitive inhibition of the mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH), R-2HG preferentially induced succinyl-CoA accumulation and hypersuccinylation in the mitochondria. IDH1 mutation-bearing glioma samples and cells were hypersuccinylated in the mitochondria. IDH1 mutation or SDH inactivation resulted in hypersuccinylation, causing respiration inhibition and inducing cancerous metabolism and mitochondrial depolarization. These mitochondrial dysfunctions induced BCL-2 accumulation at the mitochondrial membrane, leading to apoptosis resistance of hypersuccinylated cells. Relief of hypersuccinylation by overexpressing the desuccinylase SIRT5 or supplementing glycine rescued mitochondrial dysfunctions, reversed BCL-2 accumulation, and slowed the oncogenic growth of hypersuccinylated IDH1(R132C)-harboring HT1080 cells. Thus, R-2HG-induced hypersuccinylation contributes to the tumorigenicity of NADP(+)-IDH mutations, suggesting the potential of hypersuccinylation inhibition as an intervention for hypersuccinylation-related tumors.

A nickel-catalyzed, enantioselective, three-component fluoroalkylarylation of unactivated alkenes with aryl halides and perfluoroalkyl iodides has been described. This cross-electrophile coupling protocol utilizes a chiral nickel/BiOx system as well as a pendant chelating group to facilitate the challenging three-component, asymmetric difunctionalization of unactivated alkenes, providing direct access to valuable chiral β-fluoroalkyl arylalkanes with high efficiency and excellent enantioselectivity. The mild conditions allow for a broad substrate scope as well as good functional group toleration.

We report first results from a large project to measure black hole (BH) mass in high accretion rate active galactic nuclei (AGNs). Such objects may be different from other AGNs in being powered by slim accretion disks and showing saturated accretion luminosities, but both are not yet fully understood. The results are part of a large reverberation mapping (RM) campaign using the 2.4 m Shangri-La telescope at the Yunnan Observatory in China. The goals are to investigate the gas distribution near the BH and the properties of the central accretion disks, to measure BH mass and Eddington ratios, and to test the feasibility of using such objects as a new type of cosmological candles. The paper presents results for three objects, Mrk 335, Mrk 142, and IRAS F12397+3333, with Hβ time lags relative to the 5100 Å continuum of , and days, respectively. The corresponding BH masses are , , and , and the lower limits on the Eddington ratios are 0.6, 2.3, and 4.6 for the minimal radiative efficiency of 0.038. Mrk 142 and IRAS F12397+333 (extinction corrected) clearly deviate from the currently known relation between Hβ lag and continuum luminosity. The three Eddington ratios are beyond the values expected in thin accretion disks and two of them are the largest measured so far among objects with RM-based BH masses. We briefly discuss implications for slim disks, BH growth, and cosmology.

Identifying the metal ions that optimize charge transport and charge density in metal–organic frameworks is critical for systematic improvements in the electrical conductivity in these materials.

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulted from T cell-mediated destruction of pancreatic β-cells, how to regenerate β-cells and prevent the autoimmune destruction of remnant and neogenetic β-cells is a tough problem. Immunomodulatory propertity of mesenchymal stem cell make it illuminated to overcome it. We assessed the long-term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord for Newly-onset T1DM. Twenty-nine patients with newly onset T1DM were randomly divided into two groups, patients in group I were treated with WJ-MSCs and patients in group II were treated with normal saline based on insulin intensive therapy. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 21 months, the occurrence of any side effects and results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I compared with group II, both the HbA1c and C peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of WJ-MSCs for the treatment of newly-onset T1DM is safe and effective. This therapy can restore the function of islet β cells in a longer time, although precise mechanisms are unknown, the implantation of WJ-MSCs is expected to be an effective strategy for treatment of type1 diabetes.

In this paper, a consensus tracking problem of nonlinear multiagent systems is investigated under a directed communication topology. All the followers are modeled by stochastic nonlinear systems in nonstrict feedback form, where nonlinearities and stochastic disturbance terms are totally unknown. Based on the structural characteristic of neural networks (in Lemma 4), a novel distributed adaptive neural control scheme is put forward. The raised control method not only effectively handles unknown nonlinearities in nonstrict feedback systems, but also copes with the interactions among agents and coupling terms. Based on the stochastic Lyapunov functional method, it is indicated that all the signals of the closed-loop system are bounded in probability and all followers' outputs are convergent to a neighborhood of the output of leader. At last, the efficiency of the control method is testified by a numerical example.

Article28 February 2018free access Source DataTransparent process SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer Xiu-Fei Chen Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Meng-Xin Tian orcid.org/0000-0002-5315-1780 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Ren-Qiang Sun Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Meng-Li Zhang Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Li-Sha Zhou Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Lei Jin Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Lei-Lei Chen Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Wen-Jie Zhou Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Kun-Long Duan Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Yu-Jia Chen Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Chao Gao Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Zhou-Li Cheng Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Fang Wang Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Jin-Ye Zhang Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Yi-Ping Sun Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Hong-Xiu Yu Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Yu-Zheng Zhao School of Pharmacy, East China University of Science and Technology, Shanghai, China Search for more papers by this author Yi Yang School of Pharmacy, East China University of Science and Technology, Shanghai, China Search for more papers by this author Wei-Ren Liu Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Ying-Hong Shi Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Yue Xiong orcid.org/0000-0003-2744-6566 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Search for more papers by this author Kun-Liang Guan orcid.org/0000-0003-1892-0174 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Dan Ye Corresponding Author [email protected] orcid.org/0000-0003-4848-0501 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China Search for more papers by this author Xiu-Fei Chen Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Meng-Xin Tian orcid.org/0000-0002-5315-1780 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Ren-Qiang Sun Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Meng-Li Zhang Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Li-Sha Zhou Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Lei Jin Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Lei-Lei Chen Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Wen-Jie Zhou Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Kun-Long Duan Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Yu-Jia Chen Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Chao Gao Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Zhou-Li Cheng Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Fang Wang Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Jin-Ye Zhang Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Yi-Ping Sun Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Hong-Xiu Yu Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Search for more papers by this author Yu-Zheng Zhao School of Pharmacy, East China University of Science and Technology, Shanghai, China Search for more papers by this author Yi Yang School of Pharmacy, East China University of Science and Technology, Shanghai, China Search for more papers by this author Wei-Ren Liu Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Ying-Hong Shi Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China Search for more papers by this author Yue Xiong orcid.org/0000-0003-2744-6566 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Search for more papers by this author Kun-Liang Guan orcid.org/0000-0003-1892-0174 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Dan Ye Corresponding Author [email protected] orcid.org/0000-0003-4848-0501 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China Search for more papers by this author Author Information Xiu-Fei Chen1,2,3, Meng-Xin Tian4,5, Ren-Qiang Sun1,2,3, Meng-Li Zhang1,2,3, Li-Sha Zhou1,2,3, Lei Jin4,5, Lei-Lei Chen1,2,3, Wen-Jie Zhou1,2,3, Kun-Long Duan1,2,3, Yu-Jia Chen1,2,3, Chao Gao1,2,3, Zhou-Li Cheng1,2,3, Fang Wang1,2,3, Jin-Ye Zhang1,2,3, Yi-Ping Sun1,2,3, Hong-Xiu Yu1,2,3, Yu-Zheng Zhao6, Yi Yang6, Wei-Ren Liu4,5, Ying-Hong Shi4,5, Yue Xiong1,2,3,7, Kun-Liang Guan1,2,3,8 and Dan Ye *,1,2,3,9 1Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China 2Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China 3State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China 4Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China 5Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China 6School of Pharmacy, East China University of Science and Technology, Shanghai, China 7Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 8Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA 9Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China *Corresponding author. Tel: +86 21 54237834; E-mail: [email protected] EMBO Rep (2018)19:e45124https://doi.org/10.15252/embr.201745124 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2O2. ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development. Synopsis This study reveals a role for SIRT5 in regulating peroxisomal H2O2 and ROS homeostasis and indicates its potential function in liver protection and hepatocellular carcinoma suppression. SIRT5 is localized in peroxisomes where it controls H2O2 metabolism. SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation. SIRT5 downregulation increases ACOX1 activity and oxidative DNA damage response in HCC. Introduction Peroxisomes are ubiquitous and highly dynamic organelles, which are involved in the catabolism of very-long-chain fatty acids (VLCFAs), branched-chain fatty acids, D-amino acids, polyamines, and the biosynthesis of ether lipids and bile acids 1, 2. Dysfunctions in peroxisomal metabolism are linked to inherited peroxisomal disorders, age-related diseases, and human cancers 3, 4. Clinically, peroxisomal disorders refer to either peroxisome biogenesis disorders or single peroxisomal enzyme deficiencies 5. The former group is mainly associated with mutations in the genes encoding for peroxisomal biogenesis factors (also known as peroxins or PEX), which are involved in the import of peroxisomal proteins from the cytoplasm 6. The latter group is caused by defects in peroxisomal matrix enzymes or membrane proteins which can affect specific peroxisome-dependent metabolic pathways 7, 8. In peroxisomes, ACOX1 (acyl-CoA oxidase 1, EC 1.3.3.6) is the first and a rate-limiting enzyme which catalyzes the desaturation of very-long-chain acyl-CoAs to 2-trans-enoyl-CoAs, and transfers electrons in the form of H− from their prosthetic group FADH2 to molecular oxygen to generate hydrogen peroxide (H2O2) 9. This step is distinguished from the desaturation of long-, middle- and short-chain acyl-CoAs to trans 2,3-dehydroacyl-CoA catalyzed by acyl-CoA dehydrogenases (ACADs) in mitochondria, which transfers electrons to flavin adenine dinucleotide (FAD) and generates FADH2 used for ATP production in the respiratory chain 10. H2O2 is relatively stable and less reactive as compared to other reactive oxygen species (ROS), such as superoxide anion (), hydroxyl radicals (OH·), and peroxyradicals (ROO·). Lack of electric charge enables H2O2 to cross membranes. Several previous studies have reported that H2O2 generated by peroxisomes can rapidly (within seconds) diffuse across lipid bilayer membranes and enter into nuclei 11-13. H2O2 is known to be implicated in redox regulation of multiple signal transduction pathways when produced at low levels 14-16. Once entering into nuclei, H2O2 can induce stalled replication forks and DNA double-strand breaks and cause oxidative DNA damage, and is thus involved in the processes of mutagenesis, aging, and carcinogenesis 17-20. Previous studies have shown that the ACOX1 gene is under the control of peroxisome proliferator-activated receptor alpha (PPARα) 21. Abnormal upregulation of ACOX1 by PPAR activation was reported to stimulate hepatic fatty acid oxidation, accompanied by H2O2 accumulation, resulting in excess energy burning in the liver and contributing to the development of liver cancer in rodents 22, 23. Acox1-null mice exhibit growth retardation, infertility, excess VLCFAs in the blood, and develop progressive liver diseases with increased intrahepatic H2O2 levels derived from mitochondrial and microsomal fatty acid oxidation and other sources 22, 24-26. Together, these findings suggest that peroxisomal ACOX1 is crucial for fatty acid oxidation and H2O2 homeostasis in liver tissue and that ACOX1 dysfunction contributes to the development of chronic liver disease and hepatocarcinogenesis. Thus far, how ACOX1 is regulated to meet the need for VLCFA catabolism and to control cellular H2O2 levels and redox homeostasis is poorly understood. Much of efforts on understanding the regulation of ACOX1 have been focused at its transcriptional control, while the post-translational modifications of ACOX1 are greatly unknown. Large-scale proteomic studies of cellular proteins have revealed that acetylation, succinylation, malonylation, and glutarylation can regulate multiple metabolic processes 27. Among these acylations, lysine succinylation, malonylation, and glutarylation are commonly regulated by the deacylase sirtuin 5 (SIRT5) 28-30. All these post-translational modifications occur on the ε group of a Lys residue, suggesting the possibility that different modification may compete or block each other, allowing signals from different physiological conditions or pathways to be integrated on or sensed by a common protein. Notably, multiple succinylation sites in ACOX1 have been identified in SIRT5 knockout (KO) versus wild-type HeLa cells and mouse livers 30, 31, implying that ACOX1 may be a potential substrate of SIRT5. In this study, we discover that ACOX1 is a physiological substrate of SIRT5 as SIRT5-dependent desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation. We show that SIRT5 loss is associated with increased succinylation and activity of ACOX1 in cultured cells, mouse liver tissues, and human HCC cancer samples. Results SIRT5 can localize in peroxisomes where it regulates H2O2 metabolism and cellular redox status As mentioned above, significant amount of H2O2 is produced during the ACOX1-catalyzed reaction, raising the question how cells balance the need for VLCFA catabolism and control of cellular H2O2 levels and redox homeostasis. Several recent proteomic studies in mouse liver and skeletal muscle have identified a large number of succinylated proteins as potential substrates

The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People's Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189-UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.

Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Language model pre-training, such as BERT, has significantly improved the performances of many natural language processing tasks. However, pre-trained language models are usually computationally expensive, so it is difficult to efficiently execute them on resource-restricted devices. To accelerate inference and reduce model size while maintaining accuracy, we first propose a novel Transformer distillation method that is specially designed for knowledge distillation (KD) of the Transformer-based models. By leveraging this new KD method, the plenty of knowledge encoded in a large teacher BERT can be effectively transferred to a small student Tiny-BERT. Then, we introduce a new two-stage learning framework for TinyBERT, which performs Transformer distillation at both the pretraining and task-specific learning stages. This framework ensures that TinyBERT can capture he general-domain as well as the task-specific knowledge in BERT. TinyBERT with 4 layers is empirically effective and achieves more than 96.8% the performance of its teacher BERTBASE on GLUE benchmark, while being 7.5x smaller and 9.4x faster on inference. TinyBERT with 4 layers is also significantly better than 4-layer state-of-the-art baselines on BERT distillation, with only about 28% parameters and about 31% inference time of them. Moreover, TinyBERT with 6 layers performs on-par with its teacher BERTBASE.

This paper studies the finite-time stabilization of a class of stochastic nonlinear systems. Different from functions which are necessarily known in the conventional finite-time control of nonlinear systems, the nonlinear functions can be completely unknown in this paper. By applying fuzzy-logic systems to approximate the unknown nonlinearities, a novel adaptive finite-time control strategy is proposed. However, due to the existence of approximation errors, the existing finite-time stability criterion cannot be used to analyze the stability of stochastic nonlinear systems. To deal with this difficulty, a finite-time stability criterion, by utilizing the mean value theorem of integrals, is first established in Lemma 5, which plays a significant role in the finite-time stability analysis of stochastic nonlinear systems. Then, the finite-time mean square stability of a stochastic nonlinear system is proved by combining Lemma 3 with Jensen's inequality.

Bi₂WO₆/graphene exhibited higher photocatalytic activity and improved selectivity through the modification of band structure and interfacial interactions.

DNA replication is a key step to maintain the continuity of genetic information between parental generation and offspring. The initiation site of DNA replication, also called origin of replication (ORI), plays an extremely important role in the basic biochemical process. Thus, rapidly and effectively identifying the location of ORI in genome will provide key clues for genome analysis. Although biochemical experiments could provide detailed information for ORI, it requires high experimental cost and long experimental period. As good complements to experimental techniques, computational methods could overcome these disadvantages.Thus, in this study, we developed a predictor called iORI-PseKNC2.0 to identify ORIs in the Saccharomyces cerevisiae genome based on sequence information. The PseKNC including 90 physicochemical properties was proposed to formulate ORI and non-ORI samples. In order to improve the accuracy, a two-step feature selection was proposed to exclude redundant and noise information. As a result, the overall success rate of 88.53% was achieved in the 5-fold cross-validation test by using support vector machine.Based on the proposed model, a user-friendly webserver was established and can be freely accessed at http://lin-group.cn/server/iORI-PseKNC2.0. The webserver will provide more convenience to most of wet-experimental scholars.

Internal representations of relationships between events in the external world can be utilized to infer outcomes when direct experience is lacking. This process is thought to involve the orbitofrontal cortex (OFC) and hippocampus (HPC), but there is little evidence regarding the relative role of these areas and their interactions in inference. Here, we used a sensory preconditioning task and pattern-based neuroimaging to study this question. We found that associations among value-neutral cues were acquired in both regions during preconditioning but that value-related information was only represented in the OFC at the time of the probe test. Importantly, inference was accompanied by representations of associated cues and inferred outcomes in the OFC, as well as by increased HPC–OFC connectivity. These findings suggest that the OFC and HPC represent only partially overlapping information and that interactions between the two regions support model-based inference.

The surgical navigation system has experienced tremendous development over the past decades for minimizing the risks and improving the precision of the surgery. Nowadays, Augmented Reality (AR)-based surgical navigation is a promising technology for clinical applications. In the AR system, virtual and actual reality are mixed, offering real-time, high-quality visualization of an extensive variety of information to the users (Moussa et al., 2012) [1]. For example, virtual anatomical structures such as soft tissues, blood vessels and nerves can be integrated with the real-world scenario in real time. In this study, an AR-based surgical navigation system (AR-SNS) is developed using an optical see-through HMD (head-mounted display), aiming at improving the safety and reliability of the surgery. With the use of this system, including the calibration of instruments, registration, and the calibration of HMD, the 3D virtual critical anatomical structures in the head-mounted display are aligned with the actual structures of patient in real-world scenario during the intra-operative motion tracking process. The accuracy verification experiment demonstrated that the mean distance and angular errors were respectively 0.809 ± 0.05 mm and 1.038° ± 0.05°, which was sufficient to meet the clinical requirements.

Morphology of MIL-88A-Fe greatly affects their Fenton-like performance. In this work, rod-like, spindle-like and diamond-like MIL-88A-Fe was prepared by changing the ratio of solvents in solvothermal process. Their physicochemical properties are fully investigated by XRD, SEM, TEM, XPS, ESR, and DFT calculation, which confirmed that the exposed (100) ratio of MIL-88A-Fe determined its catalytic performance. The (100) surface of MIL-88A-Fe showed lower energy barrier for H2O2 dissociated into •OH (dissociated energy 0.58 eV), corresponding value is 0.8 eV for (101) surface. The Fenton-like performance has the order of r-MIL-88A (TOF 5.0 h−1) > s-MIL-88A (TOF 3.3 h−1) > d-MIL-88A (TOF 2.5 h−1), when r-MIL-88A used as catalyst, phenol could be removed 100% in 15 min by the help of H2O2 at room conditions, its activity are better than that of reported Fe-based MOFs, such as MIL-88B-Fe, MIL-101-Fe, and MIL-53(Fe) etc. This finding probably provide a Fenton-like catalyst by choosing the suitable crystal phase of Fe-based metal organic framework.

Abstract Antibody–drug conjugates (ADC) are emerging as clinically effective therapy. We hypothesized that cancers treated with ADCs would acquire resistance mechanisms unique to immunoconjugate therapy and that changing ADC components may overcome resistance. Breast cancer cell lines were exposed to multiple cycles of anti-Her2 trastuzumab–maytansinoid ADC (TM-ADC) at IC80 concentrations followed by recovery. The resistant cells, 361-TM and JIMT1-TM, were characterized by cytotoxicity, proteomic, transcriptional, and other profiling. Approximately 250-fold resistance to TM-ADC developed in 361-TM cells, and cross-resistance was observed to other non–cleavable-linked ADCs. Strikingly, these 361-TM cells retained sensitivity to ADCs containing cleavable mcValCitPABC-linked auristatins. In JIMT1-TM cells, 16-fold resistance to TM-ADC developed, with cross-resistance to other trastuzumab-ADCs. Both 361-TM and JIMT1-TM cells showed minimal resistance to unconjugated mertansine (DM1) and other chemotherapeutics. Proteomics and immunoblots detected increased ABCC1 (MRP1) drug efflux protein in 361-TM cells, and decreased Her2 (ErbB2) in JIMT1-TM cells. Proteomics also showed alterations in various pathways upon chronic exposure to the drug in both cell models. Tumors derived from 361-TM cells grew in mice and were refractory to TM-ADC compared with parental cells. Hence, acquired resistance to trastuzumab–maytansinoid ADC was generated in cultured cancer cells by chronic drug treatment, and either increased ABCC1 protein or reduced Her2 antigen were primary mediators of resistance. These ADC-resistant cell models retain sensitivity to other ADCs or standard-of-care chemotherapeutics, suggesting that alternate therapies may overcome acquired ADC resistance. Mol Cancer Ther; 14(4); 952–63. ©2015 AACR.

In this paper, CuO nanoparticles were synthetized <italic>via</italic> a sol–gel method and their corresponding gas sensor was achieved simultaneously.

Abstract An intelligent theranostic nanoplatform based on nanovalve operated metal–organic framework (MOF) core–shell hybrids, incorporating tumorous microenvironment‐triggered drug release, magnetic resonance imaging (MRI) guidance, sustained release, and effective chemotherapy in one pot is reported. The core–shell hybrids are constructed by an in situ growth method, in which Fe 3 O 4 particles with superior abilities of MRI and magnetic separation form the core and UiO‐66 MOF with high loading capacity compose the shell, and then are surface‐installed with pillararene‐based pseudorotaxanes as tightness‐adjustable nanovalves. This strategy endows the system with the ability of targeted, multistimuli responsive drug release in response to pH changes, temperature variations, and competitive agents. Water‐soluble carboxylatopillar[6]arene system achieved sustained drug release over 7 days due to stronger host–guest binding, suggesting that the nanovalve tightness further reinforces the desirable release of anticancer agent over a prolonged time at the lesion site.

This paper addresses the problem of adaptive fuzzy control for a class of stochastic pure-feedback nonlinear systems with unknown direction hysteresis. Compared with the existing researches on hysteresis problem, the stochastic disturbances and the unknown hysteresis are simultaneously considered in the pure-feedback systems. In addition, the hysteresis parameters as well as the direction of hysteresis are unknown. By introducing an auxiliary virtual controller and employing the new properties of Nussbaum function, the major technique difficulty arising from the unknown direction hysteresis is overcome. Based on the fuzzy logic system's online approximation capability, a novel adaptive fuzzy control scheme is presented via the backstepping technique. It is shown that the proposed control scheme guarantees that all the signals of the closed-loop system are semiglobally uniformly bounded in probability, and the tracking error converges to a neighborhood of the origin in the sense of mean quantic value. Finally, simulation results further demonstrate the effectiveness of the proposed control scheme.

Despite the growing number of studies on online reviews, the impact of visual cues on consumer's evaluation of review helpfulness has remained underexplored. It is not yet known whether and how images influence the way online reviews are perceived. This paper introduces and empirically examines the potential effects of reviewer profile image, a photo/image displayed next to the reviewer name, on review helpfulness by drawing on the decorative and information functions of images. With a sample of 2178 reviews from mobile gaming applications, we report that reviewer profile image can significantly enhance consumer's evaluation of review helpfulness; whereas there is no differential effect among image types (i.e. self, family, or random images). Interestingly, the effect of reviewer profile image on review helpfulness is moderated by review length, but not review valence and equivocality. Results suggest that reviewer profile image enhances the perception of review helpfulness by serving mainly as a visual decoration that creates affective responses rather than identity information.

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease. SIGNIFICANCE: This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2651/F1.large.jpg.

Lagoviruses belong to the Caliciviridae family. They were first recognized as highly pathogenic viruses of the European rabbit (Oryctolagus cuniculus) and European brown hare (Lepus europaeus) that emerged in the 1970–1980s, namely, rabbit haemorrhagic disease virus (RHDV) and European brown hare syndrome virus (EBHSV), according to the host species from which they had been first detected. However, the diversity of lagoviruses has recently expanded to include new related viruses with varying pathogenicity, geographic distribution and host ranges. Together with the frequent recombination observed amongst circulating viruses, there is a clear need to establish precise guidelines for classifying and naming lagovirus strains. Therefore, here we propose a new nomenclature based on phylogenetic relationships. In this new nomenclature, a single species of lagovirus would be recognized and called Lagovirus europaeus. The species would be divided into two genogroups that correspond to RHDV- and EBHSV-related viruses, respectively. Genogroups could be subdivided into genotypes, which could themselves be subdivided into phylogenetically well-supported variants. Based on available sequences, pairwise distance cutoffs have been defined, but with the accumulation of new sequences these cutoffs may need to be revised. We propose that an international working group could coordinate the nomenclature of lagoviruses and any proposals for revision.

<h3>Importance</h3> The long-term health outcomes and symptom burden of COVID-19 remain largely unclear. <h3>Objective</h3> To evaluate health outcomes of COVID-19 survivors 1 year after hospital discharge and to identify associated risk factors. <h3>Design, Setting, and Participants</h3> This retrospective, multicenter cohort study was conducted at 2 designated hospitals, Huoshenshan Hospital and Taikang Tongji Hospital, both in Wuhan, China. All adult patients with COVID-19 discharged between February 12 and April 10, 2020, were screened for eligibility. Of a consecutive sample of 3988 discharged patients, 1555 were excluded (796 declined to participate and 759 were unable to be contacted) and the remaining 2433 patients were enrolled. All patients were interviewed via telephone from March 1 to March 20, 2021. Statistical analysis was performed from March 28 to April 18, 2021. <h3>Exposures</h3> COVID-19. <h3>Main Outcomes and Measures</h3> All patients participated in telephone interviews using a series of questionnaires for evaluation of symptoms, along with a chronic obstructive pulmonary disease (COPD) assessment test (CAT). Logistic regression models were used to evaluate risk factors for fatigue, dyspnea, symptom burden, or higher CAT scores. <h3>Results</h3> Of 2433 patients at 1-year follow-up, 1205 (49.5%) were men and 680 (27.9%) were categorized into the severe disease group as defined by the World Health Organization guideline; the median (IQR) age was 60.0 (49.0-68.0) years. In total, 1095 patients (45.0%) reported at least 1 symptom. The most common symptoms included fatigue, sweating, chest tightness, anxiety, and myalgia. Older age (odds ratio [OR], 1.02; 95% CI, 1.01-1.02;<i>P</i> &lt; .001), female sex (OR, 1.27; 95% CI, 1.06-1.52;<i>P</i> = .008), and severe disease during hospital stay (OR, 1.43; 95% CI, 1.18-1.74;<i>P</i> &lt; .001) were associated with higher risks of fatigue. Older age (OR, 1.02; 95% CI, 1.01-1.03;<i>P</i> &lt; .001) and severe disease (OR, 1.51; 95% CI, 1.14-1.99;<i>P</i> = .004) were associated with higher risks of having at least 3 symptoms. The median (IQR) CAT score was 2 (0-4), and a total of 161 patients (6.6%) had a CAT score of at least 10. Severe disease (OR, 1.84; 95% CI, 1.31-2.58;<i>P</i> &lt; .001) and coexisting cerebrovascular diseases (OR, 1.95; 95% CI, 1.07-3.54;<i>P</i> = .03) were independent risk factors for CAT scores of at least 10. <h3>Conclusions and Relevance</h3> This study found that patients with COVID-19 with severe disease during hospitalization had more postinfection symptoms and higher CAT scores.