Publications by authors named "Manman Guo"

23 Publications

  • Page 1 of 1

Porous N-doped carbon with confined Fe-doped CoP grown on CNTs for superefficient oxygen evolution electrocatalysis.

Chem Commun (Camb) 2022 Jan 12. Epub 2022 Jan 12.

College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China.

Herein, Fe-doped CoP nanoparticles (Fe-CoP NPs) encapsulated in porous N-doped carbon (PNC)/carbon nanotubes (CNTs) have been successfully synthesized. The Fe doping and confined structures resulted in enhanced charge transfer and improved active sites for intermediates adsorption. The obtained [email protected]/CNTs materials exhibited superefficient OER performance.
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http://dx.doi.org/10.1039/d1cc06923cDOI Listing
January 2022

Long non-coding RNA LINC01559 exerts oncogenic role via enhancing autophagy in lung adenocarcinoma.

Cancer Cell Int 2021 Nov 25;21(1):624. Epub 2021 Nov 25.

Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China.

Background: Long non-coding RNAs (lncRNAs) have been verified to play fatal role in regulating the progression of lung adenocarcinoma (LUAD). Although lncRNAs play important role in regulating the autophagy of tumor cells, the function and molecular mechanism of LINC01559 in regulating lung cancer development remain to be elucidated.

Method And Materials: In this study, we used bioinformatics to screen out autophagy-related lncRNAs from TCGA-LUAD repository. Then the least absolute shrinkage and selection operator (LASSO) regression was applied to establish the signature of autophagy-related lncRNAs so that clinical characteristics and survival in LUAD patients be evaluated. Finally, we selected the most significant differences lncRNA, LINC01559, to verify its function in regulating LUAD progression in vitro.

Results: We found high expression of LINC01559 indicates lymph node metastasis and poor prognosis. Besides, LINC01559 promotes lung cancer cell proliferation and migration in vitro, by enhancing autophagy signal pathway via sponging hsa-miR-1343-3p.

Conclusion: We revealed a novel prognostic model based on autophagy-related lncRNAs, and provide a new therapeutic target and for patients with lung adenocarcinoma named LINC01559.
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http://dx.doi.org/10.1186/s12935-021-02338-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614059PMC
November 2021

Expression and prognostic significance of m6A-related genes in TP53-mutant non-small-cell lung cancer.

J Clin Lab Anal 2022 Jan 23;36(1):e24118. Epub 2021 Nov 23.

The Clinical Laboratory of the First Affiliated Hospital of Zhengzhou University, Henan, China.

Background: TP53 is an important tumor suppressor gene on human 17th chromosome with its mutations more than 60% in tumor cells. Lung cancer is the highest incidence malignancy in men around the world. N-6 methylase (m6A) is an enzyme that plays an important role in mRNA splicing, translation, and stabilization. However, its role in TP53-mutant non-small-cell lung cancer (NSCLC) remains unknown.

Method: First, we investigated 17 common m6A regulators' prognostic values in NSCLC. Then, after the establishment of risk signature, we explored the diagnostic value of m6A in TP53-mutant NSCLC. Finally, gene set enrichment analysis (GSEA), gene ontology (GO) enrichment analysis, and differential expression analysis were used to reveal the possible mechanism of m6A regulators affecting TP53-mutant NSCLC patients.

Results: Study showed that nine m6A regulators (YTHDC2, METTL14, FTO, METTL16, YTHDF1, HNRNPA2B1, RBM15, KIAA1429, and WTAP) were expressed differently between TP53-mutant and wild-type NSCLC (p < 0.05); and ALKBH5 and HNRNPA2B1 were associated with the prognostic of TP53-mutant patients. After construction of the risk signature combined ALKBH5 and HNRNPA2B1, we divided patients with TP53 mutations into high- and low-risk groups, and there was a significant survival difference between two groups. Finally, 338 differentially expression genes (DEGs) were found between high- and low-risk groups. GO enrichment analysis, PPI network, and GSEA enrichment analysis showed that m6A may affect the immune environment in extracellular and change the stability of mRNA.

Conclusion: In conclusion, m6A regulators can be used as prognostic predictors in TP53-mutant patients.
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http://dx.doi.org/10.1002/jcla.24118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761469PMC
January 2022

Highly Mesoporous Cobalt-Hybridized 2D CuP Nanosheet Arrays as Boosting Janus Electrocatalysts for Water Splitting.

Inorg Chem 2021 Dec 22;60(23):18325-18336. Epub 2021 Nov 22.

Jiangxi Key Laboratory of Nanomaterials and Sensors, Jiangxi Key Laboratory of Photoelectronics and Telecommunication, School of Physics, Communication and Electronics, Jiangxi Normal University, Nanchang, 330022 Jiangxi, P. R. China.

Recently, developing economical electrocatalysts with high performance in water decomposition has become a research hotspot. Herein, two kinds of cobalt-hybridized CuP nanostructure array electrocatalysts (including highly mesoporous 2D nanosheets and sugar gourd-like 1D nanowires) were controllably grown on a nickel foam substrate through a simple hydrothermal method combined with a subsequent phosphating treatment method. An electrocatalytic test indicated that the as-prepared 2D nanosheet array exhibited excellent activity and stability toward hydrogen evolution reaction under alkaline conditions, which offered a low overpotential of 99 mV at 10 mA/cm and a small Tafel slope of 70.4 mV/dec, whereas a competitive overpotential of 272 mV was required for oxygen evolution reaction. In addition, the 2D nanosheet array delivered a low cell voltage of 1.66 V at 10 mA/cm in a symmetric two-electrode system, implying its huge potential in overall water decomposition. The electrocatalytic performance is superior to the as-prepared 1D nanowire array and most of the CuP-related electrocatalysts previously reported. Experimental measurements and first-principles calculations show that the excellent performance of the 2D nanosheet array can be attributed to its unique 2D mesoporous structure and hybridization of cobalt, which not only provide a large electrochemically active surface and fast electrocatalytic reaction kinetics but also weaken the binding strength of electrocatalytic reaction intermediates. The present study provides a simple and controllable approach to synthesize CuP-based bimetallic phosphide nanostructures, which can be used as boosting Janus electrocatalysts for water decomposition.
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http://dx.doi.org/10.1021/acs.inorgchem.1c02954DOI Listing
December 2021

Active Site Engineering in [email protected]/Graphene Heterostructures Enabling Enhanced Hydrogen Evolution.

Inorg Chem 2021 Nov 14;60(21):16761-16768. Epub 2021 Oct 14.

Institute of Advanced Materials (IAM), College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, People's Republic of China.

As the core of an electrocatalyst, the active site is critical to determine its catalytic performance in the hydrogen evolution reaction (HER). In this work, porous N-doped carbon-encapsulated CoP nanoparticles on both sides of graphene ([email protected]/GR) are derived from a bimetallic metal-organic framework (MOF)@graphene oxide composite. Through active site engineering by tailoring the environment around CoP and engineering the structure, the HER activity of [email protected]/GR heterostructures is significantly enhanced. Both X-ray photoelectron spectroscopy (XPS) results and density functional theory (DFT) calculations manifest that the electronic structure of CoP can be modulated by the carbon matrix of NC/GR, resulting in electron redistribution and a reduction in the adsorption energy of hydrogen (Δ) from -0.53 to 0.04 eV. By engineering the sandwich-like structure, active sites in [email protected]/GR are further increased by optimizing the Zn/Co ratio in the bimetallic MOF. Benefiting from this active site engineering, the [email protected]/GR electrocatalyst exhibits small overpotentials of 105 mV in 0.5 M HSO (or 125 mV in 1 M KOH) to 10 mA cm, accelerated HER kinetics with a low Tafel slope of 47.5 mV dec, and remarkable structural and HER stability.
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http://dx.doi.org/10.1021/acs.inorgchem.1c02639DOI Listing
November 2021

N-6 methylation-related lncRNA is potential signature in lung adenocarcinoma and influences tumor microenvironment.

J Clin Lab Anal 2021 Nov 24;35(11):e23951. Epub 2021 Sep 24.

Department of Otolaryngology, The First Affiliated Hospital of Zhengzhou University, Henan, China.

Background: N-6 methylation (m6A) pushes forward an immense influence on the occurrence and development of lung adenocarcinoma (LUAD). However, the methylation on non-coding RNA in LUAD, especially long non-coding RNA (lncRNA), has not been received sufficient attention.

Methods: Spearman correlation analysis was used to screen lncRNA correlated with m6A regulators expression from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories, respectively. Then, the least absolute shrinkage and selection operator (LASSO) was applied to build a risk signature consisting m6A-related lncRNA. Univariate and multivariate independent prognostic analysis were applied to evaluate the performance of signature in predicting patients' survival. Next, we applied Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to conduct pathway enrichment analysis of 3344 different expression genes (DEGs). Finally, we set up a competing endogenous RNAs (ceRNA) network to this lncRNA.

Results: A total of 85 common lncRNAs were selected to acquire the components related to prognosis. The final risk signature established by LASSO regression contained 11 lncRNAs: ARHGEF26-AS1, COLCA1, CRNDE, DLGAP1-AS2, FENDRR, LINC00968, TMPO-AS1, TRG-AS1, MGC32805, RPARP-AS1, and TBX5-AS1. M6A-related lncRNA risk score could predict the prognostic of LUAD and was significantly associated with clinical pathological. And in the evaluation of lung adenocarcinoma tumor microenvironment (TME) by using ESTIMATE algorithm, we found a statistically significant correlation between risk score and stromal/immune cells.

Conclusion: M6A-related lncRNA was a potential prognostic and therapy target for lung adenocarcinoma.
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http://dx.doi.org/10.1002/jcla.23951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605119PMC
November 2021

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Sci Transl Med 2021 08;13(608)

Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in , the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls ( = 7.8 × 10). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques ( = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis ( = 5.2 × 10; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro ( < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain ( < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.
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http://dx.doi.org/10.1126/scitranslmed.abd6469DOI Listing
August 2021

Cereblon pathway biomarkers and immune profiles in patients with myeloma receiving post-ASCT lenalidomide maintenance (LEOPARD).

Leuk Lymphoma 2021 Dec 15;62(12):2981-2991. Epub 2021 Jul 15.

Malignant Haematology and Stem Cell Transplantation, Alfred Hospital, Melbourne, Australia.

LEOPARD was a single arm, phase II study of lenalidomide (LEN) and alternate day prednisolone maintenance in patients with newly diagnosed multiple myeloma (MM) following autologous stem cell transplantation (ASCT). Sixty patients were enrolled. Estimated median potential follow-up was 44 m, median PFS was 38.3 m, median OS was not reached (landmark 36 m OS: 71.4%). Correlative immunohistochemistry performed on pre-ASCT trephines demonstrated high MM tumor cereblon (total/cytoplasmic) was associated with superior OS ( = .045,  = .031, respectively), whereas high c-Myc was associated with inferior PFS ( = .04). Patients with high cereblon (total/nuclear) were more likely to improve depth of response, whereas patients with high c-Myc were less likely, suggesting alternative/more effective post-ASCT strategies for patients with high c-Myc need identification. Peripheral blood immune profiling (mass cytometry) informed a more sustained response to LEN maintenance, demonstrating enrichment of activated/cytotoxic NK cells and cytotoxic T cells in patients with durable responses, contrasting with enrichment of B-regs in early relapsers.
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http://dx.doi.org/10.1080/10428194.2021.1948030DOI Listing
December 2021

Rapid Synthesis of Large-Size FeO Nanoparticle Decorated NiO Nanosheets via Electrochemical Exfoliation for Enhanced Oxygen Evolution Electrocatalysis.

Inorg Chem 2021 Jan 28;60(2):959-966. Epub 2020 Dec 28.

Institute of Advanced Materials (IAM), College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, Jiangxi, People's Republic of China.

A novel nonprecious FeO nanoparticle decorated NiO nanosheet (FeO [email protected] NSs) composite has been obtained by a rapid one-pot electrochemical exfoliation method and can be used as an efficient oxygen evolution reaction (OER) catalyst. In the nanocomposite, the FeO NPs are uniformly anchored on the ultrathin graphene-like NiO nanosheets. At the same time, we also studied the influence of the Fe/Ni molar ratio on the morphology and catalytic activity. The FeO [email protected] NSs nanocomposite possessed a high BET surface area (194.1 m g), which is very conducive to the charge/mass transfer of electrolyte ions and O. Owing to the unique two-dimensional (2D) heterostructures and rational Fe content, the as-prepared FeO [email protected] NSs show high catalytic performance, a low overpotential at 10 mA cm (221 mV), a small Tafel slope (53.4 mV dec), and 2000 cycle and 20 h long-term durability. The introduction of FeO NPs is beneficial to accelerating charge transport, increasing the electrochemically active surface area (ECSA), and thus improving the release of oxygen bubbles from the electrode surface.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03073DOI Listing
January 2021

Preoperative Platelet to Albumin Ratio Predicts Outcome of Patients with Non-Small-Cell Lung Cancer.

Ann Thorac Cardiovasc Surg 2021 Apr 6;27(2):84-90. Epub 2020 Nov 6.

Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Clinical Laboratory of Henan Province, Zhengzhou, China.

Objective: The purpose of this study was to evaluate the predictive power of the platelet to albumin ratio (PAR) on survival outcomes of patients with non-small-cell lung cancer (NSCLC).

Patients And Methods: In all, 198 patients with NSCLC were recruited. The X-tile software was performed to identify the optimal cutoff values for PAR, platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ratio (NLR). The Kaplan-Meier method, univariate and multivariate analyses Cox regression were used to analyze the prognostic factors for overall survival (OS).

Results: In all, 198 patients were enrolled, containing 146 (73.7%) men and 52 (26.3%) women. The optimal cutoff values for PAR, PLR, and NLR were 8.8×10, 147.7, and 3.9, respectively. Patients with PAR > 8.8 × 10 (P <0.001), PLR > 147.7 (P <0.001), and NLR >3.9 (P = 0.007) were associated with poor OS. Multivariate analyses found that PAR was an independent predictor in NSCLC patients (hazard ratio [HR]: 4.604, 95% confidence interval [CI]: 2.557-8.290, P <0.001).

Conclusion: Preoperative PAR is a useful and potential prognostic biomarker in NSCLC patients who have received primary resection.
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http://dx.doi.org/10.5761/atcs.oa.20-00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058543PMC
April 2021

A membrane-depolarizing toxin substrate of the type VII secretion system mediates intraspecies competition.

Proc Natl Acad Sci U S A 2020 08 7;117(34):20836-20847. Epub 2020 Aug 7.

Centre for Bacterial Cell Biology, Newcastle University Biosciences Institute, Newcastle University, NE2 4HH Newcastle upon Tyne, United Kingdom;

The type VII protein secretion system (T7SS) is conserved across strains and plays important roles in virulence and interbacterial competition. To date, only one T7SS substrate protein, encoded in a subset of genomes, has been functionally characterized. Here, using an unbiased proteomic approach, we identify TspA as a further T7SS substrate. TspA is encoded distantly from the T7SS gene cluster and is found across all strains as well as in and Enterococci. Heterologous expression of TspA from strain RN6390 indicates its C-terminal domain is toxic when targeted to the periplasm and that it depolarizes the cytoplasmic membrane. The membrane-depolarizing activity is alleviated by coproduction of the membrane-bound TsaI immunity protein, which is encoded adjacent to on the chromosome. Using a zebrafish hindbrain ventricle infection model, we demonstrate that the T7SS of strain RN6390 promotes bacterial replication in vivo, and deletion of leads to increased bacterial clearance. The toxin domain of TspA is highly polymorphic and strains encode multiple homologs at the locus, suggestive of additional roles in intraspecies competition. In agreement, we demonstrate TspA-dependent growth inhibition of RN6390 by strain COL in the zebrafish infection model that is alleviated by the presence of TsaI homologs.
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http://dx.doi.org/10.1073/pnas.2006110117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456083PMC
August 2020

Magnetic Enhancement for Hydrogen Evolution Reaction on Ferromagnetic MoS Catalyst.

Nano Lett 2020 Apr 26;20(4):2923-2930. Epub 2020 Mar 26.

School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China.

Numerous efforts in improving the hydrogen evolution reaction (HER) performance of transition metal dichalcogenides mostly focus on active sites exposing, vacancy engineering, and phase engineering. However, little room is left for improvement in these approaches. It should be noted that efficient electron transfer also plays a crucial role in catalytic activity. In this work, by employment of an external vertical magnetic field, ferromagnetic bowl-like MoS flakes can afford electrons transmitting easily from a glassy carbon electrode to active sites to drive HER, and thus perform magnetic HER enhancement. The ferromagnetic bowl-like MoS flakes with an external vertical magnetic field can provide a roughly doubled current density compared to that without an external vertical magnetic field at a constant overpotential of -150 mV. Our work may provide a new pathway to break the bottleneck for further improvement of HER performance and also paves the way to utilize the magnetic enhancement in widely catalytic application.
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http://dx.doi.org/10.1021/acs.nanolett.0c00845DOI Listing
April 2020

Mass cytometry analysis reveals a distinct immune environment in peritoneal fluid in endometriosis: a characterisation study.

BMC Med 2020 01 7;18(1). Epub 2020 Jan 7.

Botnar Research Centre, NIHR Biomedical Research Unit Oxford, Nuffield Department of Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Endometriosis is a gynaecological condition characterised by immune cell infiltration and distinct inflammatory signatures found in the peritoneal cavity. In this study, we aim to characterise the immune microenvironment in samples isolated from the peritoneal cavity in patients with endometriosis.

Methods: We applied mass cytometry (CyTOF), a recently developed multiparameter single-cell technique, in order to characterise and quantify the immune cells found in peritoneal fluid and peripheral blood from endometriosis and control patients.

Results: Our results demonstrate the presence of more than 40 different distinct immune cell types within the peritoneal cavity. This suggests that there is a complex and highly heterogeneous inflammatory microenvironment underpinning the pathology of endometriosis. Stratification by clinical disease stages reveals a dynamic spectrum of cell signatures suggesting that adaptations in the inflammatory system occur due to the severity of the disease. Notably, among the inflammatory microenvironment in peritoneal fluid (PF), the presence of CD69 T cell subsets is increased in endometriosis when compared to control patient samples. On these CD69 cells, the expression of markers associated with T cell function are reduced in PF samples compared to blood. Comparisons between CD69 and CD69 populations reveal distinct phenotypes across peritoneal T cell lineages. Taken together, our results suggest that both the innate and the adaptive immune system play roles in endometriosis.

Conclusions: This study provides a systematic characterisation of the specific immune environment in the peritoneal cavity and identifies cell immune signatures associated with endometriosis. Overall, our results provide novel insights into the specific cell phenotypes governing inflammation in patients with endometriosis. This prospective study offers a useful resource for understanding disease pathology and opportunities for identifying therapeutic targets.
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http://dx.doi.org/10.1186/s12916-019-1470-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945609PMC
January 2020

Wafer-Scale Sulfur Vacancy-Rich Monolayer MoS for Massive Hydrogen Production.

J Phys Chem Lett 2019 Aug 7;10(16):4763-4768. Epub 2019 Aug 7.

Jiangxi Key Laboratory of Nanomaterials and Sensors, School of Physics, Communication and Electronics , Jiangxi Normal University , 99 Ziyang Avenue , Nanchang 330022 , Jiangxi , China.

As one of the promising low-cost and high-efficiency catalysts for the electrochemical hydrogen evolution reaction (HER), it is well-known that there are both tiny exposed catalytic active edge sites and large-area inert basal planes in two-dimensional MoS structures. For enhancing its HER activity, extensive work has been done to activate the inert basal plane of MoS. In this article, wafer-scale (2 in.) continuous monolayer MoS films with substantial in situ generated sulfur vacancies are fabricated by employing the laser molecular beam epitaxy process benefitting from ultrahigh vacuum growth condition and high substrate temperature. The intrinsic sulfur vacancies throughout the wafer-scale basal plane present an ideal electrocatalytic platform for massive hydrogen production. The fabricated vacancy-rich monolayer MoS can achieve a current density of -10 mA/cm at an overpotential of -256 mV. The wafer-scale fabrications of sulfur vacancy-rich monolayer MoS provide great leaps forward in the practical application of MoS for massive hydrogen production.
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http://dx.doi.org/10.1021/acs.jpclett.9b01399DOI Listing
August 2019

Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages.

EMBO J 2019 06 26;38(11). Epub 2019 Apr 26.

MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization.
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http://dx.doi.org/10.15252/embj.2018100299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545745PMC
June 2019

VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System.

PLoS Pathog 2016 06 28;12(6):e1005735. Epub 2016 Jun 28.

Division of Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee, United Kingdom.

The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based on a tube of Hcp topped with a VgrG spike, which can be extended by a final tip from a PAAR domain-containing protein. Effector proteins are believed to be delivered by specifically associating with particular Hcp, VgrG or PAAR proteins, either covalently ('specialised') or non-covalently ('cargo' effectors). Here we used the T6SS of the opportunistic pathogen Serratia marcescens, together with integratecd genetic, proteomic and biochemical approaches, to elucidate the role of specific VgrG and PAAR homologues in T6SS function and effector specificity, revealing new aspects and unexpected subtleties in effector delivery by the T6SS. We identified effectors, both cargo and specialised, absolutely dependent on a particular VgrG for delivery to target cells, and discovered that other cargo effectors can show a preference for a particular VgrG. The presence of at least one PAAR protein was found to be essential for T6SS function, consistent with designation as a 'core' T6SS component. We showed that specific VgrG-PAAR combinations are required to assemble a functional T6SS and that the three distinct VgrG-PAAR assemblies in S. marcescens exhibit distinct effector specificity and efficiency. Unexpectedly, we discovered that two different PAAR-containing Rhs proteins can functionally pair with the same VgrG protein. Showing that accessory EagR proteins are involved in these interactions, native VgrG-Rhs-EagR complexes were isolated and specific interactions between EagR and cognate Rhs proteins identified. This study defines an essential yet flexible role for PAAR proteins in the T6SS and highlights the existence of distinct versions of the machinery with differential effector specificity and efficiency of target cell delivery.
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http://dx.doi.org/10.1371/journal.ppat.1005735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924876PMC
June 2016

pH-triggered sustained release of arsenic trioxide by polyacrylic acid capped mesoporous silica nanoparticles for solid tumor treatment in vitro and in vivo.

J Biomater Appl 2016 07 7;31(1):23-35. Epub 2016 Apr 7.

Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China.

Arsenic trioxide (As2O3, ATO), a FDA approved drug for hematologic malignancies, was proved of efficient growth inhibition of cancer cell in vitro or solid tumor in vivo. However, its effect on solid tumor in vivo was hampered by its poor pharmacokinetics and dose-limited toxicity. In this study, a polyacrylic acid capped pH-triggered mesoporous silica nanoparticles was conducted to improve the pharmacokinetics and enhance the antitumor effect of arsenic trioxide. The mesoporous silica nanoparticles loaded with arsenic trioxide was grafted with polyacrylic acid (PAA-ATO-MSN) as a pH-responsive biomaterial on the surface to achieve the release of drug in acidic microenvironment of tumor, instead of burst release action in circulation. The nanoparticles were characterized with uniform grain size (particle sizes of 158.6 ± 1.3 nm and pore sizes of 3.71 nm, respectively), historically comparable drug loading efficiency (11.42 ± 1.75%), pH-responsive and strengthened sustained release features. The cell toxicity of amino groups modified mesoporous silica nanoparticles (NH2-MSN) was significantly reduced by capping of polyacrylic acid. In pharmacokinetic studies, the half time (t1/2β) was prolonged by 1.3 times, and the area under curve) was increased by 2.6 times in PAA-ATO-MSN group compared with free arsenic trioxide group. Subsequently, the antitumor efficacy in vitro (SMMC-7721 cell line) and in vivo (H22 xenografts) was remarkably enhanced indicated that PAA-ATO-MSN improved the antitumor effect of the drug. These results suggest that the polyacrylic acid capped mesoporous silica nanoparticles (PAA-MSN) will be a promising nanocarrier for improving pharmacokinetic features and enhancing the anti-tumor efficacy of arsenic trioxide.
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http://dx.doi.org/10.1177/0885328216637211DOI Listing
July 2016

Quantitative proteome analysis of temporally resolved phagosomes following uptake via key phagocytic receptors.

Mol Cell Proteomics 2015 May 9;14(5):1334-49. Epub 2015 Mar 9.

From the ‡MRC Protein Phosphorylation and Ubiquitylation Unit,

Macrophages operate at the forefront of innate immunity and their discrimination of foreign versus "self" particles is critical for a number of responses including efficient pathogen killing, antigen presentation, and cytokine induction. In order to efficiently destroy the particles and detect potential threats, macrophages express an array of receptors to sense and phagocytose prey particles. In this study, we accurately quantified a proteomic time-course of isolated phagosomes from murine bone marrow-derived macrophages induced by particles conjugated to seven different ligands representing pathogen-associated molecular patterns, immune opsonins or apoptotic cell markers. We identified a clear functional differentiation over the three timepoints and detected subtle differences between certain ligand-phagosomes, indicating that triggering of receptors through a single ligand type has mild, but distinct, effects on phagosome proteome and function. Moreover, our data shows that uptake of phosphatidylserine-coated beads induces an active repression of NF-κB immune responses upon Toll-like receptor (TLR)-activation by recruitment of anti-inflammatory regulators to the phagosome. This data shows for the first time a systematic time-course analysis of bone marrow-derived macrophages phagosomes and how phagosome fate is regulated by the receptors triggered for phagocytosis.
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http://dx.doi.org/10.1074/mcp.M114.044594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424403PMC
May 2015

High-resolution quantitative proteome analysis reveals substantial differences between phagosomes of RAW 264.7 and bone marrow derived macrophages.

Proteomics 2015 Sep 5;15(18):3169-74. Epub 2015 Feb 5.

MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Science, University of Dundee, Scotland, UK.

Macrophages are important immune cells operating at the forefront of innate immunity by taking up foreign particles and microbes through phagocytosis. The RAW 264.7 cell line is commonly used for experiments in the macrophage and phagocytosis field. However, little is known how its functions compare to primary macrophages. Here, we have performed an in-depth proteomics characterization of phagosomes from RAW 264.7 and bone marrow derived macrophages by quantifying more than 2500 phagosomal proteins. Our data indicate that there are significant differences for a large number of proteins including important receptors such as mannose receptor 1 and Siglec-1. Moreover, bone marrow derived macrophages phagosomes mature considerably faster by fusion with endosomes and the lysosome which we validated using fluorogenic phagocytic assays. We provide a valuable resource for researcher in the field and recommend careful use of the RAW 264.7 cell line when studying phagosome functions. All MS data have been deposited in the ProteomeXchange with identifier PXD001293 (http://proteomecentral.proteomexchange.org/dataset/PXD001293).
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http://dx.doi.org/10.1002/pmic.201400431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833182PMC
September 2015

A holin and an endopeptidase are essential for chitinolytic protein secretion in Serratia marcescens.

J Cell Biol 2014 Dec;207(5):615-26

Division of Molecular Microbiology and Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK

Pathogenic bacteria adapt to their environment and manipulate the biochemistry of hosts by secretion of effector molecules. Serratia marcescens is an opportunistic pathogen associated with healthcare-acquired infections and is a prolific secretor of proteins, including three chitinases (ChiA, ChiB, and ChiC) and a chitin binding protein (Cbp21). In this work, genetic, biochemical, and proteomic approaches identified genes that were required for secretion of all three chitinases and Cbp21. A genetic screen identified a holin-like protein (ChiW) and a putative l-alanyl-d-glutamate endopeptidase (ChiX), and subsequent biochemical analyses established that both were required for nonlytic secretion of the entire chitinolytic machinery, with chitinase secretion being blocked at a late stage in the mutants. In addition, live-cell imaging experiments demonstrated bimodal and coordinated expression of chiX and chiA and revealed that cells expressing chiA remained viable. It is proposed that ChiW and ChiX operate in tandem as components of a protein secretion system used by gram-negative bacteria.
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http://dx.doi.org/10.1083/jcb.201404127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259817PMC
December 2014

Determination and pharmacokinetic study of the diacid metabolite of norcantharidin in beagle plasma by use of liquid chromatography-tandem mass spectrometry.

Anal Bioanal Chem 2013 Nov 6;405(28):9273-83. Epub 2013 Oct 6.

College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, 310053, Hangzhou, China.

Because norcantharidin (NCTD) is unstable and subject to ring opening and hydrolysis, the diacid metabolite of norcantharidin (DM-NCTD) is the stable form of NCTD found in normal saline solution. Conversion of NCTD to DM-NCTD is almost 100%, making it possible to determine and investigate the pharmacokinetics of DM-NCTD converted from NCTD. In this paper, a sensitive, simple and selective liquid chromatographic-tandem mass spectrometric method was developed and validated for determination of DM-NCTD in beagle plasma. DM-NCTD was detected in multiple-reaction monitoring (MRM) mode by using the dehydrated ion 169.3 as precursor ion and its product ion 123.1 as the detected ion. Ribavirin was used as internal standard and detected in MRM mode by use of precursor ions, resulting in a product ion transition of m/z 267.1 → 135.1. This method was successfully used for a pharmacokinetic study of DM-NCTD in beagles after intravenous administration of DM-NCTD in normal saline solution at doses of 0.39, 0.78, and 1.6 mg kg(-1). DM-NCTD had dose-dependent kinetics across the dosage range investigated, with enhanced T(1/2α) and AUC(0-12) and apparently decreasing V(d) and CL with increasing dosage. After single-dose administration, T(1/2α) ranged from 0.20 to 0.55 h, AUC(0-12) from 1.81 to 43.6 μg mL(-1) h(-1), V(d) from 228 to 55.9 mL kg(-1), and CL from 220 to 36.5 mL kg(-1) h(-1) (P < 0.01). The results indicated nonlinear pharmacokinetic behavior of DM-NCTD in beagles, suggesting that the risk of DM-NCTD in normal saline solution intoxication may be non-proportionally increased at higher doses.
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http://dx.doi.org/10.1007/s00216-013-7300-8DOI Listing
November 2013

Proteomic identification of novel secreted antibacterial toxins of the Serratia marcescens type VI secretion system.

Mol Cell Proteomics 2013 Oct 9;12(10):2735-49. Epub 2013 Jul 9.

Division of Molecular Microbiology and.

It has recently become apparent that the Type VI secretion system (T6SS) is a complex macromolecular machine used by many bacterial species to inject effector proteins into eukaryotic or bacterial cells, with significant implications for virulence and interbacterial competition. "Antibacterial" T6SSs, such as the one elaborated by the opportunistic human pathogen, Serratia marcescens, confer on the secreting bacterium the ability to rapidly and efficiently kill rival bacteria. Identification of secreted substrates of the T6SS is critical to understanding its role and ability to kill other cells, but only a limited number of effectors have been reported so far. Here we report the successful use of label-free quantitative mass spectrometry to identify at least eleven substrates of the S. marcescens T6SS, including four novel effector proteins which are distinct from other T6SS-secreted proteins reported to date. These new effectors were confirmed as antibacterial toxins and self-protecting immunity proteins able to neutralize their cognate toxins were identified. The global secretomic study also unexpectedly revealed that protein phosphorylation-based post-translational regulation of the S. marcescens T6SS differs from that of the paradigm, H1-T6SS of Pseudomonas aeruginosa. Combined phosphoproteomic and genetic analyses demonstrated that conserved PpkA-dependent threonine phosphorylation of the T6SS structural component Fha is required for T6SS activation in S. marcescens and that the phosphatase PppA can reverse this modification. However, the signal and mechanism of PpkA activation is distinct from that observed previously and does not appear to require cell-cell contact. Hence this study has not only demonstrated that new and species-specific portfolios of antibacterial effectors are secreted by the T6SS, but also shown for the first time that PpkA-dependent post-translational regulation of the T6SS is tailored to fit the needs of different bacterial species.
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http://dx.doi.org/10.1074/mcp.M113.030502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790287PMC
October 2013

Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system.

Genome Res 2009 Jul 18;19(7):1301-8. Epub 2009 Feb 18.

National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.

Sequence-specific DNA-binding transcription factors have widespread biological significance in the regulation of gene expression. However, in lower prokaryotes and eukaryotic metazoans, it is usually difficult to find transcription regulatory factors that recognize specific target promoters. To address this, we have developed in this study a new bacterial one-hybrid reporter vector system that provides a convenient and rapid strategy to determine the specific interaction between target DNA sequences and their transcription factors. Using this system, we have successfully determined the DNA-binding specificity of the transcription regulator Rv3133c to a previously reported promoter region of the gene Rv2031 in Mycobacterium tuberculosis. In addition, we have tested more than 20 promoter regions of M. tuberculosis genes using this approach to determine if they interact with approximately 150 putative regulatory proteins. A variety of transcription factors are found to participate in the regulation of stress response and fatty acid metabolism, both of which comprise the core of in vivo-induced genes when M. tuberculosis invades macrophages. Interestingly, among the many new discovered potential transcription factors, the WhiB-like transcriptional factor WhiB3 was identified for the first time to bind with the promoter sequences of most in vivo-induced genes. Therefore, this study offers important data in the dissection of the transcription regulations in M. tuberculosis, and the strategy should be applicable in the study of DNA-binding factors in a wide range of biological organisms.
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http://dx.doi.org/10.1101/gr.086595.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704442PMC
July 2009
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