Publications by authors named "Shihua Wang"

210 Publications

Suppressing the DSCAM/PAK1 pathway reverses neurogenesis deficits in Down Syndrome patient iPSC-derived cerebral organoids.

J Clin Invest 2021 May 4. Epub 2021 May 4.

School of Pharmacy, Institute for Stem Cell and Neural Regeneration, Nanjing Medical University, Nanjing, China.

Down syndrome (DS), caused by trisomy of chromosome 21, occurs in 1 of every 800 live births. Early defects in cortical development likely account for the cognitive impairments in DS, although the underlying molecular mechanism remains elusive. Here, we performed histological assays and unbiased single-cell RNA sequencing (scRNA-seq) analysis on cerebral organoids derived from four euploid cell lines and from induced pluripotent stem cells (iPSCs) from three individuals with trisomy 21 to explore cell type-specific abnormalities associated with DS during early brain development. We found that neurogenesis was significantly affected based on diminished proliferation and decreased expression of layer II and IV markers in cortical neurons in the subcortical regions; this may be responsible for the reduced size of the organoids. Furthermore, suppression of the DSCAM-PAK1 pathway which showed enhanced activities in DS) via CRISPR/Cas9, CRISPRi or small-molecule inhibitor treatment reverses abnormal neurogenesis, thereby increasing the size of organoids derived from DS iPSCs. Our study demonstrated that 3D cortical organoids developed in vitro are a valuable model of DS and provided a direct link between dysregulation of the DSCAM-PAK1 pathway and developmental brain defects in DS.
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http://dx.doi.org/10.1172/JCI135763DOI Listing
May 2021

The Fungi-specific histone Acetyltransferase Rtt109 mediates morphogenesis, Aflatoxin synthesis and pathogenicity in Aspergillus flavus by acetylating H3K9.

IMA Fungus 2021 Apr 7;12(1). Epub 2021 Apr 7.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

Aspergillus flavus is a common saprophytic filamentous fungus that produces the highly toxic natural compound aflatoxin during its growth process. Synthesis of the aflatoxins, which can contaminate food crops causing huge losses to the agricultural economy, is often regulated by epigenetic modification, such as the histone acetyltransferase. In this study, we used Aspergillus flavus as an experimental model to construct the acetyltransferase gene rtt109 knockout strain (△rtt109) and its complementary strain (△rtt109·com) by homologous recombination. The growth of △rtt109 was significantly suppressed compared to the wild type (WT) strain and the △rtt109·com strain. The sclerotium of △rtt109 grew smaller, and the amount of sclerotia generated by △rtt109 was significantly reduced. The number of conidiums of △rtt109 was significantly reduced, especially on the yeast extract sucrose (YES) solid medium. The amount of aflatoxins synthesized by △rtt109 in the PDB liquid medium was significantly decreased We also found that the △rtt109 strain was extremely sensitive to DNA damage stress. Through the maize seed infection experiment, we found that the growth of △rtt109 on the surface of affected corn was largely reduced, and the amount of aerial mycelium decreased significantly, which was consistent with the results on the artificial medium. We further found that H3K9 was the acetylated target of Rtt109 in A. flavus. In conclusion, Rtt109 participated in the growth, conidium formation, sclerotia generation, aflatoxin synthesis, environmental stress response, regulation of infection of A. flavus. The results from this study of rtt109 showed data for acetylation in the regulation of life processes and provided a new thought regarding the prevention and control of A. flavus hazards.
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http://dx.doi.org/10.1186/s43008-021-00060-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025522PMC
April 2021

Proteogenomic Characterization of the Pathogenic Fungus Aspergillus flavus Reveals Novel Genes Involved in Aflatoxin Production.

Mol Cell Proteomics 2020 Dec 13;20:100013. Epub 2020 Dec 13.

State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China. Electronic address:

Aspergillus flavus (A. flavus), a pathogenic fungus, can produce carcinogenic and toxic aflatoxins that are a serious agricultural and medical threat worldwide. Attempts to decipher the aflatoxin biosynthetic pathway have been hampered by the lack of a high-quality genome annotation for A. flavus. To address this gap, we performed a comprehensive proteogenomic analysis using high-accuracy mass spectrometry data for this pathogen. The resulting high-quality data set confirmed the translation of 8724 previously predicted genes and identified 732 novel proteins, 269 splice variants, 447 single amino acid variants, 188 revised genes. A subset of novel proteins was experimentally validated by RT-PCR and synthetic peptides. Further functional annotation suggested that a number of the identified novel proteins may play roles in aflatoxin biosynthesis and stress responses in A. flavus. This comprehensive strategy also identified a wide range of posttranslational modifications (PTMs), including 3461 modification sites from 1765 proteins. Functional analysis suggested the involvement of these modified proteins in the regulation of cellular metabolic and aflatoxin biosynthetic pathways. Together, we provided a high-quality annotation of A. flavus genome and revealed novel insights into the mechanisms of aflatoxin production and pathogenicity in this pathogen.
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http://dx.doi.org/10.1074/mcp.RA120.002144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950108PMC
December 2020

Hydrogen Peroxide-Induced Senescence Reduces the Wound Healing-Promoting Effects of Mesenchymal Stem Cell-Derived Exosomes Partially via miR-146a.

Aging Dis 2021 Feb 1;12(1):102-115. Epub 2021 Feb 1.

1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing 100005, China.

Mesenchymal stem cells (MSCs) have beneficial effects on wound healing. MSCs function through direct cell-cell communication or indirectly through paracrine secretion of exosomes. Here, we found that MSC-derived exosomes had pro-wound healing effects via promotion of angiogenesis; however, this promoting effect was significantly reduced when senescence was induced in parental MSCs by hydrogen peroxide (HO). Further experiments showed that decreased miR-146a expression in exosomes derived from senescent MSCs (s-exo) contributed to these findings. , the pro-angiogenic effect of s-exo on tube formation in human umbilical vein endothelial cells was significantly reduced compared with that of exosomes derived from control MSCs (c-exo). , higher tube numbers and longer tube lengths were observed in the c-exo group compared with the s-exo group. Using microarray analysis, we found that miR-146a level in s-exo was lower than that in c-exo. Knockdown of miR-146a in c-exo decreased its capacity to promote angiogenesis, and overexpression of miR-146a in s-exo partially rescued its impaired pro-angiogenic capacity, thereby confirming that downregulation of miR-146a contributed to the reduced pro-wound healing capacity of s-exo. Our study is the first to demonstrate that cell senescence induced by HO alters the pro-angiogenic ability of exosomes by modulating the expression of exosomal miRNAs, especially miR-146a, thus providing new insights into the correlation between parental cell state and exosome content and function.
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http://dx.doi.org/10.14336/AD.2020.0624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801275PMC
February 2021

Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25.

Sci Adv 2021 Jan 1;7(1). Epub 2021 Jan 1.

State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.

Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer's disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of , a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of reduces neuroinflammation and rescues synaptic and cognitive function in 5×FAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5×FAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.
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http://dx.doi.org/10.1126/sciadv.abe1340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775784PMC
January 2021

Combating COVID-19 With Mesenchymal Stem/Stromal Cell Therapy: Promise and Challenges.

Front Cell Dev Biol 2020 5;8:627414. Epub 2021 Jan 5.

Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.3389/fcell.2020.627414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813676PMC
January 2021

Development of immunoassay methods based on monoclonal antibody and its application in the determination of cadmium ion.

J Hazard Mater 2021 Jun 31;411:124992. Epub 2020 Dec 31.

The Ministry of Education Key Laboratory of Biopesticide and Chemical Biology, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China. Electronic address:

Owing to the threat of cadmium (Cd) to public health, it is an urgent demand to develop effective, sensitive, and rapid methods for the detection of cadmium. In this study, indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) and immunochromatographic test strips (ICTS) were established for the determination of Cd based on the obtained mAb with high specificity and high affinity (Kaff = 3.0 × 10 L/moL). The linear range of ic-ELISA detection was 0.03-1.11 ng/mL and 50% inhibitive concentration (IC50) of cadmium ion was determined to be 0.15 ng/mL. The visual limit of detection (vLOD) of the AuNS-based strip was 0.375 ng/mL. The vLOD of AuNF-based strip using higher intensity reporter determined to be 0.03 ng/mL, which was enhanced 12 times compared to the traditional strip. In summary, the developed immunoassays based on mAb shows great potential for monitoring the cadmium ion in environmental samples.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124992DOI Listing
June 2021

A novel phosphoinositide kinase Fab1 regulates biosynthesis of pathogenic aflatoxin in .

Virulence 2021 12;12(1):96-113

School of Life Sciences, and Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Fujian Agriculture and Forestry University , Fuzhou, China.

() is one of the most important model environmental fungi which can produce a potent toxin and carcinogen known as aflatoxin. Aflatoxin contamination causes massive agricultural economic loss and a critical human health issue each year. Although a functional vacuole has been highlighted for its fundamental importance in fungal virulence, the molecular mechanisms of the vacuole in regulating the virulence of remain largely unknown. Here, we identified a novel vacuole-related protein in , the ortholog of phosphatidylinositol-3-phosphate-5-kinase (Fab1) in . This kinase was located at the vacuolar membrane, and loss of function was found to affect the growth, conidia and sclerotial development, cellular acidification and metal ion homeostasis, aflatoxin production and pathogenicity of . Further functional analysis revealed that Fab1 was required to maintain the vacuole size and cell morphology. Additional quantitative proteomic analysis suggested that Fab1 was likely to play an important role in maintaining vacuolar/cellular homeostasis, with vacuolar dysregulation upon deletion leading to impaired aflatoxin synthesis in this fungus. Together, these results provide insight into the molecular mechanisms by which this pathogen produces aflatoxin and mediates its pathogenicity, and may facilitate dissection of the vacuole-mediated regulatory network in .
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http://dx.doi.org/10.1080/21505594.2020.1859820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781676PMC
December 2021

Ssu72 Regulates Fungal Development, Aflatoxin Biosynthesis and Pathogenicity in .

Toxins (Basel) 2020 11 13;12(11). Epub 2020 Nov 13.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

The RNA polymerase II (Pol II) transcription process is coordinated by the reversible phosphorylation of its largest subunit-carboxy terminal domain (CTD). Ssu72 is identified as a CTD phosphatase with specificity for phosphorylation of Ser5 and Ser7 and plays critical roles in regulation of transcription cycle in eukaryotes. However, the biofunction of Ssu72 is still unknown in , which is a plant pathogenic fungus and produces one of the most toxic mycotoxins-aflatoxin. Here, we identified a putative phosphatase Ssu72 and investigated the function of Ssu72 in . Deletion of resulted in severe defects in vegetative growth, conidiation and sclerotia formation. Additionally, we found that phosphatase Ssu72 positively regulates aflatoxin production through regulating expression of aflatoxin biosynthesis cluster genes. Notably, seeds infection assays indicated that phosphatase Ssu72 is crucial for pathogenicity of . Furthermore, the Δ mutant exhibited more sensitivity to osmotic and oxidative stresses. Taken together, our study suggests that the putative phosphatase Ssu72 is involved in fungal development, aflatoxin production and pathogenicity in , and may provide a novel strategy to prevent the contamination of this pathogenic fungus.
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http://dx.doi.org/10.3390/toxins12110717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696088PMC
November 2020

The membrane mucin Msb2 regulates aflatoxin biosynthesis and pathogenicity in fungus Aspergillus flavus.

Microb Biotechnol 2021 03 7;14(2):628-642. Epub 2020 Nov 7.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

As a pathogenic fungus, Aspergillus flavus can produce carcinogenic aflatoxins (AFs), which poses a great threat to crops and animals. Msb2, the signalling mucin protein, is a part of mitogen-activated protein kinase (MAPK) pathway which contributes to a range of physiological processes. In this study, the roles of membrane mucin Msb2 were explored in A. flavus by the application of gene disruption. The deletion of msb2 gene (Δmsb2) caused defects in vegetative growth, sporulation and sclerotia formation when compared to WT and complement strain (Δmsb2 ) in A. flavus. Using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analysis, it was found that deletion of msb2 down-regulated aflatoxin B (AFB ) synthesis and decreased the infection capacity of A. flavus. Consistently, Msb2 responds to cell wall stress and osmotic stress by positively regulating the phosphorylation of MAP kinase. Notably, Δmsb2 mutant exhibited cell wall defect, and it was more sensitive to inhibitor caspofungin when compared to WT and Δmsb2 . Taking together, these results revealed that Msb2 plays key roles in morphological development process, stresses adaptation, secondary metabolism and pathogenicity in fungus A. flavus.
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http://dx.doi.org/10.1111/1751-7915.13701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936294PMC
March 2021

Transcriptome Sequencing Revealed an Inhibitory Mechanism of Asexual Development and Aflatoxin Metabolism by Soy-Fermenting Non-Aflatoxigenic .

Int J Mol Sci 2020 Sep 23;21(19). Epub 2020 Sep 23.

School of Life Science, Jiangsu Normal University, Xuzhou 221116, China.

Aflatoxins (AFs) have always been regarded as the most effective carcinogens, posing a great threat to agriculture, food safety, and human health. is the major producer of aflatoxin contamination in crops. The prevention and control of and aflatoxin continues to be a global problem. In this study, we demonstrated that the cell-free culture filtrate of and a non-aflatoxigenic can effectively inhibit the production of AFB1 and the growth and reproduction of , indicating that both of the non-aflatoxigenic strains secrete inhibitory compounds. Further transcriptome sequencing was performed to analyze the inhibitory mechanism of treated with fermenting cultures, and the results revealed that genes involved in the AF biosynthesis pathway and other biosynthetic gene clusters were significantly downregulated, which might be caused by the reduced expression of specific regulators, such as AflS, FarB, and MtfA. The WGCNA results further revealed that genes involved in the TCA cycle and glycolysis were potentially involved in aflatoxin biosynthesis. Our comparative transcriptomics also revealed that two conidia transcriptional factors, and , were found to be significantly downregulated, which might lead to the downregulation of conidiation-specific genes, such as the conidial hydrophobins genes and . In summary, our research provides new insights for the molecular mechanism of controlling AF synthesis to control the proliferation of and AF pollution.
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http://dx.doi.org/10.3390/ijms21196994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583960PMC
September 2020

MSC-derived exosomes promote recovery from traumatic brain injury via microglia/macrophages in rat.

Aging (Albany NY) 2020 Sep 23;12(18):18274-18296. Epub 2020 Sep 23.

Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy, Beijing 100005, China.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young individuals worldwide. There is currently no effective clinical treatment for TBI, but mesenchymal stem cell-derived exosomes have exhibited promising therapeutic effects. In this study, we performed intracerebroventricular microinjection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-ex) in a weight-drop-induced TBI rat model. We found that hADSC-ex promoted functional recovery, suppressed neuroinflammation, reduced neuronal apoptosis, and increased neurogenesis in TBI rats. The therapeutic effects of hADSC-ex were comparable to those of hADSC. Sequential imaging revealed increasing aggregation of DiR-labeled hADSC-ex in the lesion area. Immunofluorescent staining of coronal brain sections and primary mixed neural cell cultures revealed distinct overlap between CM-DiI-labeled hADSC-ex and microglia/macrophages, indicating that hADSC-ex were mainly taken up by microglia/macrophages. In a lipopolysaccharide-induced inflammatory model, hADSC-ex suppressed microglia/macrophage activation by inhibiting nuclear factor κB and P38 mitogen-activated protein kinase signaling. These data suggest that hADSC-ex specifically enter microglia/macrophages and suppress their activation during brain injury, thereby inhibiting inflammation and facilitating functional recovery. They also offer new insight into the cellular targeting, uptake and migration of hADSC-ex, and provide a theoretical basis for new therapeutic strategies for central nervous system diseases.
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http://dx.doi.org/10.18632/aging.103692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585083PMC
September 2020

Sensitive immunoassays based on specific monoclonal IgG for determination of bovine lactoferrin in cow milk samples.

Food Chem 2021 Feb 13;338:127820. Epub 2020 Aug 13.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Marine Biotechnology of Fujian Province, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China. Electronic address:

Lactoferrin (LF), a bioactive multifunctional protein of the transferrin family, is found mainly in the secretions of all mammals, especially in milk. In the present study, a hybridoma cell (LF8) secreting IgG against bovine LF was screened, and the purified LF8 mAb showed high specificity and affinity to bovine LF. The linear range of ic-ELISA to detect LF was 9.76 ~ 625 ng/mL, with a limit of detection (LOD) of 0.01 ng/mL. The average recovery of intra- and inter-assay were (104.45 ± 4.12)% and (107.13 ± 4.72)%, respectively. The LOD of colloidal gold- and AuNFs-based strip by naked eye were 9.7 and 2.4 ng/mL, respectively, and the detection time was less than 10 min without any samples pretreatment and expensive equipment. The developed ELISA and lateral flow immunosensors based on specific IgG could be used directly for rapid detection of the bovine LF content in cow milk samples.
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http://dx.doi.org/10.1016/j.foodchem.2020.127820DOI Listing
February 2021

MAPK pathway-related tyrosine phosphatases regulate development, secondary metabolism and pathogenicity in fungus Aspergillus flavus.

Environ Microbiol 2020 12 7;22(12):5232-5247. Epub 2020 Sep 7.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

Mitogen-activated protein kinase (MAPK) cascades are highly conserved in eukaryotic cells and are known to play crucial roles in the regulation of various cellular processes. However, compared with kinase-mediated phosphorylation, dephosphorylation catalysed by phosphatases has not been well characterized in filamentous fungi. In this study, we identified five MAPK pathway-related phosphatases (Msg5, Yvh1, Ptp1, Ptp2 and Oca2) and characterized their functions in Aspergillus flavus, which produces aflatoxin B (AFB ), one of the most toxic and carcinogenic secondary metabolites. These five phosphatases were identified as negative regulators of MAPK (Slt2, Fus3 and Hog1) pathways. Deletion of Msg5 and Yvh1 resulted in significant defects in conidiation, sclerotia formation, aflatoxin production and crop infection. Additionally, double knockout mutants (ΔMsg5/ΔPtp1, ΔMsg5/ΔPtp2 and ΔMsg5/ΔOca2) displayed similar defects to those observed in the ΔMsg5 single mutant, indicating that Msg5 plays a major role in the regulation of development and pathogenicity in A. flavus. Importantly, we found that the active site at C439 is essential for the function of the Msg5 phosphatase. Furthermore, the MAP kinase Fus3 was found to be involved in the regulation of development, aflatoxin biosynthesis and pathogenicity, and its conserved phosphorylation residues (Thr and Tyr) were critical for the full range of its functions in A. flavus. Overall, our results reveal that MAPK related tyrosine phosphatases play important roles in the regulation of development, secondary metabolism and pathogenicity in A. flavus, and could be developed as potential targets for preventing damage caused by this fungal pathogen.
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http://dx.doi.org/10.1111/1462-2920.15202DOI Listing
December 2020

The bZIP Transcription Factor AflRsmA Regulates Aflatoxin B Biosynthesis, Oxidative Stress Response and Sclerotium Formation in .

Toxins (Basel) 2020 04 23;12(4). Epub 2020 Apr 23.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

Fungal secondary metabolites play important roles not only in fungal ecology but also in humans living as beneficial medicine or harmful toxins. In filamentous fungi, bZIP-type transcription factors (TFs) are associated with the proteins involved in oxidative stress response and secondary metabolism. In this study, a connection between a bZIP TF and oxidative stress induction of secondary metabolism is uncovered in an opportunistic pathogen , which produces carcinogenic and mutagenic aflatoxins. The bZIP transcription factor AflRsmA was identified by a homology research of . genome with the bZIP protein RsmA, involved in secondary metabolites production in . The deletion strain () displayed less sensitivity to the oxidative reagents tert-Butyl hydroperoxide (tBOOH) in comparison with wild type (WT) and overexpression strain (), while strain increased sensitivity to the oxidative reagents menadione sodium bisulfite (MSB) compared to WT and strains. Without oxidative treatment, aflatoxin B (AFB) production of strains was consistent with that of WT, but strain produced more AFB than WT; tBOOH and MSB treatment decreased AFB production of compared to WT. Besides, relative to WT, strain decreased sclerotia, while strain increased sclerotia. The decrease of AFB by but increase of AFB by was on corn. Our results suggest that AFB biosynthesis is regulated by AflRsmA by oxidative stress pathways and provide insights into a possible function of AflRsmA in mediating AFB biosynthesis response host defense in pathogen . .
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http://dx.doi.org/10.3390/toxins12040271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232220PMC
April 2020

Comprehensive circular RNA expression profiling with associated ceRNA network reveals their therapeutic potential in cholesteatoma.

Oncol Rep 2020 Apr 12;43(4):1234-1244. Epub 2020 Feb 12.

Department of Otolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.

Cholesteatoma is a chronic disease that pathologically displays a benign tumor with excessive squamous epithelial cell proliferation in the middle ear. Clinically, however, it can manifest malignant behavior by destroying adjacent tissues and organs. Although previous studies have demonstrated that the pathogenesis of cholesteatoma is correlated with epigenetic dysregulation, the exact mechanism remains unclear. Circular RNAs (circRNAs) have been revealed as being abundantly expressed in various organisms and have been found to contribute to the regulation of many diseases. To date, no reports have elucidated their expression profiles and functions in cholesteatoma. In the present study, the circRNA expression profile in cholesteatoma was explored for the first time by using microarray analysis. We obtained a total of 355 significantly differentially expressed circRNAs in cholesteatoma, among which 101 were identified to be upregulated and 254 downregulated. By constructing circRNA‑lncRNA‑miRNA‑mRNA competing endogenous RNA (ceRNA) network, it was discovered that circRNAs may function as ceRNAs and contribute to the formation of cholesteatoma. These results provide novel insight into the pathogenesis of cholesteatoma and suggest circRNAs as potential promising therapeutic targets for cholesteatoma.
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http://dx.doi.org/10.3892/or.2020.7501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058062PMC
April 2020

Transplantation of ACE2 Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia.

Aging Dis 2020 Apr 9;11(2):216-228. Epub 2020 Mar 9.

9The Executive Committee on Anti-aging and Disease Prevention in the framework of Science and Technology, Pharmacology and Medicine Themes under an Interactive Atlas along the Silk Roads, UNESCO, Paris, France.

A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11b regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2 and TMPRSS2 which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
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http://dx.doi.org/10.14336/AD.2020.0228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069465PMC
April 2020

Antioxidant-related catalase CTA1 regulates development, aflatoxin biosynthesis, and virulence in pathogenic fungus Aspergillus flavus.

Environ Microbiol 2020 07 15;22(7):2792-2810. Epub 2020 Apr 15.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

Reactive oxygen species (ROS) induce the synthesis of a myriad of secondary metabolites, including aflatoxins. It raises significant concern as it is a potent environmental contaminant. In Aspergillus flavus., antioxidant enzymes link ROS stress response with coordinated gene regulation of aflatoxin biosynthesis. In this study, we characterized the function of a core component of the antioxidant enzyme catalase (CTA1) of A. flavus. Firstly, we verified the presence of cta1 corresponding protein (CTA1) by Western blot analysis and mass-spectrometry based analysis. Then, the functional study revealed that the growth, sporulation and sclerotia formation significantly increased, while aflatoxins production and virulence were decreased in the cta1 deletion mutant as compared with the WT and complementary strains. Furthermore, the absence of the cta1 gene resulted in a significant rise in the intracellular ROS level, which in turn added to the oxidative stress level of cells. A further quantitative proteomics investigation hinted that in vivo, CTA1 might maintain the ROS level to facilitate the aflatoxin synthesis. All in all, the pleiotropic phenotype of A. flavus CTA1 deletion mutant revealed that the antioxidant system plays a crucial role in fungal development, aflatoxins biosynthesis and virulence.
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http://dx.doi.org/10.1111/1462-2920.15011DOI Listing
July 2020

The MAP kinase AflSlt2 modulates aflatoxin biosynthesis and peanut infection in the fungus Aspergillus flavus.

Int J Food Microbiol 2020 Jun 2;322:108576. Epub 2020 Mar 2.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China. Electronic address:

Aflatoxin contamination in food and feed products has been brought into sharp focus over the last few decades in the world. However, there is no effective strategy for solving the problem thus far. Therefore, basic research on the aflatoxin-producer Aspergillus flavus is an urgent need. The vital role of mitogen-activated protein kinases (MAPKs) in signal transduction has been documented in various pathogenic fungi, but their functions in A. flavus have rarely been investigated. Herein, we characterized the detailed function of one of these MAPKs, AflSlt2. Targeted deletion of AflSlt2 gene indicates that this kinase is required for vegetative growth, conidia generation, and sclerotium formation. The analysis of AflSlt2 deletion mutant revealed hypersensitivity to cell wall-damaging chemicals and resistance against hydrogen peroxide. Interestingly, the ability of the ΔAflSlt2 mutant to generate aflatoxins in medium was significantly increased compared to wild type. However, a pathogenicity assay indicated that the ΔAflSlt2 mutant was deficient in peanut infection. Site-directed mutation study uncovered that the function of AflSlt2 was dependent on the phosphorylated residues (Thr-186 and Tyr-188) within the activation loop and the phosphotransfer residue (Lys-52) within the subdomain II. Interestingly, an autophosphorylation mutant of AflSlt2 (AflSlt2) displayed wild type-like phenotypes. Bringing these observations together, we propose that Slt2-MAPK pathway is involved in development, stress response, aflatoxin biosynthesis, and pathogenicity in A. flavus. This study may be useful to unveil the regulation mechanism of aflatoxin biosynthesis and provide strategy to control A. flavus contamination.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2020.108576DOI Listing
June 2020

Development of ELISA and Lateral Flow Immunoassays for Ochratoxins (OTA and OTB) Detection Based on Monoclonal Antibody.

Front Cell Infect Microbiol 2020 6;10:80. Epub 2020 Mar 6.

Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, Fujian Agriculture and Forestry University, Fuzhou, China.

Ochratoxins were important secondary metabolites secreted by fungi, and OTA and OTB are mainly significant mycotoxin, having toxic effects on humans and animals. Therefore, it is important to establish a rapid, sensitive, and precise method for ochratoxins detection and quantification in real samples. In this study, a stable monoclonal antibody (mAb) that recognizing both OTA and OTB toxins was employed for the establishment of indirect competitive ELISA (ic-ELISA), colloidal gold nanoparticles (CGNs), and nanoflowers gold strips (AuNFs) for detection of ochratoxins in real samples. A 6E5 hybridoma cell line stable secreting mAb against both OTA and OTB toxins was obtained by fusion of splenocytes with myeloma SP2/0 cells. The 6E5 mAb had a high affinity (3.7 × 10 L/mol) to OTA, and also showed similar binding activity to OTB. The optimized ic-ELISA resulted in a linear range of 0.06-0.6 ng/mL for ochratoxins (OTA and OTB) detection. The IC50 was 0.2 ng/mL and the limit of detection (LOD) was 0.03 ng/mL. The mean recovery rate from the spiked samples was 89.315 ± 2.257%, with a coefficient variation of 2.182%. The result from lateral flow immunoassays indicated that the LOD of CGNs and AuNFs were 5 and 1 μg/mL, respectively. All these results indicated that the developed ic-ELISA, CGNs, and AuNFs in this study could be used for the analysis of the residual of ochratoxins (OTA and OTB) in food and agricultural products.
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http://dx.doi.org/10.3389/fcimb.2020.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067699PMC
April 2021

Preparation of monoclonal antibody against penicillic acid (PA) and its application in the immunological detection.

Food Chem 2020 Jul 27;319:126505. Epub 2020 Feb 27.

The Ministry of Education Key Laboratory of Biopesticide and Chemical Biology, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China. Electronic address:

The high content of Penicillic acid (PA) in the feed pose threat to human health and cause serious losses to economic wealth through the enrichment effect of the food chain. The reliable and rapidly detection of PA is of significant importance to ensure food safety. In this study, indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) and immunochromatographic test strips (ICTS) were established for PA determination based on anti-PA mAb secreted by 4H9 cell line. The linear range of ic-ELISA detection was 0.12-1.95 μg/mL, and the limit of detection (LOD) was 0.03 μg/mL. Then, conventional gold nanospheres (AuNS) with the average diameter of 20 nm were synthetized and AuNS-based strip was developed for rapidly detection of PA. The visual LOD (vLOD) of the AuNS-based strip was 3.9 μg/mL and the assay time of visual evaluation was less than 10 min without any instrument. To enhance the signal sensitivity of the ICTS, the larger size (about 85 nm) of gold nanoflowers (AuNFs) was prepared in our work, and was used as higher signal reporter to establish the AuNF-based strip for PA determination. Fortunately, the vLOD of AuNF-based strip was 0.97 μg/mL, which was approximately 4-fold lower than that of traditional AuNS-based strip. In summary, the rapid and sensitive immunoassays established in this study could be applied to detect and analyze the contamination of PA toxin in real food samples.
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http://dx.doi.org/10.1016/j.foodchem.2020.126505DOI Listing
July 2020

The Methyltransferase AflSet1 Is Involved in Fungal Morphogenesis, AFB1 Biosynthesis, and Virulence of .

Front Microbiol 2020 18;11:234. Epub 2020 Feb 18.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.

The filament fungal pathogen, , spreads worldwide and contaminates several important crops. Histone posttranslational modifications are deeply involved in fungal development and virulence, but the biological function of the histone methyltransferase AflSet1 in is still unknown. In the study, deletion strain was constructed through homologous recombination, and it was found that AflSet1 up-regulates hyphae growth, and promotes conidiation by sporulation regulation genes: and . It was also found that AflSet1 involves in sclerotia formation and AFB1 biosynthesis via sclerotia related transcriptional factors and orthodox AFB1 synthesis pathway, respectively. Crop models revealed that AflSet1 plays critical roles in colonization and AFB1 production on crop kernels. Lipase activity analysis suggested that AflSet1 affects fungal virulence to crops via digestive enzymes. Stresses tests revealed that AflSet1 is deeply involved in fungal resistance against osmotic, oxidative and cell membrane stress. The preparation of N_SET, SET domain deletion mutants and H988K mutant revealed that both domains play critical roles in fungal development and AFB1 production, and that H988 is very important in executing biological functions on morphogenesis and AFB1 synthesis. Subcellular location analysis revealed that AflSet1 is stably accumulated in nuclei in both spore germination and hyphae growth stages, even under the stress of SDS. Through immunoblot analysis, it was found that AflSet1 methylates H3K4me2 and me3 as well as H3K9me2. This study provides a solid evidence to discover the biological functions of histone methyltransferase in pathogenic fungi.
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http://dx.doi.org/10.3389/fmicb.2020.00234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040179PMC
February 2020

Gas Chromatography-Mass Spectrometry Profiling of Volatile Compounds Reveals Metabolic Changes in a Non-Aflatoxigenic Induced by 5-Azacytidine.

Toxins (Basel) 2020 01 19;12(1). Epub 2020 Jan 19.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, 350002 Fuzhou, China.

is one of the most opportunistic pathogens invading many important oilseed crops and foodstuffs with such toxic secondary metabolites as aflatoxin (AF) and Cyclopiazonic acid. We previously used the DNA methylation inhibitor 5-azacytidine to treat with an AF-producing A133 strain, and isolated a mutant (NT) of , which displayed impaired abilities of AF biosynthesis and fungal development. In this study, gas chromatography-mass spectrometry (GC-MS) analysis was used to reveal the metabolic changes between these two strains. A total of 1181 volatiles were identified in these two strains, among which 490 volatiles were found in these two strains in vitro and 332 volatiles were found in vivo. The NT mutant was found to produce decreasing volatile compounds, among which most of the fatty acid-derived volatiles were significantly downregulated in the NT mutant compared to the A133 strain, which are important precursors for AF biosynthesis. Two antioxidants and most of the amino acids derived volatiles were found significantly upregulated in the NT mutant. Overall, our results reveal the difference of metabolic profiles in two different isolates, which may provide valuable information for controlling infections of this fungal pathogen.
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http://dx.doi.org/10.3390/toxins12010057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020457PMC
January 2020

A Cell Wall Integrity-Related MAP Kinase Kinase Kinase Is Required for Growth and Virulence in Fungus .

Mol Plant Microbe Interact 2020 Apr 4;33(4):680-692. Epub 2020 Mar 4.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

represents an important fungal pathogen, causing severe economic losses in crops. The mitogen-activated protein (MAP) kinase signaling pathway contributes to many physiological processes, but its precise role in is not yet fully understood. In this study, we focused on the gene, which encodes a MAP kinase kinase kinase of the Slt2-MAPK pathway. Targeted deletion of led to a significant defect in growth and development, and a -deleted mutant (∆) showed higher sensitivity to cell-wall stress than wild type (WT). Importantly, we observed that ∆ displayed an enhanced ability to produce aflatoxin, a potential carcinogenic mycotoxin. However, the pathogenicity of the ∆ mutant was markedly reduced in peanut seeds. We also presented evidence that AflBck1 was genetically epistatic to AflMkk2 in the Slt2-MAPK pathway. Finally, we found that loss of the proline-rich region at the N terminus of AflBck1 affected the reproduction of . Collectively, this study not only extended the understanding that the MAPK pathway regulated pathogenicity but also provided a possible strategy to control contamination.
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http://dx.doi.org/10.1094/MPMI-11-19-0327-RDOI Listing
April 2020

AflSte20 Regulates Morphogenesis, Stress Response, and Aflatoxin Biosynthesis of .

Toxins (Basel) 2019 12 13;11(12). Epub 2019 Dec 13.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

Various signaling pathways in filamentous fungi help cells receive and respond to environmental information. Previous studies have shown that the mitogen-activated protein kinase (MAPK) pathway is phosphorylation-dependent and activated by different kinase proteins. Serine/threonine kinase plays a very important role in the MAPK pathway. In this study, we selected the serine/threonine kinase AflSte20 in for functional study. By constructing knockout mutants and complemented strains, it was proven that the knockout mutant (Δ) showed a significant decrease in growth, sporogenesis, sclerotinogenesis, virulence, and infection compared to the WT (wild type) and complemented strain (Δ). Further research indicated that Δ has more sensitivity characteristics than WT and Δ under various stimuli such as osmotic stress and other types of environmental stresses. Above all, our study showed that the mitogen-activated kinase AflSte20 plays an important role in the growth, conidia production, stress response and sclerotia formation, as well as aflatoxin biosynthesis, in .
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http://dx.doi.org/10.3390/toxins11120730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950481PMC
December 2019

Regulation of Morphology, Aflatoxin Production, and Virulence of by the Major Nitrogen Regulatory Gene .

Toxins (Basel) 2019 12 10;11(12). Epub 2019 Dec 10.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

is a renowned plant, animal and human pathogen. is a global nitrogen regulatory gene of the GATA transcription factor family, shown to be the major nitrogen regulator. In this study, we identified in and studied its function. The AreA protein contained a signatory zinc finger domain, which is extremely conserved across fungal species. Gene deletion (Δ) and over-expression (OE::) strains were constructed by homologous recombination to elucidate the role of in . The Δ strain was unable to efficiently utilize secondary nitrogen sources for growth of , and it had poorly developed conidiophores, when observed on complete medium, resulting in the production of significantly less conidia than the wild-type strain (WT). Aflatoxin B1 (AFB1) production was reduced in Δ compared with the WT strain in most conditions tested, and Δ had impaired virulence in peanut seeds. also played important roles in the sensitivity of to osmotic, cell wall and oxidative stresses. Hence, was found to be important for the growth, aflatoxin production and pathogenicity of . This work sheds light on the function of in the regulation of the nitrogen metabolism of and consequently aims at providing new ways for controlling the crossover pathogen, .
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http://dx.doi.org/10.3390/toxins11120718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950533PMC
December 2019

Association of XPD Asp312Asn polymorphism and response to oxaliplatin-based first-line chemotherapy and survival in patients with metastatic colorectal cancer.

Adv Clin Exp Med 2019 Nov;28(11):1459-1468

Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, USA.

Background: Identification of biomarkers predicting a response to chemotherapeutic drugs would greatly ease the selection of personalized therapy. The protein xeroderma pigmentosum group D (XPD) functions in nucleotide excision repair (NER) to remove DNA cross-links and in the regulation of transcription. The potential role of the Asp312Asn polymorphism in predicting the response to chemotherapy has not been established.

Objectives: This prospective study was designed to determine the role of the XPD Asp312Asn polymorphism in predicting the response to oxaliplatin-based first-line chemotherapy and survival in patients with metastatic colorectal cancer.

Material And Methods: A total of 106 patients treated with 2 cycles of either FOLFOX4 (n = 72) or XELOX (n = 34) regimen as the chemotherapy were enrolled. The genotype of XPD Asp312Asn polymorphism was analyzed using TaqMan probe-based real-time polymerase chain reaction (PCR). Logistic regression was applied to predict the response to treatment protocols. Cox regression models were applied to predict overall survival.

Results: The overall response to chemotherapy was 57.6% (61/106). FOLFOX4 and XELOX regimens demonstrated comparable efficacy. The XPD Asp312Asn polymorphism was not associated with the response to either FOLFOX4 or XELOX regimen in univariate and in multivariate logistic regression analyses. Levels of carcinoembryonic antigen (CEA) ≥5 ng/mL and female gender were associated with a lack of response to FOLFOX4, but not to XELOX regimen. In a multivariate survival analysis, XPD Asp312Asn AA genotype, lack of response to chemotherapy, CEA ≥ 5 ng/mL, and age ≥65 were significantly associated with worse overall survival.

Conclusions: The XPD Asp312Asn polymorphism is associated with overall survival, but it is not a biomarker in predicting the response to oxaliplatin-based first-line chemotherapy in patients with metastatic colorectal cancer.
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http://dx.doi.org/10.17219/acem/108552DOI Listing
November 2019

Lysine acetylation contributes to development, aflatoxin biosynthesis and pathogenicity in Aspergillus flavus.

Environ Microbiol 2019 12 25;21(12):4792-4807. Epub 2019 Oct 25.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.

Aspergillus flavus is a pathogenic fungus that produces carcinogenic aflatoxins, posing a great threat to crops, animals and humans. Lysine acetylation is one of the most important reversible post-translational modifications and plays a vital regulatory role in various cellular processes. However, current information on the extent and function of lysine acetylation and aflatoxin biosynthesis in A. flavus is limited. Here, a global acetylome analysis of A. flavus was performed by peptide pre-fractionation, pan-acetylation antibody enrichment and liquid chromatography-mass spectrometry. A total of 1313 high-confidence acetylation sites in 727 acetylated proteins were identified in A. flavus. These acetylation proteins are widely involved in glycolysis/gluconeogenesis, pentose phosphate pathway, citric acid cycle and aflatoxin biosynthesis. AflO (O-methyltransferase), a key enzyme in aflatoxin biosynthesis, was found to be acetylated at K241 and K384. Deletion of aflO not only impaired conidial and sclerotial developments, but also dramatically suppressed aflatoxin production and pathogenicity of A. flavus. Further site-specific mutations showed that lysine acetylation of AflO could also result in defects in development, aflatoxin production and pathogenicity, suggesting that acetylation plays a vital role in the regulation of the enzymatic activity of AflO in A. flavus. Our findings provide evidence for the involvement of lysine acetylation in various biological processes in A. flavus and facilitating in the elucidation of metabolic networks.
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http://dx.doi.org/10.1111/1462-2920.14825DOI Listing
December 2019

Urban public bicycle dispatching optimization method.

PeerJ Comput Sci 2019 14;5:e224. Epub 2019 Oct 14.

School of Computer Science and Technology, Hangzhou Dianzi University, Hangzhou, China.

Unreasonable public bicycle dispatching area division seriously affects the operational efficiency of the public bicycle system. To solve this problem, this paper innovatively proposes an improved community discovery algorithm based on multi-objective optimization ( ). The data set is preprocessed into a lease/return relationship, thereby it calculated a similarity matrix, and the community discovery algorithm is executed on the matrix to obtain a scheduling scheme. For the results obtained by the algorithm, the workload indicators (scheduled distance, number of sites, and number of scheduling bicycles) should be adjusted to maximize the overall benefits, and the entire process is continuously optimized by a multi-objective optimization algorithm . The experimental results show that compared with the clustering algorithm and the community discovery algorithm, the method can shorten the estimated scheduling distance by 20%-50%, and can effectively balance the scheduling workload of each area. The method can provide theoretical support for the public bicycle dispatching department, and improve the efficiency of public bicycle dispatching system.
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http://dx.doi.org/10.7717/peerj-cs.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924461PMC
October 2019