Publications by authors named "Lili Fu"

111 Publications

Unmethylated CpG motif-containing genomic DNA fragments of bacillus calmette-guerin improves immune response towards a DNA vaccine for COVID-19.

Vaccine 2021 Sep 3. Epub 2021 Sep 3.

Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC) and WHO Collaborating Center for Standardization and Evaluation of Biologicals, No.31 Huatuo Street, Daxing District, Beijing 102629, China. Electronic address:

The development of an effective vaccine to control the global coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) is of utmost importance. In this study, a synthetic DNA-based vaccine candidate, known as pSV10-SARS-CoV-2, expressing the SARS-CoV-2 spike protein was designed and tested in 39 BALB/c mice with BC01, an adjuvant derived from unmethylated CpG motif-containing DNA fragments from the Bacillus Calmette-Guerin genome. Mice vaccinated with pSV10-SARS-CoV-2 with BC01 produced early neutralizing antibodies and developed stronger humoral and cellular immune responses compared to mice that received the DNA vaccine only. Moreover, sera from mice vaccinated with pSV10-SARS-CoV-2 with BC01 can neutralize certain variants, including 614G, 614G + 472 V, 452R, 483A, 501Y.V2, and B.1.1.7. The results of this study demonstrate that the addition of BC01 to a DNA-vaccine for COVID-19 could elicit more effective neutralizing antibody titers for disease prevention.
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http://dx.doi.org/10.1016/j.vaccine.2021.08.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413458PMC
September 2021

SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca flux to mitochondria.

Nat Commun 2021 Sep 13;12(1):5404. Epub 2021 Sep 13.

Department of Biochemistry, McGill University, Montreal, QC, Canada.

Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.
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http://dx.doi.org/10.1038/s41467-021-25260-9DOI Listing
September 2021

An Unusual Enteric Yolk Sac Tumor: First Report of an Ovarian Germ Cell Tumor Associated With a Germline Pathogenic Variant in DICER1.

Int J Gynecol Pathol 2021 Aug 11. Epub 2021 Aug 11.

Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK (W.G.M.C.) Department of Pathology, McGill University Health Centre (L.F.) Cancer Axis, Lady Davis Institute, Jewish General Hospital (K.M., N.S., W.D.F.) Department of Human Genetics, McGill University (W.D.F.), Montréal, Québec Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario (L.D.K.) Hereditary Cancer Program and High Risk Clinic, British Columbia Cancer Agency (A.M.) Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada (C.B.G.) Department of Histopathology, King Edward Memorial Hospital, Perth, Western Australia (C.J.R.S.).

A variety of unusual tumors are associated with both germline and somatic DICER1 pathogenic variants (PVs), including, in the female genital tract, embryonal rhabdomyosarcoma at various sites and ovarian Sertoli-Leydig cell tumor. There have been occasional reported cases of ovarian germ cell tumors [mainly yolk sac tumor (YST)] harboring DICER1 PVs but, as far as we are aware, none of these has been proven to have a germline provenance. We report an unusual enteric variant of ovarian YST in a 28-yr-old woman associated with a germline PV c.901C>T (p.Gln301Ter) in exon 7 of DICER1, accompanied by a somatic (YST-only) hotspot mutation: c.5437G>A, p.E1813K. To our knowledge, this is the first report of an ovarian germ cell tumor associated with a germline DICER1 PV. We review other reported cases of ovarian germ cell tumor with DICER1 PVs and discuss the differential diagnosis of this unusual variant of YST which was originally diagnosed as a mucinous adenocarcinoma.
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http://dx.doi.org/10.1097/PGP.0000000000000818DOI Listing
August 2021

A novel indazole derivative, compound Cyy-272, attenuates LPS-induced acute lung injury by inhibiting JNK phosphorylation.

Toxicol Appl Pharmacol 2021 Oct 17;428:115648. Epub 2021 Jul 17.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; Institute of Chronic Kidney Disease, Wenzhou Medical University, Wenzhou, China. Electronic address:

Acute lung injury (ALI) is a diffuse lung dysfunction disease characterized by high prevalence and high mortality. Thus far, no effective pharmacological treatment has been made for ALI in clinics. Inflammation is critical to the development of ALI. Therefore, anti-inflammation may be a potential therapy strategy for ALI. Indazole-containing derivatives, representing one of the most important heterocycles in drug molecules, are endowed with a broad range of biological properties, such as anti-cancer and anti-inflammation. In the current study, we investigated the biological effects of Cyy-272, a newly synthesized indazole compound, on LPS-induced ALI both in vivo and in vitro. Results show that Cyy-272 can inhibit the release of inflammatory cytokines in LPS-stimulated macrophage and alleviate LPS induced ALI. Further experiment revealed that Cyy-272 exhibit anti-inflammation activity by inhibiting JNK phosphorylation. Overall, our studies show that an indazole derivative, Cyy-272, is effective in suppressing LPS-induced JNK activation and inflammatory signaling.
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http://dx.doi.org/10.1016/j.taap.2021.115648DOI Listing
October 2021

Near-Infrared Fluorescent Probe for Imaging and Evaluating the Role of Vanin-1 in Chemotherapy.

Anal Chem 2021 07 18;93(29):10378-10387. Epub 2021 Jul 18.

School of Pharmacy, Binzhou Medical University, Yantai 264003, China.

Pantetheinase (also known as Vanin-1) is highly expressed in the liver, kidneys, and intestine and is closely associated with a number of diseases. Vanin-1 can hydrolyze pantetheine to pantothenic acid (vitamin B5) and cysteamine and participate in the synthesis of glutathione (GSH). GSH is highly expressed in tumor cells and plays a major role in the resistance of tumor cells to cisplatin. Therefore, we urgently need a method to monitor the activity level of Vanin-1 in tumor cells and tissues and elucidate the relationship between the role of Vanin-1 in GSH synthesis and tumor resistance. Herein, we report a Cy-Pa fluorescent probe for imaging Vanin-1 in cells and in vivo that can qualitatively and quantitatively detect the fluctuation of Vanin-1 concentrations in HepG2 and HepG2/DDP cells or tumor tissues of tumor-bearing mice. This probe shows excellent potential in in situ real-time monitoring of endogenous Vanin-1. Moreover, we proved that Vanin-1 can inhibit GSH synthesis using the probe. When the Vanin-1 inhibitor RR6 was used in combination with cisplatin, HepG2 and HepG2/DDP cells showed increased resistance to cisplatin, while the therapeutic efficiency of cisplatin was reduced in HepG2 and HepG2/DDP xenografts. In this study, Vanin-1 was shown to play an important role in the treatment of cancer, and the study of Vanin-1 may provide an idea for the treatment of cancer in the future.
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http://dx.doi.org/10.1021/acs.analchem.1c02386DOI Listing
July 2021

Single-Dose Immunization With a Chimpanzee Adenovirus-Based Vaccine Induces Sustained and Protective Immunity Against SARS-CoV-2 Infection.

Front Immunol 2021 28;12:697074. Epub 2021 Jun 28.

Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

The development of a safe and effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we aim to develop novel SARS-CoV-2 vaccines based on a derivative of less commonly used rare adenovirus serotype AdC68 vector. Three vaccine candidates were constructed expressing either the full-length spike (AdC68-19S) or receptor-binding domain (RBD) with two different signal sequences (AdC68-19RBD and AdC68-19RBDs). Single-dose intramuscular immunization induced robust and sustained binding and neutralizing antibody responses in BALB/c mice up to 40 weeks after immunization, with AdC68-19S being superior to AdC68-19RBD and AdC68-19RBDs. Importantly, immunization with AdC68-19S induced protective immunity against high-dose challenge with live SARS-CoV-2 in a golden Syrian hamster model of SARS-CoV-2 infection. Vaccinated animals demonstrated dramatic decreases in viral RNA copies and infectious virus in the lungs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in rhesus macaques. Taken together, these results confirm that AdC68-19S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.
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http://dx.doi.org/10.3389/fimmu.2021.697074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273614PMC
July 2021

Residual characteristics and potential integrated risk assessment of synthetic pyrethroids in leafy vegetables from Zhejiang in China - Based on a 3-year investigation.

Food Chem 2021 Dec 16;365:130389. Epub 2021 Jun 16.

Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China.

Leafy vegetables have high nutritional value and are very popular in China. However, the long-term variation in residues and integrated risks of synthetic pyrethroids (SPs) in these vegetables have not been well examined. In this study, a total of 1005 samples were collected from 55 markets during 2017-2019. The cumulative exposure to nine kinds of SPs in Zhejiang, China, through the consumption of nine leafy vegetables was analyzed, and the potential integrated risk was assessed by the relative potency factor. A total of 191 samples were detected with SPs residues. The most frequently detected SPs were λ-cyhalothrin and cypermethrin. The integrated risk assessment results revealed that the dietary risk for these SPs via leafy vegetable exposure is acceptable for children, adults and elderly individuals. The data provided here will be helpful for the government to formulate food policies in China.
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http://dx.doi.org/10.1016/j.foodchem.2021.130389DOI Listing
December 2021

Potent and protective IGHV3-53/3-66 public antibodies and their shared escape mutant on the spike of SARS-CoV-2.

Nat Commun 2021 07 9;12(1):4210. Epub 2021 Jul 9.

Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province, China.

Neutralizing antibodies (nAbs) to SARS-CoV-2 hold powerful potentials for clinical interventions against COVID-19 disease. However, their common genetic and biologic features remain elusive. Here we interrogate a total of 165 antibodies from eight COVID-19 patients, and find that potent nAbs from different patients have disproportionally high representation of IGHV3-53/3-66 usage, and therefore termed as public antibodies. Crystal structural comparison of these antibodies reveals they share similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor angiotensin-converting enzyme-2 (ACE2) in binding to RBD. Site-directed mutagenesis confirms these common binding features although some minor differences are found. One representative antibody, P5A-3C8, demonstrates extraordinarily protective efficacy in a golden Syrian hamster model against SARS-CoV-2 infection. However, virus escape analysis identifies a single natural mutation in RBD, namely K417N found in B.1.351 variant from South Africa, abolished the neutralizing activity of these public antibodies. The discovery of public antibodies and shared escape mutation highlight the intricate relationship between antibody response and SARS-CoV-2, and provide critical reference for the development of antibody and vaccine strategies to overcome the antigenic variation of SARS-CoV-2.
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http://dx.doi.org/10.1038/s41467-021-24514-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270942PMC
July 2021

Depression of caregivers is significantly associated with depression and hospitalization of hemodialysis patients.

Hemodial Int 2021 Jul 5. Epub 2021 Jul 5.

Department of Nephrology, People's Hospital of Pudong New Area, Shanghai University of medicine & Health Sciences, Shanghai, China.

Introduction: The current study aims to elucidate the relationships of depression of caregivers with depression of hemodialysis patients and determine predictors of hospitalization of hemodialysis patients.

Methods: The single-center, cross-sectional study consisted of 200 pairs of eligible hemodialysis patients and caregivers from January 2019 to January 2020. Depression was evaluated using Hospital Anxiety and Depression Scale (HADS) questionnaire.

Findings: There were 89 hemodialysis patients with depression (44.5%) and 74 caregivers with depression (37.0%). In multi-variable logistic regression analysis, the hemodialysis patients with depressed caregivers were at increased risk of depression after adjusting for potential confounders (OR = 2.36, p = 0.04). Depression of hemodialysis patients (β = 0.51, p = 0.00) and depression of caregivers (β = 0.36, p = 0.04) were predictors of hospitalization of hemodialysis patients.

Discussion: Depression was prevalent among hemodialysis patients and their caregivers. Depression of caregivers was a risk factor for depression and hospitalization of hemodialysis patients. Implementation of appropriate screening programs and specific interventions for depression of hemodialysis patients and their caregivers is required.
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http://dx.doi.org/10.1111/hdi.12967DOI Listing
July 2021

Single-Cell RNA Sequencing Analysis of the Immunometabolic Rewiring and Immunopathogenesis of Coronavirus Disease 2019.

Front Immunol 2021 14;12:651656. Epub 2021 Apr 14.

Center for Life Sciences, Tsinghua University, Beijing, China.

Although immune dysfunction is a key feature of coronavirus disease 2019 (COVID-19), the metabolism-related mechanisms remain elusive. Here, by reanalyzing single-cell RNA sequencing data, we delineated metabolic remodeling in peripheral blood mononuclear cells (PBMCs) to elucidate the metabolic mechanisms that may lead to the progression of severe COVID-19. After scoring the metabolism-related biological processes and signaling pathways, we found that mono-CD14 cells expressed higher levels of glycolysis-related genes ( and ) and PPPrelated genes ( and ) in severe patients than in mild patients. These genes may contribute to the hyperinflammation in mono-CD14 cells of patients with severe COVID-19. The mono-CD16 cell population in COVID-19 patients showed reduced transcription levels of genes related to lysine degradation (, and ) and elevated transcription levels of genes involved in OXPHOS (, , , and ), which may inhibit M2-like polarization. Plasma cells also expressed higher levels of the OXPHOS gene in COVID-19 patients, which was positively associated with antibody secretion and survival of PCs. Moreover, enhanced glycolysis or OXPHOS was positively associated with the differentiation of memory B cells into plasmablasts or plasma cells. This study comprehensively investigated the metabolic features of peripheral immune cells and revealed that metabolic changes exacerbated inflammation in monocytes and promoted antibody secretion and cell survival in PCs in COVID-19 patients, especially those with severe disease.
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http://dx.doi.org/10.3389/fimmu.2021.651656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079812PMC
May 2021

Stereoisomeric selectivity in the endocrine-disrupting potential of cypermethrin using in vitro, in vivo, and in silico assays.

J Hazard Mater 2021 07 20;414:125389. Epub 2021 Feb 20.

Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, PR China.

Despite the ubiquity of cypermethrin (CYP) stereoisomers in environment biota, the stereoisomeric selectivity of endocrine-disrupting potency of α-CYP, β-CYP, and θ-CYP has not been well studied. In this study, dual-luciferase reporter gene assays were adopted to analyze their potential endocrine-disrupting effects via four receptors (ERα, GRα, MR and RXR). The results showed that α-CYP was antagonistic to ERα, GRα, and MR with RIC of 9.1 × 10, 7.6 × 10, and 1.0 × 10 M, respectively. β-CYP exhibited only ERα-mediated agonistic activity with a REC of 2.1 × 10 M. None of the CYP stereoisomers interacted with RXR. Molecular docking indicated that α-CYP had the strongest binding capacity to GRα among the compounds. The expression levels of steroid hormone-related genes in human adrenocortical carcinoma (H295R) cells displayed that all three compounds inhibited the transcription of 3-βHSD, indicating the block of turning cholesterol into different hormones. Both α-CYP and β-CYP upregulated genes encoding estrogen- and aldosterone-forming enzymes including 17-βHSD, CYP19, STAR, and CYP11B2. Mortality and malformation toxicity assays in zebrafish embryos revealed that the order of toxicity was α-CYP > β-CYP > θ-CYP. Our results indicated that α-CYP may pose the strongest endocrine-disrupting effects. The data provided here will be helpful to systematically understand stereoisomeric selectivity in the endocrine-disrupting effects of cypermethrin.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125389DOI Listing
July 2021

The chloroplast genome of a unicellular green alga strain isolated from the rubber processing wastewater.

Mitochondrial DNA B Resour 2021 Jan 21;6(1):15-16. Epub 2021 Jan 21.

Institute of Tropical Bioscience and Biotechnology, MOA Key Laboratory of Tropical Crops Biology and Genetic Resources, Hainan Bioenergy Center, Chinese Academy of Tropical Agricultural Sciences, Haikou, China.

ITBBA3-12 has a role in the purification of the rubber processing wastewater. Its complete chloroplast genome contains 168369 bp, with a G + C content of 33.0%. A total of 147 genes were annotated, including 113 protein-coding genes, three rRNA (rrn23, rrn16, and rrn5) genes, and 31 tRNA genes. The significant feature of the chloroplast genome is that the genes encoding subunit V (petG), VI (petL), and apocytochrome f (petA) of the cytochrome b6/f complex are in triplicate, which was not observed in the other strains. Phylogenetic analysis using the chloroplast genomes of Chlorophyta species indicated that ITBBA3-12 is closely related to strain UTEX259 and NJ-7, and they clustered in the lineage.
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http://dx.doi.org/10.1080/23802359.2020.1844090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872553PMC
January 2021

Molecular characterization of DICER1-mutated pituitary blastoma.

Acta Neuropathol 2021 06 1;141(6):929-944. Epub 2021 Mar 1.

Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada.

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.
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http://dx.doi.org/10.1007/s00401-021-02283-6DOI Listing
June 2021

The Adsorption Ability of NCFM to Benzo(a)pyrene in PM.

J Toxicol 2021 7;2021:6290524. Epub 2021 Jan 7.

College of Biological Science & Biotechnology, Beijing Forestry University, Beijing 100083, China.

The objective of this work was to explore the ability of lactic acid bacteria strains to bind benzo(a)pyrene (B(a)P) existing in PM. In this study, we examined the ability of NCFM to bind B(a)P in the simulated PM environment. Among the tested 5 strains, NCFM exhibited the best capacity to bind B(a)P, and its B(a)P binding percentage was 60.00%. Simulations of organic and inorganic systems which represent PM indicated that B(a)P could be absorbed by strain NCFM. For the inorganic system of pH 5, NCFM bound 92.74% B(a)P with a cell concentration of 1 × 10 cfu/mL at 37°C for 8 hr. Regarding the organic system with pH 6, 73.00% B(a)P was bound by strain NCFM after this bacterium was incubated at 37°C for 10 min. A quick B(a)P binding by this probiotic bacterium took place in the organic system. The removal of B(a)P from PM was significantly related to incubation time, cultivation temperature, pH, and cell concentration. Thus, our finding shows that long-term consumption of NCFM is beneficial for the reduction of B(a)P towards the population who are exposed to PM, although the ability of this bacterium to adsorb B(a)P is partly affected by the differences in the origin of PM.
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http://dx.doi.org/10.1155/2021/6290524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808799PMC
January 2021

Characterization of the mitochondrion genome of a strain isolated from rubber processing wastewater.

Mitochondrial DNA B Resour 2020 Jul 10;5(3):2732-2733. Epub 2020 Jul 10.

Institute of Tropical Bioscience and Biotechnology, MOA Key Laboratory of Tropical Crops Biology and Genetic Resources, Hainan Bioenergy Center, Chinese Academy of Tropical Agricultural Sciences, Haikou, China.

ITBBA3-12 was isolated from the rubber processing wastewater and has a role in wastewater purification. Its complete mitogenome contains 88754 bp, with a G + C content of 29.7%. A total of 64 genes were annotated, including 34 protein-coding genes, 27 tRNA genes, three rRNA (rrn23, rrn16, and rrn5). Phylogenetic analysis using the mitogenomes of Trebouxiophyceae species indicated that the strain ITBBA3-12 is closely related to strain UTEX259 and NJ-7, and they clustered in the lineage.
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http://dx.doi.org/10.1080/23802359.2020.1789004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782133PMC
July 2020

[A single arm clinical study of 86 patients with common type of coronavirus disease 2019 treated by integrated traditional Chinese and Western medicine: multicenter case observation from 7 designated hospitals in Henan Province].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020 Aug;32(8):922-927

Department of Respiratory Diseases, the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan, China.

Objective: To evaluate the clinical effect of integrated traditional Chinese and Western medicine on common type of coronavirus disease 2019 (COVID-19) in Henan Province.

Methods: A prospective single arm clinical study was performed. Patients with common type of COVID-19 admitted to seven designated hospitals for COVID-19 in Henan Province from January 25th to February 26th, 2020 were enrolled, and treated with integrated traditional Chinese and Western medicine. The negative transformation of 2019 novel coronavirus (2019-nCoV) nucleic acid, disease outcome, hospital stay, clinical symptoms and signs scores, and chest imaging performance were observed.

Results: Totally 86 cases were included in the analysis, including 48 males (55.8%), aged 43.5 (35.0, 53.3) years old, 24 patients (27.9%) with previous medical history. Fifty-eight patients were primarily diagnosed COVID-19 and 28 patients were transferred. The 2019-nCoV nucleic acid of 86 cases (100%) turned negative, and the median time of turning negative was 10 (7, 14) days. Eighty-six cases (100%) were discharged from hospital, and none turned into the severe type; the average length of hospital stay was (13.8±5.6) days. The scores of fever, cough, chest tightness, shortness of breath, and fatigue decreased with the treatment time, and the scores of 7 days and 14 days after treatment were significantly lower than those before treatment [fever (points): 0 (0, 0), 0 (0, 0) vs. 1 (0, 1); cough (points): 1 (0, 1), 0 (0, 1) vs. 1 (0, 2); chest tightness (points): 0 (0, 0), 0 (0, 0) vs. 0 (0, 1); shortness of breath (points): 0 (0, 0), 0 (0, 0) vs. 0 (0, 1); fatigue (points): 0 (0, 1), 0 (0, 1) vs. 1 (0, 1); all P < 0.05]. The improvement rate of X ray and CT image was 42.9% (12/28) and 81.0% (64/79), respectively.

Conclusions: The treatment with integrated traditional Chinese and Western medicine has good curative effect on common type of COVID-19 in 7 designated hospitals of Henan Province. It can improve the clinical symptoms, promote the absorption of pulmonary inflammation, and to some extent control the progress of disease and shorten the time of turning negative of virus nucleic acid and hospital stay.
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http://dx.doi.org/10.3760/cma.j.cn121430-20200528-00485DOI Listing
August 2020

Assessing the ecological regime and spatial spillover effects of a reclaimed mining subsided lake: A case study of the Pan'an Lake wetland in Xuzhou.

PLoS One 2020 27;15(8):e0238243. Epub 2020 Aug 27.

School of Environmental Science and Spatial Informatics, China University of Mining and Technology, Xuzhou, China.

In the North China Plain, coal mining subsided lakes are surface water bodies that form after the conclusion of coal mining. In China, mining subsided lakes are often transformed into artificial wetland parks for ecological restoration. While many studies have focused on evaluating coal mining subsidence lake ecosystem service value and water pollution, little attention has been paid to changes in ecological regimes and ecological spillover effects before and after the reclamation of mining areas. This paper examines the Pan'an Lake artificial wetland in Jiawang District, Xuzhou, as a case study. Changes in the ecological regime of the mining subsidence area before and after land reclamation and corresponding spatial spillover effect on land prices are assessed based on remote sensing, GIS raster calculations and geostatistical methods. The results show that the ecosystem service value and ecological storage capacity changed significantly after the mining subsided lake was transformed into an artificial wetland and the wetland ecosystem has been developing well with significantly positive spillover effects on surrounding land prices. From 2008 to 2017, service functions of the artificial wetland ecosystem of Pan'an Lake increased by 81.95%, and the system's ecological storage capacity increased from RMB 6,754 yuan/hm2 in 2008 to RMB 12,289 yuan/hm2 in 2017. The average impact of the Pan'an Lake artificial wetland on the spillover effects of surrounding residential land prices was measured at RMB 195.18 yuan/m2, and the total spillover value of planned residential land in the study area was measured at RMB 805,422,100 yuan. The present study can serve as a useful guide for evaluating the economic feasibility of land reclamation planning and ecological restoration in mining subsidence areas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238243PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451651PMC
October 2020

Transcriptional analysis reveals potential genes and regulatory networks involved in salicylic acid-induced flowering in duckweed (Lemna gibba).

Plant Physiol Biochem 2020 Oct 18;155:512-522. Epub 2020 Aug 18.

Institute of Tropical Bioscience and Biotechnology, MOA Key Laboratory of Tropical Crops Biology and Genetic Resources, Hainan Bioenergy Center, Chinese Academy of Tropical Agricultural Sciences, Xueyuan Road 4, Haikou, 571101, China; Hainan Key Laboratory for Protection and Utilization of Tropical Bioresources, Hainan Institute for Tropical Agricultural Resources, Chinese Academy of Tropical Agricultural Sciences, Xueyuan Road 4, Haikou, 571101, China. Electronic address:

Duckweed is a simple aquatic floating plant having great potential in sewage treatment and bioenergy production. Duckweed rarely flowers in nature, which greatly limits its germplasm collection, conservation, and heterosis usage. Salicylic acid (SA) can efficiently induce flowering of duckweed (e.g., Lemna gibba); however, the related genes and regulatory networks remain unclear. In this work, we demonstrated that L. gibba flowering induced by SA was photoperiod-dependent, stress-involved, and abscisic acid (ABA)-disrupted. Totally 202, 78, and 413 differentially expressed (DE) genes were up-regulated, while 429, 72, and 307 were down-regulated at flower induction, flower initiation, and flowering stages, respectively. At the flower induction stage, the down-regulated genes were mainly involved in cell wall, auxin and ABA, light reaction, and abiotic stress, while the up-regulated genes were involved in development, brassinosteroid, major CHO metabolism, and redox. At the flower initiation stage, the down-regulated genes were enriched in light reaction and lipid metabolism, whereas the up-regulated genes were enriched in starch degradation and Ca signaling. At the flowering stage, the down-regulated genes were significantly enriched in photosynthesis, gibberellic acid, starch synthesis, nitrogen metabolism, and redox, while the up-regulated genes were enriched in cell wall, jasmonic acid, secondary metabolism, and Ca signaling. Besides, 46 transcription factors and 13 flowering-related DE genes were identified. Finally, a possible floral pathway, where LgTEM1, LgSVP, and LgFT1 might play critical roles in SA-induced flowering in L. gibba, was discussed. These findings provide a useful foundation for further investigation of genes and regulatory networks of SA-induced flowering in duckweed.
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http://dx.doi.org/10.1016/j.plaphy.2020.08.001DOI Listing
October 2020

Highly dynamic, coordinated, and stage-specific profiles are revealed by a multi-omics integrative analysis during tuberous root development in cassava.

J Exp Bot 2020 12;71(22):7003-7017

Hainan Key Laboratory for Biosafety Monitoring and Molecular Breeding in Off-Season Reproduction Regions, Key Laboratory of Biology and Genetic Resources of Tropical Crops, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou, China.

Cassava (Manihot esculenta) is an important starchy root crop that provides food for millions of people worldwide, but little is known about the regulation of the development of its tuberous root at the multi-omics level. In this study, the transcriptome, proteome, and metabolome were examined in parallel at seven time-points during the development of the tuberous root from the early to late stages of its growth. Overall, highly dynamic and stage-specific changes in the expression of genes/proteins were observed during development. Cell wall and auxin genes, which were regulated exclusively at the transcriptomic level, mainly functioned during the early stages. Starch biosynthesis, which was controlled at both the transcriptomic and proteomic levels, was mainly activated in the early stages and was greatly restricted during the late stages. Two main branches of lignin biosynthesis, coniferyl alcohol and sinapyl alcohol, also functioned during the early stages of development at both the transcriptomic and proteomic levels. Metabolomic analysis further supported the stage-specific roles of particular genes/proteins. Metabolites related to lignin and flavonoid biosynthesis showed high abundance during the early stages, those related to lipids exhibited high abundance at both the early and middle stages, while those related to amino acids were highly accumulated during the late stages. Our findings provide a comprehensive resource for broadening our understanding of tuberous root development and will facilitate future genetic improvement of cassava.
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http://dx.doi.org/10.1093/jxb/eraa369DOI Listing
December 2020

Efficient solar-blind ultraviolet detection based on a Sn ion-activated fluosilicate glass.

Opt Lett 2020 Apr;45(8):2140-2143

As an effective method to improve the sensitivity of detection, spectral conversion technology has been widely used in solar-blind ultraviolet communication (UVC). However, producing a spectral converter with high efficiency, short decay lifetime, and excellent stability in the field of UVC detection remains an outstanding challenge. In this Letter, a kind of ${{\rm Sn}^{2 + }}$Sn activated fluosilicate (SFS) glass as a spectral converter for UVC detection has been prepared, which has a short lifetime (5.65 µs) and a high quantum efficiency (85%). The SFS decorated Si-based PIN photodiode enables strong absorption and subtly UVC shifts to an emission band optimized for the detector. Moreover, the outstanding performance of detection with responsivity of 27 µA/[email protected] nm, frequency limit up to 50 KHz, and rise/fall time scale of 15.14/18.71 µ[email protected] KHz is achieved. The comprehensive performance shows that SFS glass has the potential for efficient UVC detection in a scalable and low-cost strategy.
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http://dx.doi.org/10.1364/OL.387375DOI Listing
April 2020

Stabilized diverse HIV-1 envelope trimers for vaccine design.

Emerg Microbes Infect 2020 Dec;9(1):775-786

Comprehensive AIDS Research Center and Center for Global Health and Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China.

One of the major goals in HIV-1 vaccine development is to achieve properly folded and stabilized envelope glycoprotein (Env) trimers that mimic the native Env on the mature virion. Here, we design and characterize uncleaved prefusion-optimized (UFO) trimers for 12 Envs currently circulating in China. Biochemical and biophysical characterization of these UFO trimers identified two subtype B/B' Envs, CNE6 and MG13, which exhibited the highest trimer content and stability at a level comparable to the subtype A reference, BG505. Replacing the gp41 ectodomain (gp41) of CRF01_AE trimers with that of CNE6, MG13, and BG505 resulted in chimeric constructs with significantly improved trimer content and stability. Negative-stain electron microscopy (EM) confirmed the structural integrity of these chimeric UFO trimers with CNE6 gp41. Antibody binding assays showed that the chimeric trimers shared similar antigenic profiles to those with their original gp41 domains. Our results thus revealed the intrinsic differences among HIV-1 Envs of diverse origins and the critical role of gp41 in stabilizing the trimeric spike. By taking advantage of naturally stable Envs, gp41 swapping may represent a universal approach for the generation of stable trimers with the desired structural and antigenic properties for downstream in vivo evaluation and vaccine development.
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http://dx.doi.org/10.1080/22221751.2020.1745093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178897PMC
December 2020

Genetic Analysis and Immunoelectron Microscopy of Wild and Mutant Strains of the Rubber Tree Endophytic Bacterium Strain ITBB B5-1 Reveal Key Roles of a Macrovesicle in Storage and Secretion of Prodigiosin.

J Agric Food Chem 2020 May 10;68(20):5606-5615. Epub 2020 Apr 10.

Institute of Tropical Bioscience and Biotechnology, MOA Key Laboratory of Tropical Crops Biology and Genetic Resources, CATAS, Xueyuan Road 4, Haikou 571101, China.

Rubber tree is an economically important tropical crop. Its endophytic bacterial strain ITBB B5-1 contains an intracellular macrovesicle and red pigment. In this research, the red pigment was identified as prodigiosin by quadrupole time-of-flight mass spectrometry. Prodigiosin has a wide range of potential medical values such as anticancer and antiorgan transplant rejection. The strain ITBB B5-1 accumulated prodigiosin up to 2000 mg/L, which is higher production compared to most known strains. The formation of the macrovesicle and prodigiosin biosynthesis were highly associated and were both temporal- and temperature-dependent. A mutant strain B5-1mu that failed to produce prodigiosin was obtained by ultraviolet mutagenesis. Whole genome sequencing of wild-type and mutant strains indicated that the gene encoding the last-step enzyme in the prodigiosin biosynthesis pathway was mutated in B5-1mu by a 17-bp deletion. Transmission electron microscopy analysis showed that the macrovesicle was absent in the mutant strain, indicating that formation of the macrovesicle relied on prodigiosin biosynthesis. Immunoelectron microscopy using prodigiosin-specific antiserum showed the presence of prodigiosin in the macrovesicle, the cell wall, and the extracellular vesicles, while immuno-reaction was not observed in the mutant cell. These results indicate that the macrovesicle serves as a storage organelle of prodigiosin, and secretes prodigiosin into cell envelop and culture medium as extracellular vesicles.
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http://dx.doi.org/10.1021/acs.jafc.0c00078DOI Listing
May 2020

The Capacity of High-Grade Serous Ovarian Cancer Cells to Form Multicellular Structures Spontaneously along Disease Progression Correlates with Their Orthotopic Tumorigenicity in Immunosuppressed Mice.

Cancers (Basel) 2020 Mar 16;12(3). Epub 2020 Mar 16.

Experimental Pathology Unit, Department of Pathology, Faculty of Medicine, McGill University, Montreal, QC H3A 2B4, Canada.

Many studies have examined the biology, genetics, and chemotherapeutic response of ovarian cancer's solid component; its liquid facet, however, remains critically underinvestigated. Floating within peritoneal effusions known as ascites, ovarian cancer cells form multicellular structures, creating a cancer niche in suspension. This study explores the pathobiology of spontaneously formed, multicellular, ovarian cancer structures derived from serous ovarian cancer cells isolated along disease evolution. It also tests their capacity to cause peritoneal disease in immunosuppressed mice. Results stem from an analysis of cell lines representing the most frequently diagnosed ovarian cancer histotype (high-grade serous ovarian cancer), derived from ascites of the same patient at distinct stages of disease progression. When cultured under adherent conditions, in addition to forming cellular monolayers, the cultures developed areas in which the cells grew upwards, forming densely packed multilayers that ultimately detached from the bottom of the plates and lived as free-floating, multicellular structures. The capacity to form foci and to develop multicellular structures was proportional to disease progression at the time of ascites extraction. Self-assembled in culture, these structures varied in size, were either compact or hollow, irregular, or spheroidal, and exhibited replicative capacity and an epithelial nature. Furthermore, they fully recreated ovarian cancer disease in immunosuppressed mice: accumulation of malignant ascites and pleural effusions; formation of discrete, solid, macroscopic, peritoneal tumors; and microscopic growths in abdominal organs. They also reproduced the histopathological features characteristic of high-grade serous ovarian cancer when diagnosed in patients. The following results encourage the development of therapeutic interventions to interrupt the formation and/or survival of multicellular structures that constitute a floating niche in the peritoneal fluid, which in turn halts disease progression and prevents recurrence.
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http://dx.doi.org/10.3390/cancers12030699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140084PMC
March 2020

De novo assembly, transcriptome characterization, and simple sequence repeat marker development in duckweed .

Physiol Mol Biol Plants 2020 Jan 9;26(1):133-142. Epub 2019 Dec 9.

1Institute of Tropical Bioscience and Biotechnology, MOA Key Laboratory of Tropical Crops Biology and Genetic Resources, Hainan Bioenergy Center, Chinese Academy of Tropical Agricultural Sciences, Xueyuan Road 4, Haikou, 571101 China.

is a species of duckweed showing great potential in bioenergy production and wastewater treatment. However, the relevant transcriptomic and genomic resources are very limited for this species, which dramatically hinders its genetic diversity and genome mapping researches. In this work, ~ 233.5 million clean reads were generated from by Illumina paired-end sequencing, and subsequently they were de novo assembled into 131,870 unigenes, of which 61,622 were annotated and 43,319 were expressed with Fragments Per Kilobase of transcript per Million fragments mapped (FPKM) > 5. In total, 19,297 simple sequence repeats (SSRs) were identified from 15,261 SSR-containing unigenes. Dinucleotide (78.4%) were the most abundant SSRs, followed by tri- (14.9%), tetra- (4.1%), and penta-nucleotides (1.5%). The top three motifs were AG/CT (69.9%), AC/GT (6.5%), and ATC/ATG (4.9%). Further analysis revealed that the presence of SSR motif was independent of the expression level for a given gene. Based on the sequence of these SSR-containing unigenes, a total of 10,292 SSR markers were developed, of which only 2671 were further retained after removing those derived from unannotated or extra-low expressed (e.g., FPKM ≤ 5) unigenes. Finally, a subset of 70 SSR markers was randomly selected and examined in nine diverse genotypes for the PCR amplification and polymorphism, as well as in other duckweed species for the inter-specifically amplifiability. This work is the first report on the transcriptome-based large-scale SSR markers development and analysis in . The transcriptome generated and the SSR markers developed in this work will provide a valuable resource for genetic diversity assessment in and also for species relationship investigation in family.
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http://dx.doi.org/10.1007/s12298-019-00726-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036385PMC
January 2020

New Insights in the Endocrine Disrupting Effects of Three Primary Metabolites of Organophosphate Flame Retardants.

Environ Sci Technol 2020 04 13;54(7):4465-4474. Epub 2020 Mar 13.

College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.

Despite the ubiquity of organophosphate flame retardants (OPFRs) metabolites in the biota, the endocrine disrupting potency has not been well examined. Herein, we chose three primary metabolites of OPFRs (BCIPP, BDCIPP, and DPHP) to investigate their potential endocrine disrupting effects by in vitro, in vivo, and in silico assays. Three metabolites were agonistic to rat estrogenic receptor alpha (ERα) and antagonists to human mineralocorticoid receptor (MR). BCIPP exerted endocrine disrupting effect contrasting to the negative response of its parental compound. It also poses the strongest binding capacity to ERα among the tested compounds. Both BCIPP and BDCIPP upregulated the genes encoded for estrogenic synthesis enzymes in H295R cells, including and . All three compounds stimulated the transcription of , whereas BCIPP and DPHP also triggered , encoding for corticoid production. BDCIPP inhibits genes for progesterone synthesis including , , and . The induction of mortality and low hatchability of zebrafish embryo were ranked as BCIPP ≥ BDCIPP > DPHP. All compounds lead to malformation of zebrafish larvae. Both of the hypothalamic-pituitary-adrenocortical and hypothalamic-pituitary-gonadal axes were disrupted, with the highest impact by BCIPP. Altogether, the data clarified OPFRs metabolites may produce comparable or even higher endocrine disrupting effects than OPFRs.
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http://dx.doi.org/10.1021/acs.est.9b07874DOI Listing
April 2020

Genome-wide discovery and functional prediction of salt-responsive lncRNAs in duckweed.

BMC Genomics 2020 Mar 5;21(1):212. Epub 2020 Mar 5.

Institute of Tropical Bioscience and Biotechnology, MOA Key Laboratory of Tropical Crops Biology and Genetic Resources, Hainan Bioenergy Center, Chinese Academy of Tropical Agricultural Sciences, Xueyuan Road 4, Haikou, 571101, China.

Background: Salt significantly depresses the growth and development of the greater duckweed, Spirodela polyrhiza, a model species of floating aquatic plants. Physiological responses of this plant to salt stress have been characterized, however, the roles of long noncoding RNAs (lncRNAs) remain unknown.

Results: In this work, totally 2815 novel lncRNAs were discovered in S. polyrhiza by strand-specific RNA sequencing, of which 185 (6.6%) were expressed differentially under salinity condition. Co-expression analysis indicated that the trans-acting lncRNAs regulated their co-expressed genes functioning in amino acid metabolism, cell- and cell wall-related metabolism, hormone metabolism, photosynthesis, RNA transcription, secondary metabolism, and transport. In total, 42 lncRNA-mRNA pairs that might participate in cis-acting regulation were found, and these adjacent genes were involved in cell wall, cell cycle, carbon metabolism, ROS regulation, hormone metabolism, and transcription factor. In addition, the lncRNAs probably functioning as miRNA targets were also investigated. Specifically, TCONS_00033722, TCONS_00044328, and TCONS_00059333 were targeted by a few well-studied salt-responsive miRNAs, supporting the involvement of miRNA and lncRNA interactions in the regulation of salt stress responses. Finally, a representative network of lncRNA-miRNA-mRNA was proposed and discussed to participate in duckweed salt stress via auxin signaling.

Conclusions: This study is the first report on salt-responsive lncRNAs in duckweed, and the findings will provide a solid foundation for in-depth functional characterization of duckweed lncRNAs in response to salt stress.
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http://dx.doi.org/10.1186/s12864-020-6633-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059339PMC
March 2020

Transcriptome analysis of polysaccharide-based microbial flocculant MBFA9 biosynthesis regulated by nitrogen source.

Sci Rep 2020 02 19;10(1):2918. Epub 2020 Feb 19.

College of Municipal & Environmental Engineering, Shenyang Jianzhu University, Shenyang, 110168, China.

Microbial flocculant (MBF), an environmentally friendly water treatment agent, can be widely used in various water treatments. However, its use is limited by low yield and high cost. This problem can be solved by clarifying its biosynthesis mechanism and regulating it. Paenibacillus shenyangensis A9, a flocculant-producing bacterium, was used to produce polysaccharide-type MBFA9 by regulating the nitrogen source (nitrogen adequacy/nitrogen deficiency). In this study, RNA-Seq high-throughput sequencing technology and bioinformatic approaches were used to investigate the fermentation and biosynthesis of polysaccharide-type MBFA9 by regulating the nitrogen source (high nitrogen/low nitrogen) in the flocculant-producing bacteria Paenibacillus shenyangensis A9. Differentially expressed genes, functional clustering, and functional annotation of key genes were assessed. Then the MBFA9 biosynthesis and metabolic pathway were reconstructed. Our results showed that when cultured under different nitrogen conditions, bacterial strain A9 had a greater ability to synthesize polysaccharide-type MBFA9 under low nitrogen compared to high nitrogen conditions, with the yield of MBFA9 reaching 4.2 g/L at 36 h of cultivation. The quality of transcriptome sequencing data was reliable, with a matching rate of 85.38% and 85.48% when L36/H36 was mapped to the reference genome. The total expressed genes detected were 4719 and 4730, with 265 differentially expressed genes. The differentially expressed genes were classified into 3 categories: molecular function (MF), cell component (CC), and biological process (BP), and can be further divided into 22 subcategories. There were 192 upregulated genes and 73 downregulated genes, with upregulation being predominant under low nitrogen. UDP-Gal, UDP-Glc, UDP-GlcA, and UDP-GlcNAc, which are in the polysaccharide metabolic pathway, could all be used as precursors for MBFA9 biosynthesis, and murA, wecB, pgm, galU/galF, fcl, gmd, and glgC were the main functional genes capable of affecting the growth of bacteria and the biosynthesis of MBF. Results from this study provide evidence that high-level expression of key genes in MBFA9 biosynthesis, regulation, and control can achieve MBFA9 directional synthesis for large-scale applications.
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http://dx.doi.org/10.1038/s41598-020-59114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031244PMC
February 2020

Potential of Inactivated Strain in Attenuating Benzo(A)Pyrene Exposure-Induced Damage in Colon Epithelial Cells In Vitro.

Toxics 2020 Feb 11;8(1). Epub 2020 Feb 11.

College of Biological Science & Biotechnology, Beijing Forestry University, Beijing 100083, China.

Long-term exposure to benzo(a)pyrene (BaP) poses a serious genotoxic threat to human beings. This in vitro study investigated the potential of inactivated subsp BI-04 in alleviating the damage caused by BaP in colon epithelial cells. A concentration of BaP higher than 50 μM strongly inhibited the growth of colon epithelial cells. The colon epithelial cells were treated with 50 μM BaP in the presence or absence of inactivated strain BI-04 (~5 ´ 10 CFU/mL). The BaP-induced apoptosis of the colon epithelial cells was retarded in the presence of BI-04 through activation of the PI3K/ AKT signaling pathway, and p53 gene expression was decreased. The presence of the BI-04 strain reduced the intracellular oxidative stress and DNA damage incurred in the colon epithelial cells by BaP treatment due to the enhanced expression of antioxidant enzymes and metabolism-related enzymes (CYP1A1) The data from comet assay, qRT-PCR, and western blot analysis showed that the cytotoxic effects of BaP on colon epithelial cells were largely alleviated because the bifidobacterial strain could bind to this carcinogenic compound. The in vitro study highlights that the consumption of commercial probiotic strain BI-04 might be a promising strategy to mitigate BaP cytotoxicity.
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http://dx.doi.org/10.3390/toxics8010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151743PMC
February 2020

Compound 15c, a Novel Dual Inhibitor of EGFR and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers.

Front Pharmacol 2019 10;10:1533. Epub 2020 Jan 10.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

In the past decades, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved as an effective treatment strategy for the patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the tolerance for the EGFR-TKI always occurred after continuous administration for a period of time and limiting the application of these drugs. Activation of FGFR1 signaling pathway was one of the important escape mechanisms for EGFR-TKI resistant in NSCLC. Here, a novel dual inhibitor of EGFR and FGFR1, compound15c, was found and can efficiently overcame the EGFR-TKI resistance its simultaneous inhibition of their kinase activities. Comparison with EGFR and FGFR1 inhibitor treatment alone or combined revealed that the inhibition of EGFR and FGFR1 activity by 15c was responsible for surmounting the intrinsic EGFR-TKI resistance in EGFR-mutated H1975 cells and the acquired resistance in Afatinib-tolerant PC9 cells (AFA-PC9). Flow Cytometry and Caspase3 activity analysis assay showed that 15c induced significant the early apoptosis of H1975 cells. Xenograft tumor formation in BALB/c mice induced by a H1975 cells was suppressed by 15c treatment, with no changes in animal body weight. Generally, 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.
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http://dx.doi.org/10.3389/fphar.2019.01533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965315PMC
January 2020

Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.

Nat Chem Biol 2020 03 20;16(3):267-277. Epub 2020 Jan 20.

Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.

A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.
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http://dx.doi.org/10.1038/s41589-019-0455-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040854PMC
March 2020
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