Publications by authors named "Haibo Zhou"

248 Publications

Exploring Boron Applications in Modern Agriculture: A Structure-Activity Relationship Study of a Novel Series of Multi-Substitution Benzoxaboroles for Identification of Potential Fungicides.

Bioorg Med Chem Lett 2021 May 5:128089. Epub 2021 May 5.

Boragen, Inc., 5 Laboratory Drive, Suite 2150, Research Triangle Park, Durham, NC 27709, USA.

Several boron-containing small molecules have been approved by the US FDA to treat human diseases. We explored potential applications of boron-containing compounds in modern agriculture by pursuing multiple research and development programs. Here, we report a novel series of multi-substitution benzoxaboroles (1-36), a compound class that we recently reported as targeting geranylgeranyl transferase I (GGTase I) and thereby inhibiting protein prenylation. These compounds were designed, synthesized, and tested against the agriculturally important fungal pathogens Mycosphaerella fijiensis and Colletotrichum sublineolum in a structure-activity relationship (SAR) study. Compounds 13, 28, 30, 34 and 36 were identified as active leads with excellent antifungal MIC values in the range of 1.56 to 3.13 ppm against M. fijiensis and 0.78 to 3.13 ppm against C. sublineolum.
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http://dx.doi.org/10.1016/j.bmcl.2021.128089DOI Listing
May 2021

Glycyrrhizic Acid Nanoparticles as Antiviral and Anti-inflammatory Agents for COVID-19 Treatment.

ACS Appl Mater Interfaces 2021 May 30;13(18):20995-21006. Epub 2021 Apr 30.

Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.

COVID-19 has been diffusely pandemic around the world, characterized by massive morbidity and mortality. One of the remarkable threats associated with mortality may be the uncontrolled inflammatory processes, which were induced by SARS-CoV-2 in infected patients. As there are no specific drugs, exploiting safe and effective treatment strategies is an instant requirement to dwindle viral damage and relieve extreme inflammation simultaneously. Here, highly biocompatible glycyrrhizic acid (GA) nanoparticles (GANPs) were synthesized based on GA. investigations revealed that GANPs inhibit the proliferation of the murine coronavirus MHV-A59 and reduce proinflammatory cytokine production caused by MHV-A59 or the N protein of SARS-CoV-2. In an MHV-A59-induced surrogate mouse model of COVID-19, GANPs specifically target areas with severe inflammation, such as the lungs, which appeared to improve the accumulation of GANPs and enhance the effectiveness of the treatment. Further, GANPs also exert antiviral and anti-inflammatory effects, relieving organ damage and conferring a significant survival advantage to infected mice. Such a novel therapeutic agent can be readily manufactured into feasible treatment for COVID-19.
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http://dx.doi.org/10.1021/acsami.1c02755DOI Listing
May 2021

PPE31 Contributes to Host Cell Death.

Front Cell Infect Microbiol 2021 13;11:629836. Epub 2021 Apr 13.

Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhongshan School of Medicine, Sun Yat-sen University, Zhuhai, China.

Genome scale mutagenesis identifies many genes required for mycobacterial infectivity and survival, but their contributions and mechanisms of action within the host are poorly understood. Using CRISPR interference, we created a knockdown of gene in (), which reduced the resistance to acid medium. To further explore the function of PPE31, the mutant strain was generated in and (), respectively. Macrophages infected with the mutant strain caused a reduced inflammatory mediator expressions. In addition, macrophages infected with Δ had decreased host cell death dependent on JNK signaling. Consistent with these results, deletion of from increased the sensitivity to acid medium and reduced cell death in macrophages. Furthermore, we demonstrate that both mutants from and resulted in reduced survival in macrophages, and the survivability of was deceased in zebrafish due to loss of . Our findings confirm that PPE31 as a virulence associated factor that modulates innate immune responses to mycobacterial infection.
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http://dx.doi.org/10.3389/fcimb.2021.629836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078103PMC
April 2021

GE11 Peptide Conjugated Liposomes for EGFR-Targeted and Chemophotothermal Combined Anticancer Therapy.

Bioinorg Chem Appl 2021 31;2021:5534870. Epub 2021 Mar 31.

Department of Clinical Immunology, Institute of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, China.

How to actively target tumor sites manipulating the controllable release of the encapsulated anticancer drugs and photosensitizers for synergistic anticancer therapy remains a big challenge. In this study, a cancer cell-targeted, near-infrared (NIR) light-triggered and anticancer drug loaded liposome system (LPs) was developed for synergistic cancer therapy. Photosensitizer indocyanine green (ICG) and chemotherapy drug Curcumin (CUR) were coencapsulated into the liposomes, followed by the surface conjugation of GE11 peptide for epidermal growth factor receptor (EGFR) targeting on the cancer cell surface. Strictly controlled by NIR light, GE11 peptide modified and CUR/ICG-loaded LPs (GE11-CUR/ICG-LPs) could introduce hyperthermia in EGFR overexpressed A549 cancer cells for photothermal therapy, which could also trigger the increased release of CUR for enhanced cancer cell inhibition. GE11-CUR/ICG-LPs synergized photochemotherapy could induce reactive oxygen species (ROS) generation and cytoskeleton disruption to activate stronger apoptotic signaling events than the photothermal therapy or chemotherapy alone by regulating Bax/Bcl-2 and PI3K/AKT pathways. This EGFR-targeted drug-delivery nanosystem with NIR sensitivity may potentially serve in more effective anticancer therapeutics with reduced off-target effects.
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http://dx.doi.org/10.1155/2021/5534870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035035PMC
March 2021

Multi-platform omics analysis reveals molecular signature for COVID-19 pathogenesis, prognosis and drug target discovery.

Signal Transduct Target Ther 2021 04 15;6(1):155. Epub 2021 Apr 15.

BGI-Shenzhen, Shenzhen, China.

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.
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http://dx.doi.org/10.1038/s41392-021-00508-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047575PMC
April 2021

Label-Free and Highly-Sensitive Detection of Ochratoxin A Using One-Pot Synthesized Reduced Graphene Oxide/Gold Nanoparticles-Based Impedimetric Aptasensor.

Biosensors (Basel) 2021 Mar 19;11(3). Epub 2021 Mar 19.

Zhejiang Key Laboratory of Pathophysiology, Department of Preventative Medicine, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo 315211, China.

Ochratoxin A (OTA) primarily obtained by the genera and , is one of the toxic substances for different organs and systems of the human body such as the kidney, liver, neurons and the immune system. Moreover, it is considered to cause tumors and fetal malformation even at a very low concentration. Fast and sensitive assay for detection of OTA at ultralow levels in foods and agricultural products has been an increasing demand. In this study, a new label-free electrochemical biosensor based on three-dimensional reduced graphene oxide/gold nanoparticles/aptamer for OTA detection was constructed. The 3D-rGO/Au NPs nanocomposites were firstly synthesized using a one-pot hydrothermal process under optimized experimental conditions. The 3D-rGO/Au NPs with considerable particular surface area and outstanding electrical conductivity was then coated on a glass carbon electrode to provide tremendous binding sites for -SH modified aptamer via the distinctive Au-S linkage. The presence of OTA was specifically captured by aptamer and resulted in electrochemical impedance spectroscopy (EIS) signal response accordingly. The constructed impedimetric aptasensor obtained a broad linear response from 1 pg/mL to 10 ng/mL with an LOD of 0.34 pg/mL toward OTA detection, highlighting the excellent sensitivity. Satisfactory reproducibility was also achieved with the relative standard deviation (RSD) of 1.393%. Moreover, the proposed aptasensor obtained a good recovery of OTA detection in red wine samples within the range of 93.14 to 112.75% along with a low LOD of 0.023 ng/mL, indicating its applicability for OTA detection in real samples along with economical, specific, susceptible, fast, easy, and transportable merits.
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http://dx.doi.org/10.3390/bios11030087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003581PMC
March 2021

Indiscriminate ssDNA cleavage activity of CRISPR-Cas12a induces no detectable off-target effects in mouse embryos.

Protein Cell 2021 Apr 1. Epub 2021 Apr 1.

Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.

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http://dx.doi.org/10.1007/s13238-021-00824-zDOI Listing
April 2021

Semiparametric regression analysis of case-cohort studies with multiple interval-censored disease outcomes.

Stat Med 2021 Mar 29. Epub 2021 Mar 29.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Interval-censored failure time data commonly arise in epidemiological and biomedical studies where the occurrence of an event or a disease is determined via periodic examinations. Subject to interval-censoring, available information on the failure time can be quite limited. Cost-effective sampling designs are desirable to enhance the study power, especially when the disease rate is low and the covariates are expensive to obtain. In this work, we formulate the case-cohort design with multiple interval-censored disease outcomes and also generalize it to nonrare diseases where only a portion of diseased subjects are sampled. We develop a marginal sieve weighted likelihood approach, which assumes that the failure times marginally follow the proportional hazards model. We consider two types of weights to account for the sampling bias, and adopt a sieve method with Bernstein polynomials to handle the unknown baseline functions. We employ a weighted bootstrap procedure to obtain a variance estimate that is robust to the dependence structure between failure times. The proposed method is examined via simulation studies and illustrated with a dataset on incident diabetes and hypertension from the Atherosclerosis Risk in Communities study.
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http://dx.doi.org/10.1002/sim.8962DOI Listing
March 2021

The enrichment of neutrophil extracellular traps impair the placentas of systemic lupus erythematosus through accumulating decidual NK cells.

Sci Rep 2021 Mar 25;11(1):6870. Epub 2021 Mar 25.

Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.

Despite the advances made in the management of pregnancies in women with systemic lupus erythematosus (SLE), the rate of adverse pregnancy outcomes is still higher than that in the general population. In the last few years, neutrophil extracellular traps (NETs) were proven to be detrimental in both autoimmune diseases and placental injury. We investigated whether NETs could be detected in the placentas of pregnant individuals with SLE and explored the relationship between NETs and decidual natural killer cells (dNKs), which comprise the majority of immune cells at the maternal-fetal interface, using clinical samples and animal models. In this study, we found that the infiltration of NETs and dNKs, especially CD56CD16 NK cells, was significantly increased in pregnant individuals with SLE with placental insufficiency. In the murine models of SLE, the number of dNKs was significantly decreased due to the decreased formation of NETs affected by Ly6G. Moreover, the histopathological placental injury was reduced, with a remarkable increase in fetal birth weight. This study shows that NETs may contribute to immunological disorder in the placenta and the pathological changes in pregnancies with SLE, which provides a research basis for further explorations of the mechanism of SLE in placental impairment.
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http://dx.doi.org/10.1038/s41598-021-86390-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994714PMC
March 2021

Retracted: Ferruginol Diterpenoid Selectively Inhibits Human Thyroid Cancer Growth by Inducing Mitochondrial Dependent Apoptosis, Endogenous Reactive Oxygen Species (ROS) Production, Mitochondrial Membrane Potential Loss and Suppression of Mitogen-Activated Protein Kinase (MAPK) and PI3K/AKT Signaling Pathways.

Med Sci Monit 2021 Mar 25;27:e932341. Epub 2021 Mar 25.

Department of Cardiothoracic Surgery, Qingyuan People's Hospital (The Sixth Affiliated Hospital of Guangzhou Medical University), Qingyuan, Guangdong, China (mainland).

An editorial decision has been made to retract this manuscript due to breach of publishing guidelines, following the identification of non-original and manipulated figures. Reference: Guoqing Luo, Jingjing Zhou, Guanjie Li, Ningdong Hu, Xu Xia, Haibo Zhou: Ferruginol Diterpenoid Selectively Inhibits Human Thyroid Cancer Growth by Inducing Mitochondrial Dependent Apoptosis, Endogenous Reactive Oxygen Species (ROS) Production, Mitochondrial Membrane Potential Loss and Suppression of Mitogen-Activated Protein Kinase (MAPK) and PI3K/AKT Signaling Pathways.  Med Sci Monit 2019; 25:2935-2942. 10.12659/MSM.914348.
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http://dx.doi.org/10.12659/MSM.932341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009249PMC
March 2021

Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection.

Nat Commun 2021 03 19;12(1):1724. Epub 2021 Mar 19.

State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.

T-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed individuals. Here we report virus-specific CD4 and CD8 T-cell memory in recovered COVID-19 patients and close contacts. We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. Overall, this study demonstrates the versatility and potential of memory T cells from COVID-19 patients and close contacts, which may be important for host protection.
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http://dx.doi.org/10.1038/s41467-021-22036-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979809PMC
March 2021

Linear active disturbance rejection control for the electro-hydraulic position servo system.

Sci Prog 2021 Jan-Mar;104(1):368504211000907

Tai'an Hualu Forging Machine Co. Ltd, Tai'an, P. R. China.

Valve-controlled asymmetric cylinder is widely used in servo loading system. As a kind of typical electro-hydraulic servo system (EHSS), it inherently has the characteristics such as high order nonlinear, strong coupling, and uncertain, therefore, conventional control strategy is difficult to satisfy the requirements of high-performance control. In this paper, a novel linear active disturbance rejection control (LADRC) method was proposed, in which the internal and external disturbances were actively estimated by the third-order linear extended state observer (LESO) in real-time, and rejected by the control law of proportional integral control (PID) with acceleration feed-forward. The stability of the proposed method was proved, and the influence rules of the LADRC parameters on the control performance were revealed by simulation. Finally, comparative experiments between LADRC and PID control were carried out, results showed that the disturbances can be effectively compensated and the control goals can be successfully achieved with the proposed method.
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http://dx.doi.org/10.1177/00368504211000907DOI Listing
March 2021

Cox regression analysis for distorted covariates with an unknown distortion function.

Biom J 2021 Mar 9. Epub 2021 Mar 9.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

We study inference for censored survival data where some covariates are distorted by some unknown functions of an observable confounding variable in a multiplicative form. An example of this kind of data in medical studies is normalizing some important observed exposure variables by patients' body mass index , weight, or age. Such a phenomenon also appears frequently in environmental studies where an ambient measure is used for normalization and in genomic studies where the library size needs to be normalized for the next generation sequencing of data. We propose a new covariate-adjusted Cox proportional hazards regression model and utilize the kernel smoothing method to estimate the distorting function, then employ an estimated maximum likelihood method to derive the estimator for the regression parameters. We establish the large sample properties of the proposed estimator. Extensive simulation studies demonstrate that the proposed estimator performs well in correcting the bias arising from distortion. A real dataset from the National Wilms' Tumor Study is used to illustrate the proposed approach.
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http://dx.doi.org/10.1002/bimj.202000209DOI Listing
March 2021

Transcription factor E2F4 is an indicator of poor prognosis and is related to immune infiltration in hepatocellular carcinoma.

J Cancer 2021 21;12(6):1792-1803. Epub 2021 Jan 21.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

Recent studies have shown that the transcription factor E2F4 is involved in the progression of various tumors, but its expression and influence on immune cell infiltration and biological functions are largely unknown in hepatocellular carcinoma (HCC). The Cancer Genome Atlas (TCGA) database, the Tumor Immune Estimation Resource (TIMER) and related online tools as well as a tissue microarray (TMA) were used for analyses in our study. E2F4 expression was elevated in HCC tumor tissue compared with adjacent normal tissue at both the mRNA and protein levels. Overexpression of E2F4 was markedly related to a poor prognosis in HCC patients. In addition, positively and negatively correlated significant genes of E2F4 were identified in HCC. Pathway enrichment analyses revealed that the top 100 positively correlated significant genes of E2F4 were closely related to nuclear splicing and degradation-related pathways. Furthermore, nine hub genes correlated with E2F4 expression were validated based on a protein-protein interaction (PPI) network. It was also demonstrated that E2F4 expression was negatively correlated to immune purity and positively correlated to immune cell infiltration. E2F4 could serve as a novel biomarker for HCC diagnosis and prognosis prediction.
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http://dx.doi.org/10.7150/jca.51616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890309PMC
January 2021

Real-time monitoring of aristolochic acid I reduction process using surface-enhanced Raman Spectroscopy with DFT simulation.

Biosens Bioelectron 2021 May 11;179:113061. Epub 2021 Feb 11.

College of Pharmacy, Jinan University, Guangzhou, 510632, China. Electronic address:

With the increasing number of reports on aristolochic acid I (AAI), more and more toxic and side effects have been discovered successively. The main recognized carcinogenic mechanism is that AAI is metabolized into aristololactam I (AAT) in the body by nitroreductases, ultimately forming AAT-DNA adducts that cause disease. However, the carcinogenic mechanism is still not well understood by currently reported indirect method, there has always been a great demand to develop a direct method for real-time monitoring such process. In this work, surface-enhanced Raman spectroscopy (SERS) was used for the first time to monitor the process of AAI under the action of reducing agent sodium borohydride and catalyst Raney nickel to form AAT. We first found the abundant intermediate product-amino derivative of AAI, which was never reported before by other methods. The AAT was then obtained by a one-step dehydration reaction from the amino derivative of AAI under such reduction conditions. The product of amino derivative of AAI and AAT were further verified by thin-layer chromatography, H nuclear magnetic resonance spectra, mass spectrometry, and ultra-high performance liquid chromatography. Furthermore, a density functional theory-supported in-depth vibrational characterization of AAI and AAT was performed. The monitoring of the AAI reduction process by SERS can be of great significance for further exploration of its pathogenic mechanism, prevention, and monitoring of "nephropathy" and other diseases caused by AAI.
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http://dx.doi.org/10.1016/j.bios.2021.113061DOI Listing
May 2021

Genomics-Driven Activation of Silent Biosynthetic Gene Clusters in by Screening Recombineering System.

Molecules 2021 Jan 29;26(3). Epub 2021 Jan 29.

Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.

The genus possesses ecological and metabolic diversities. A large number of silent biosynthetic gene clusters (BGCs) in the genome remain uncharacterized and represent a promising resource for new natural product discovery. However, exploitation of the metabolomic potential of is limited by the absence of efficient genetic manipulation tools. Here, we screened a bacteriophage recombinase system Redγ-BAS, which was functional for genome modification in the plant pathogen ATCC 10248. By using this recombineering tool, the constitutive promoters were precisely inserted in the genome, leading to activation of two silent nonribosomal peptide synthetase gene clusters ( and ) and production of corresponding new classes of lipopeptides, burriogladiodins A-H (-) and haereogladiodins A-B (-). Structure elucidation revealed an unnatural amino acid - dehydrobutyrine (Dhb) in - and an -Dhb in -. Notably, compounds - and feature an unusual threonine tag that is longer than the predicted collinearity assembly lines. The structural diversity of burriogladiodins was derived from the relaxed substrate specificity of the fifth adenylation domain as well as chain termination conducted by water or threonine. The recombinase-mediating genome editing system is not only applicable in but also possesses great potential for mining meaningful silent gene clusters from other species.
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http://dx.doi.org/10.3390/molecules26030700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866175PMC
January 2021

[Recombineering facilitates the discovery of natural product biosynthetic pathways in Pseudomonas parafulva].

Biotechnol J 2021 Jan 23:e2000575. Epub 2021 Jan 23.

Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China.

Microbial natural products among other functions they play a vital role in the disease prevention in humans, animals and plants. Pseudomonas parafulva CRS01-1 is a broad-spectrum antagonistic bacterium present in plants. However, no natural products have been isolated from this strain till date. Corresponding biosynthetic gene clusters to natural products is an effective method for bioprospecting, for which, genome manipulation tools are essential. We previously developed Pseudomonas-specific phage-derived homologous recombination systems for genetic engineering in four Pseudomonas species. Herein, we report the application of these recombineering systems in Pseudomonas parafulva CRS01-1, along with structural elucidation and bioactivity evaluation of natural products. The Pseudomonas recombineering toolbox established before in different four species is efficient for genome mining and bioactive metabolite discovery from more distant species. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/biot.202000575DOI Listing
January 2021

Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis.

Nat Commun 2021 01 12;12(1):296. Epub 2021 Jan 12.

Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237, China.

Nonribosomal peptide synthetases containing starter condensation domains direct the biosynthesis of nonribosomal lipopeptides, which generally exhibit wide bioactivities. The acyl chain has strong impacts on bioactivity and toxicity, but the lack of an in-depth understanding of starter condensation domain-mediated lipoinitiation limits the bioengineering of NRPSs to obtain novel derivatives with desired acyl chains. Here, we show that the acyl chains of the lipopeptides rhizomide, holrhizin, and glidobactin were modified by engineering the starter condensation domain, suggesting a workable approach to change the acyl chain. Based on the structure of the mutated starter condensation domain of rhizomide biosynthetic enzyme RzmA in complex with octanoyl-CoA and related point mutation experiments, we identify a set of residues responsible for the selectivity of substrate acyl chains and extend the acyl chains from acetyl to palmitoyl. Furthermore, we illustrate three possible conformational states of starter condensation domains during the reaction cycle of the lipoinitiation process. Our studies provide further insights into the mechanism of lipoinitiation and the engineering of nonribosomal peptide synthetases.
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http://dx.doi.org/10.1038/s41467-020-20548-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804268PMC
January 2021

Semiparametric regression based on quadratic inference function for multivariate failure time data with auxiliary information.

Lifetime Data Anal 2021 04 8;27(2):269-299. Epub 2021 Jan 8.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7420, USA.

This paper deals with statistical inference procedure of multivariate failure time data when the primary covariate can be measured only on a subset of the full cohort but the auxiliary information is available. To improve efficiency of statistical inference, we use quadratic inference function approach to incorporate the intra-cluster correlation and use kernel smoothing technique to further utilize the auxiliary information. The proposed method is shown to be more efficient than those ignoring the intra-cluster correlation and auxiliary information and is easy to implement. In addition, we develop a chi-squared test for hypothesis testing of hazard ratio parameters. We evaluate the finite-sample performance of the proposed procedure via extensive simulation studies. The proposed approach is illustrated by analysis of a real data set from the study of left ventricular dysfunction.
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http://dx.doi.org/10.1007/s10985-020-09513-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943434PMC
April 2021

Model based on five tumour immune microenvironment-related genes for predicting hepatocellular carcinoma immunotherapy outcomes.

J Transl Med 2021 01 6;19(1):26. Epub 2021 Jan 6.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.

Background: Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified.

Methods: A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms.

Results: Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan-Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures.

Conclusions: We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients.
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http://dx.doi.org/10.1186/s12967-020-02691-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788940PMC
January 2021

Endogenous promoter-driven sgRNA for monitoring the expression of low-abundance transcripts and lncRNAs.

Nat Cell Biol 2021 01 4;23(1):99-108. Epub 2021 Jan 4.

Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Detection of endogenous signals and precise control of genetic circuits in the natural context are essential to understand biological processes. However, the tools to process endogenous information are limited. Here we developed a generalizable endogenous transcription-gated switch that releases single-guide RNAs in the presence of an endogenous promoter. When the endogenous transcription-gated switch is coupled with the highly sensitive CRISPR-activator-associated reporter we developed, we can reliably detect the activity of endogenous genes, including genes with very low expression (<0.001 relative to Gapdh; quantitative-PCR analysis). Notably, we could also monitor the transcriptional activity of typically long non-coding RNAs expressed at low levels in living cells using this approach. Together, our method provides a powerful platform to sense the activity of endogenous genetic elements underlying cellular functions.
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http://dx.doi.org/10.1038/s41556-020-00610-9DOI Listing
January 2021

Bacteria Detection: From Powerful SERS to Its Advanced Compatible Techniques.

Adv Sci (Weinh) 2020 Dec 19;7(23):2001739. Epub 2020 Oct 19.

College of Pharmacy Jinan University Guangzhou Guangdong 510632 China.

The rapid, highly sensitive, and accurate detection of bacteria is the focus of various fields, especially food safety and public health. Surface-enhanced Raman spectroscopy (SERS), with the advantages of being fast, sensitive, and nondestructive, can be used to directly obtain molecular fingerprint information, as well as for the on-line qualitative analysis of multicomponent samples. It has therefore become an effective technique for bacterial detection. Within this progress report, advances in the detection of bacteria using SERS and other compatible techniques are discussed in order to summarize its development in recent years. First, the enhancement principle and mechanism of SERS technology are briefly overviewed. The second part is devoted to a label-free strategy for the detection of bacterial cells and bacterial metabolites. In this section, important considerations that must be made to improve bacterial SERS signals are discussed. Then, the label-based SERS strategy involves the design strategy of SERS tags, the immunomagnetic separation of SERS tags, and the capture of bacteria from solution and dye-labeled SERS primers. In the third part, several novel SERS compatible technologies and applications in clinical and food safety are introduced. In the final part, the results achieved are summarized and future perspectives are proposed.
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http://dx.doi.org/10.1002/advs.202001739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710000PMC
December 2020

Cobalt oxide nanoparticle-synergized protein degradation and phototherapy for enhanced anticancer therapeutics.

Acta Biomater 2021 02 28;121:605-620. Epub 2020 Nov 28.

Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL 60612, USA. Electronic address:

How to enable protein degradation pathways including the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) to enhance the efficacy of anticancer treatments remains a substantial challenge. Cobalt oxide nanoparticles (CoO NPs) have attracted interest in recent years for their potential use as a synergistic anticancer treatment, although their therapeutic mechanisms of action are still poorly understood. Here, we describe the synergistic use of CoO NPs as an autophagy inhibitor, chemosensitizer and photosensitizer, which manipulate protein degradation pathways (ALP and UPS) and photothermal therapy for enhanced anticancer treatments both in vitro and in vivo. We show that CoO NPs can induce autolysosome accumulation and lysosomal functions damage by inhibiting lysosomal proteolytic activity and reducing intracellular ATP levels. Notably, CoO NPs can be combined with the proteasome inhibitor, Carfilzomib (Cfz), to promote the accumulation of autophagic substrates, protein ubiquitination, and endoplasmic reticulum stress, and in doing so, inhibit cancer progression. By taking advantage of their photothermal conversion efficiency, CoO NPs can also serve as photothermal sensitizer, which synergistically enhances the anticancer efficacy of Cfz both in vitro and in vivo. In summary, we provide evidence of a nanomaterial-synergized, photothermal anticancer strategy that synergistically targets cancer cell survival pathways and may eventually serve to enhance the anticancer efficacy of established cancer therapeutics.
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http://dx.doi.org/10.1016/j.actbio.2020.11.036DOI Listing
February 2021

Design and analysis of biomarker-integrated clinical trials with adaptive threshold detection and flexible patient enrichment.

J Biopharm Stat 2020 11 11;30(6):1060-1076. Epub 2020 Nov 11.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

We propose a new adaptive threshold detection and enrichment design in which the biomarker threshold is adaptively estimated and updated by optimizing a trade-off between the size of the biomarker positive population and the magnitude of the treatment effect in that population. Enrichment is based on an enrollment criterion that accounts for the uncertainty in estimation of the threshold. Early termination for futility is allowed based on predictive success probability. Valid testing and estimation techniques for the treatment effect overall and inpatient subgroups are studied. Simulations and an example demonstrate advantages of the proposed design over existing designs.
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http://dx.doi.org/10.1080/10543406.2020.1832110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954851PMC
November 2020

Click-Reaction-Triggered SERS Signals for Specific Detection of Monoamine Oxidase B Activity.

Anal Chem 2020 11 26;92(22):15050-15058. Epub 2020 Oct 26.

College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.

Human monoamine oxidases (MAOs) play important roles in maintaining the homeostasis of biogenic amines. One of its isoforms, monoamine oxidase B (MAOB), is thought to be involved in several neurodegenerative diseases, which make the selective detection of MAOB activity essential. In this work, a novel surface-enhanced Raman scattering (SERS) sensor was fabricated and the MAOB activity was specifically determined by detecting the SERS signals of an enzyme-catalyzed reaction product via an amine-aldehyde click reaction. This process was simply achieved by coating core-shell gold-silver nanoparticles (Au@Ag NPs) on 3-aminopropyl aminopropyl triethoxysilane (APTES)-modified glass, and then, a monolayer of cysteamine (CA) was attached to the nanoparticle surface as a linker through Ag-S bonds. Using phenethylamine (PA) as a specific substrate of MAOB, the enzyme product phenylacetaldehyde (PAA) will produce significant Raman signals via the amine-aldehyde click reaction with CA, while other molecules, such as MAOB and PA, have no signal output because they cannot form close interaction with nanoparticles due to the existence of a CA layer. This sensor was further used for the specific determination of MAOB activity in clinical blood samples and the MAOB inhibitor assessment successfully. Meanwhile, by changing the click reaction types and taking advantage of the SERS fingerprint peaks for the specific click reaction products, this strategy offers huge potential to detect multiple enzyme activities simultaneously and can be used for new click reaction screening, enzyme-related disease diagnosis, drug screening, and clinical diagnosis.
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http://dx.doi.org/10.1021/acs.analchem.0c03017DOI Listing
November 2020

Efficacy and Safety of Drug-Eluting Beads Bronchial Arterial Chemoembolization in Treating Patients with Lung Cancer Who Were Complicated with Hemoptysis.

Cancer Biother Radiopharm 2020 Oct 14. Epub 2020 Oct 14.

Department of Radiology, Yichang First People's Hospital, Yichang, China.

This study aimed to explore the effectiveness and safety of drug-eluting beads bronchial arterial chemoembolization (DEB-BACE) in patients with lung cancer who were complicated with hemoptysis. Totally, 11 patients with lung cancer who were complicated with hemoptysis and underwent DEB-BACE treatment were analyzed. Clinical success was defined as no hemoptysis or reduction of hemoptysis volume >50% after treatment. Hemoptysis recurrence was recorded, and overall survival (OS) was calculated. After DEB-BACE treatment, the clinical and technical success was 100%: in detail, 10 (90.0%) patients presented with no hemoptysis and 1 (9.1%) patient exhibited a reduction of hemoptysis volume >50%. Regarding the prognosis, 1 (9.1%) patient had hemoptysis recurrence at 46 d after DEB-BACE treatment. Furthermore, 4 (36.4%) patients died (1 [9.1%] patient died of nonhemoptysis asphyxia; 1 [9.1%] patient died of massive gastrointestinal hemorrhage; 1 [9.1%] patient died of respiratory failure; and 1 [9.1%] patient died of hemoptysis recurrence). Additionally, the mean OS in total patients was 14.2 (95% confidence interval: 8.2-20.3) months. As to adverse events, 1 (9.1%) patient showed high fever, 2 (18.2%) patients exhibited low fever, and 1 (9.1%) patient suffered from chest pain. DEB-BACE can be considered an effective and safe treatment in treating hemoptysis in patients with lung cancer.
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http://dx.doi.org/10.1089/cbr.2020.3954DOI Listing
October 2020

Accelerated failure time model for data from outcome-dependent sampling.

Lifetime Data Anal 2021 01 12;27(1):15-37. Epub 2020 Oct 12.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Outcome-dependent sampling designs such as the case-control or case-cohort design are widely used in epidemiological studies for their outstanding cost-effectiveness. In this article, we propose and develop a smoothed weighted Gehan estimating equation approach for inference in an accelerated failure time model under a general failure time outcome-dependent sampling scheme. The proposed estimating equation is continuously differentiable and can be solved by the standard numerical methods. In addition to developing asymptotic properties of the proposed estimator, we also propose and investigate a new optimal power-based subsamples allocation criteria in the proposed design by maximizing the power function of a significant test. Simulation results show that the proposed estimator is more efficient than other existing competing estimators and the optimal power-based subsamples allocation will provide an ODS design that yield improved power for the test of exposure effect. We illustrate the proposed method with a data set from the Norwegian Mother and Child Cohort Study to evaluate the relationship between exposure to perfluoroalkyl substances and women's subfecundity.
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http://dx.doi.org/10.1007/s10985-020-09508-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856009PMC
January 2021

Association of Cardiovascular Risk Assessment with Early Colorectal Neoplasia Detection in Asymptomatic Population: A Systematic Review and Meta-Analysis.

Clin Epidemiol 2020 11;12:865-873. Epub 2020 Aug 11.

Oncology Department of Shenzhen Hospital of University of Chinese Academy of Sciences, Shenzhen, People's Republic of China.

Previous studies have shown a strong coexistence of colorectal neoplasia (CRN) and cardiovascular diseases (CVD). This study was aimed to summarize the available evidence on association of CVD risk with early CRN detection in asymptomatic populations. PubMed, Web of Science, and Embase were systematically searched for eligible studies published until Dec 20, 2019. Studies exploring the associations of recommended CVD risk assessment methods (e.g., risk scores, carotid artery plaque, and coronary artery calcium score [CACS]) with risk of CRN were included. Meta-analyses were conducted to determine the overall association of CVD risk with the CRN. A total of 12 studies were finally included. The association of carotid artery plaque with the risk of colorectal adenoma (AD) was weakest (pooled odds ratio [OR)] 1.27, 95% confidence interval [CI), 1.12, 1.45]. Participants with CACS>100 had about 2-fold increased risk of AD than those with CACS=0. The pooled ORs were 3.36 (95% CI, 2.15, 5.27) and 2.30 (95% CI, 1.69, 3.13) for the risk of advanced colorectal neoplasia (AN) and AD, respectively, in participants with Framingham risk score (FRS)>20%, when compared to participants at low risk (FRS<10%). FRS might help identify subgroups at increased risk for AN, but further studies are needed.
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http://dx.doi.org/10.2147/CLEP.S262939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429103PMC
August 2020

Design of the footprints of uncertainty for a class of typical interval type-2 fuzzy PI and PD controllers.

ISA Trans 2021 Feb 14;108:1-9. Epub 2020 Aug 14.

College of Mechanical and Electrical Engineering, Central South University, Changsha, Hunan 410083, China; State Key Laboratory of High Performance Complex Manufacturing, Central South University, Changsha, Hunan 410083, China. Electronic address:

The Footprint of Uncertainty (FOU) for an Interval type-2 (IT2) input fuzzy set is a key parameter of IT2 fuzzy PI and PD (FPI and FPD) controllers because it provides additional options to handle uncertainties. Because the effects of FOUs on IT2 FPI and FPD controller are still unclear, it is necessary to provide a guideline for designing the FOUs. In this study, from the input-output relationship of IT2 FPI and FPD controllers using typical and popular configuration, the variation trend of variable gains, in relation to the increase of FOUs, was analyzed. It is mathematically proven that variable gains of typical controllers decrease or not increase as the FOUs increase. These theoretical results can be extended to provide a guideline for designing FOUs of typical IT2 FPI and FPD controllers. Real-time response of linear voice coil motor is used to show the effectiveness of our results.
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http://dx.doi.org/10.1016/j.isatra.2020.08.009DOI Listing
February 2021