Publications by authors named "Yongzheng Li"

14 Publications

  • Page 1 of 1

Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines.

Cell Res 2021 May 21. Epub 2021 May 21.

School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.

SARS-CoV-2 variants could induce immune escape by mutations on the receptor-binding domain (RBD) and N-terminal domain (NTD). Here we report the humoral immune response to circulating SARS-CoV-2 variants, such as 501Y.V2 (B.1.351), of the plasma and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine), ZF2001 (RBD-subunit vaccine) and natural infection. Among 86 potent NAbs identified by high-throughput single-cell VDJ sequencing of peripheral blood mononuclear cells from vaccinees and convalescents, near half anti-RBD NAbs showed major neutralization reductions against the K417N/E484K/N501Y mutation combination, with E484K being the dominant cause. VH3-53/VH3-66 recurrent antibodies respond differently to RBD variants, and K417N compromises the majority of neutralizing activity through reduced polar contacts with complementarity determining regions. In contrast, the 242-244 deletion (242-244Δ) would abolish most neutralization activity of anti-NTD NAbs by interrupting the conformation of NTD antigenic supersite, indicating a much less diversity of anti-NTD NAbs than anti-RBD NAbs. Plasma of convalescents and CoronaVac vaccinees displayed comparable neutralization reductions against pseudo- and authentic 501Y.V2 variants, mainly caused by E484K/N501Y and 242-244Δ, with the effects being additive. Importantly, RBD-subunit vaccinees exhibit markedly higher tolerance to 501Y.V2 than convalescents, since the elicited anti-RBD NAbs display a high diversity and are unaffected by NTD mutations. Moreover, an extended gap between the third and second doses of ZF2001 leads to better neutralizing activity and tolerance to 501Y.V2 than the standard three-dose administration. Together, these results suggest that the deployment of RBD-vaccines, through a third-dose boost, may be ideal for combating SARS-CoV-2 variants when necessary, especially for those carrying mutations that disrupt the NTD supersite.
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http://dx.doi.org/10.1038/s41422-021-00514-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138844PMC
May 2021

Periosteal Tissue Engineering: Current Developments and Perspectives.

Adv Healthc Mater 2021 May 3:e2100215. Epub 2021 May 3.

Department of Stomatology, The Ningbo Hospital of Zhejiang University, and Ningbo First Hospital, 59 Liuting street, Ningbo, Zhejiang, 315000, China.

Periosteum, a highly vascularized bilayer connective tissue membrane plays an indispensable role in the repair and regeneration of bone defects. It is involved in blood supply and delivery of progenitor cells and bioactive molecules in the defect area. However, sources of natural periosteum are limited, therefore, there is a need to develop tissue-engineered periosteum (TEP) mimicking the composition, structure, and function of natural periosteum. This review explores TEP construction strategies from the following perspectives: i) different materials for constructing TEP scaffolds; ii) mechanical properties and surface topography in TEP; iii) cell-based strategies for TEP construction; and iv) TEP combined with growth factors. In addition, current challenges and future perspectives for development of TEP are discussed.
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http://dx.doi.org/10.1002/adhm.202100215DOI Listing
May 2021

NEPdb: A Database of T-Cell Experimentally-Validated Neoantigens and Pan-Cancer Predicted Neoepitopes for Cancer Immunotherapy.

Front Immunol 2021 13;12:644637. Epub 2021 Apr 13.

State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.

T-cell recognition of somatic mutation-derived cancer neoepitopes can lead to tumor regression. Due to the difficulty to identify effective neoepitopes, constructing a database for sharing experimentally validated cancer neoantigens will be beneficial to precise cancer immunotherapy. Meanwhile, the routine neoepitope prediction is important but laborious for clinical use. Here we present NEPdb, a database that contains more than 17,000 validated human immunogenic neoantigens and ineffective neoepitopes within human leukocyte antigens (HLAs) curating published literature with our semi-automatic pipeline. Furthermore, NEPdb also provides pan-cancer level predicted HLA-I neoepitopes derived from 16,745 shared cancer somatic mutations, using state-of-the-art predictors. With a well-designed search engine and visualization modes, this database would enhance the efficiency of neoantigen-based cancer studies and treatments. NEPdb is freely available at http://nep.whu.edu.cn/.
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http://dx.doi.org/10.3389/fimmu.2021.644637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078594PMC
April 2021

Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy.

Oncoimmunology 2021 01 15;10(1):1868130. Epub 2021 Jan 15.

State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.

Genetic mutations lead to the production of mutated proteins from which peptides are presented to T cells as cancer neoantigens. Evidence suggests that T cells that target neoantigens are the main mediators of effective cancer immunotherapies. Although algorithms have been used to predict neoantigens, only a minority are immunogenic. The factors that influence neoantigen immunogenicity are not completely understood. Here, we classified human neoantigen/neopeptide data into three categories based on their TCR-pMHC binding events. We observed a conservative mutant orientation of the anchor residue from immunogenic neoantigens which we termed the "NP" rule. By integrating this rule with an existing prediction algorithm, we found improved performance in neoantigen prioritization. To better understand this rule, we solved several neoantigen/MHC structures. These structures showed that neoantigens that follow this rule not only increase peptide-MHC binding affinity but also create new TCR-binding features. These molecular insights highlight the value of immune-based classification in neoantigen studies and may enable the design of more effective cancer immunotherapies.
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http://dx.doi.org/10.1080/2162402X.2020.1868130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833777PMC
January 2021

Effects of nursing methods for emergency pci and non-emergency PCI on the treatment of patients with acute myocardial infarction.

J Pak Med Assoc 2020 Sep;70 [Special Issue](9):31-37

Department of Anus & Intestine, Hiser Hospital, Shibei District, Qingdao, Shandong, China.

Objective: To study the effect of emergency nursing methods on the treatment of acute myocardial infarction (AMI).

Methods: A total of 100 patients with AMI were divided into emergency percutaneous coronary intervention (PCI) group (group A, 50 cases) and non-emergency PCI control group (group B, 50 cases). The clinical outcome, average left ventricular ejection fraction (LVEF), angina pectoris, heart failure, and reperfusion arrhythmia after myocardial infarction were compared between the two groups.

Results: The average hospitalization days of emergency PCI group were less than those of the control group, and the incidence of angina pectoris and heart failure after myocardial infarction was lower than that of the control group. The average LVEF of emergency PCI group was higher than that of the control group.

Conclusions: This shows that emergency nursing of AMI can quickly and efficiently dredge the infarcted artery, reduce the occurrence of cardiovascular events after AMI and the average hospitalization days of patients, improve the left ventricular function and prevent heart failure. This method is a very effective treatment for improving the prognosis in patients with AMI.
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September 2020

Macrophages in pancreatic cancer: An immunometabolic perspective.

Cancer Lett 2021 02 26;498:188-200. Epub 2020 Oct 26.

Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China. Electronic address:

As one of the most fatal gastrointestinal cancers, pancreatic cancer (PC) has a long-term survival rate that has shown limited improvement during recent decades and remains dismal. The poor prognosis is attributed to challenges in early detection, low opportunity for radical resection and resistance to chemotherapy and radiation. Macrophages are one of the most abundant infiltrating immune cells in PC stroma, and they can crosstalk with cancer cells, adipocytes and other stromal cells to modulate metabolism, inflammation and immune status, create an immunosuppressive tumor microenvironment (TME), and ultimately facilitate tumor initiation and progression. In this review, we summarize recent advances in our understanding of macrophage origin, distribution and polarization, as well as provide a thorough review of the role macrophages in PC carcinogenesis and development, as well as the underlying molecular mechanism. Additionally, we investigated macrophage targets in preclinical and clinical trials to evaluate their potential therapeutic value in PC.
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http://dx.doi.org/10.1016/j.canlet.2020.10.029DOI Listing
February 2021

Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis.

Front Cell Dev Biol 2020 22;8:868. Epub 2020 Sep 22.

The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Neural epidermal growth factor-like 1 protein (Nell-1) is first studied because of its association with human craniosynostosis. Nell-1 has been used to accelerate the process of fracture healing because of the osteoinductive ability in recent years. However, the role of Nell-1 during the process of osteointegration is unknown. Here we show that activation of Nell-1 in the BMSC sheet promotes osseointegration and . We found that overexpression of Nell-1 improved osteogenic differentiation and enhanced matrix mineralization of BMSCs through increasing expression of Runx2 and Osterix. Activation of Nell-1 up-regulated the expression ratio of OPG/RANKL, which might have a negative influence on osteoclast differentiation. Furthermore, we obtained BMSC sheet-implant complexes transfected with lentivirus overexpressing and interfering Nell-1 in study, and confirmed that overexpression of Nell-1 promoted new bone formation around the implant and increased the bone-implant contacting area percentage. Our results demonstrate that activation of Nell-1 improves implant osteointegration by regulating Runx2/Osterix axis and shows the potential of BMSC sheet-implant complexes in gene therapy.
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http://dx.doi.org/10.3389/fcell.2020.00868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536315PMC
September 2020

Adenovirus-Mediated LAMA3 Transduction Enhances Hemidesmosome Formation and Periodontal Reattachment during Wound Healing.

Mol Ther Methods Clin Dev 2020 Sep 4;18:291-303. Epub 2020 Jun 4.

Department of Implantology, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.

A robust dento-epithelial junction prevents external pathogenic factors from entering connective tissue and could be crucial for periodontal reattachment after periodontal surgery. The junctional epithelium (JE) is attached to the tooth surface through the hemidesmosome (HD) and internal basal lamina, where the primary component is laminin-332. Destruction of the JE leads to the loss of periodontal attachment. Traditional treatments are effective in eliminating local inflammation of the gingiva; however, few directly promote periodontal reattachment and HD formation. Here, we designed a gene-therapy strategy using the adenovirus-mediated human laminin-332 α3 chain (LAMA3) gene (Ad-LAMA3) transduced into a human-immortalized epidermal cell line (HaCaT) to study the formation of HD . Ad-LAMA3 promoted early adhesion and fast migration of HaCaT cells and increased expression of LAMA3 and type XVII collagen (BP180) significantly. Furthermore, HaCaT cells could facilitate formation of mature HDs after LAMA3 overexpression. experiments demonstrated that the JE transduced with Ad-LAMA3 could increase expression of LAMA3 and BP180 and "biological sealing" between the tooth and gingival epithelium. These results suggested that adenovirus-mediated LAMA3 transduction is a novel therapeutic strategy that promotes the stability and integration of the JE around the tooth during wound healing.
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http://dx.doi.org/10.1016/j.omtm.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334303PMC
September 2020

Surfce Functionalized via AdLAMA3 Multilayer Coating for Re-epithelization Around Titanium Implants.

Front Bioeng Biotechnol 2020 11;8:624. Epub 2020 Jun 11.

The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, China.

The peri-implant epithelium (PIE) forms a crucial seal between the oral environment and the implant surface. Compared with the junctional epithelium (JE), the biological sealing of PIE is fragile, which lacks hemidesmosomes (HDs) and internal basal lamina (extracellular matrix containing laminin332, IBL) on the upper part of the interface. In the study, we aim to prepare a coating with good biocompatibility and ability to immobilize the recombinant adenovirus vector of LAMA3 (AdLAMA3) for promoting the re-epithelization of PIE. The titanium surface functionalized with AdLAMA3 was established via layer-by-layer assembly technique and antibody-antigen specific binding. The biological evaluations including cell adhesion and the re-epithelization of PIE were investigated. The results demonstrated that the AdLAMA3 coating could improve epithelial cell attachment and cell spreading in the early stage. experiments indicated that the AdLAMA3 coating on the implant surface has the potential to accelerate the healing of the PIE, and could promote the expression of laminin α3 and the formation of hemidesmosomes. This study might provide a novel approach and experimental evidence for the precise attachment of LAMA3 to titanium surfaces. The process could improve the re-epithelization of PIE.
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http://dx.doi.org/10.3389/fbioe.2020.00624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300264PMC
June 2020

Superresolution imaging reveals spatiotemporal propagation of human replication foci mediated by CTCF-organized chromatin structures.

Proc Natl Acad Sci U S A 2020 06 15;117(26):15036-15046. Epub 2020 Jun 15.

State Key Laboratory of Membrane Biology, Peking University, 100871 Beijing, China;

Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome. However, it remains unclear whether the replication origins within each RD are activated stochastically or preferentially near certain chromatin features. To understand how DNA replication in single human cells is regulated at the sub-RD level, we directly visualized and quantitatively characterized the spatiotemporal organization, morphology, and in situ epigenetic signatures of individual replication foci (RFi) across S-phase at superresolution using stochastic optical reconstruction microscopy. Importantly, we revealed a hierarchical radial pattern of RFi propagation dynamics that reverses directionality from early to late S-phase and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a "CTCF-organized REplication Propagation" (CoREP) model, which suggests a nonrandom selection mechanism for replication activation at the sub-RD level during early S-phase, mediated by CTCF-organized chromatin structures. Collectively, these findings offer critical insights into the key involvement of local epigenetic environment in coordinating DNA replication across the genome and have broad implications for our conceptualization of the role of multiscale chromatin architecture in regulating diverse cell nuclear dynamics in space and time.
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http://dx.doi.org/10.1073/pnas.2001521117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334649PMC
June 2020

HOXA10 inhibit the osteogenic differentiation of periodontal ligament stem cells by regulating β-catenin localization and DKK1 expression.

Connect Tissue Res 2020 Apr 27:1-9. Epub 2020 Apr 27.

The Affiliated Stomatology Hospital, Zhejiang University, School of Medicine, Hangzhou, China.

: Human periodontal ligament stem cells (hPDLSCs) are stem cells found near the tooth periodontal ligament. These cels are involved in the regeneration of the periodontal ligament and alveolar bone during orthodontic treatment and chronic periodontitis.: The Homeobox gene HOXA10 regulates the osteogenic differentiation of stem cells. However, the role of HOXA10 in hPDLSCs remains unclear. Therefore, we studied the effects of HOXA10 on human PDLSC osteogenic differentiation .: First, hPDLSCs were isolated and characterized. Second, we assessed the effects of overexpression and knockdown of HOXA10 on PDLSC osteogenic differentiation. Finally, the specific Wnt signaling pathway activator lithium chloride (LiCl) and inhibitor ICG-001 were used to investigate the involvement of the Wnt signaling pathway in HOXA10-induced regulation of osteogenic differentiation.: Overexpressing HOXA10 inhibited PDLSC osteogenic differentiation , shown by ALP and Alizarin Red staining, while HOXA10 knockdown demonstrated the opposite effects. HOXA10 negatively regulated nuclear β-catenin and osteogenic differentiation markers including alkaline phosphatase () and integrin-binding sialoprotein (). Upregulating HOXA10 reduced nuclear β-catenin and increased DKK1 expression. However, HOXA10 knockdown enhanced nuclear β-catenin accumulation and reduced DKK1 expression. These negative effects on osteogenic differentiation by HOXA10 overexpression were restored by the Wnt/β-catenin pathway activator LiCl. The increased osteogenic differentiation effects of HOXA10 knockdown were antagonized by ICG-001, a Wnt pathway inhibitor.: These data demonstrate that HOXA10 inhibits the osteogenic differentiation of periodontal ligament stem cells by regulating β-catenin localization and DKK1.
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http://dx.doi.org/10.1080/03008207.2020.1756271DOI Listing
April 2020

A Cas12a ortholog with stringent PAM recognition followed by low off-target editing rates for genome editing.

Genome Biol 2020 03 25;21(1):78. Epub 2020 Mar 25.

State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, China.

Background: AsCas12a and LbCas12a nucleases are reported to be promising tools for genome engineering with protospacer adjacent motif (PAM) TTTV as the optimal. However, the C-containing PAM (CTTV, TCTV, TTCV, etc.) recognition by Cas12a might induce extra off-target edits at these non-canonical PAM sites.

Results: Here, we identify a novel Cas12a nuclease CeCas12a from Coprococcus eutactus, which is a programmable nuclease with genome-editing efficiencies comparable to AsCas12a and LbCas12a in human cells. Moreover, CeCas12a is revealed to be more stringent for PAM recognition in vitro and in vivo followed by very low off-target editing rates in cells. Notably, CeCas12a renders less off-target edits located at C-containing PAM at multiple sites compared to LbCas12a and AsCas12a, as assessed by targeted sequencing methods.

Conclusions: Our study shows that CeCas12a nuclease is active in human cells and the stringency of PAM recognition could be an important factor shaping off-target editing in gene editing. Thus, CeCas12a provides a promising candidate with distinctive characteristics for research and therapeutic applications.
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http://dx.doi.org/10.1186/s13059-020-01989-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093978PMC
March 2020

BMP2-mimicking peptide modified with E7 coupling to calcined bovine bone enhanced bone regeneration associating with activation of the Runx2/SP7 signaling axis.

J Biomed Mater Res B Appl Biomater 2020 01 25;108(1):80-93. Epub 2019 Mar 25.

Department of Implantology, Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

Commercial bone substitute, such as calcined bovine bone (CBB), is currently extensively used as an alternative to autogenous bone. However, CBB lacks osteoinductivity and merely serves as a scaffold for native bone formation. To address this issue, we designed and prepared a heptaglutamate (E7)-modified BMP2-mimicking peptide (7E) and carried out a series of comprehensive physical characterizations and in vivo and in vitro studies to evaluate its role in the repair of cranial defects. The data elucidated that the amount of peptide anchoring to the bone graft materials was remarkably increased after modified with E7. Of note, 7E had a relatively stable and durable release, which promoted the osteogenic differentiation of rat derived bone marrow mesenchymal stem cells (BMSCs) and enhanced the bone regeneration of a rabbit calvarial defect by regulating the expression of the Runx2/SP7 axis. In summary, the composite biomaterials incorporating the E7-modified BMP2-mimicking peptide and CBB prepared in this study is a novel bone augmentation material with the merits of non-immunotoxicity, convenience, and low cost. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:80-93, 2020.
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http://dx.doi.org/10.1002/jbm.b.34368DOI Listing
January 2020

Sustained Release of Antimicrobial Peptide from Self-Assembling Hydrogel Enhanced Osteogenesis.

J Biomater Sci Polym Ed 2018 10 29;29(15):1812-1824. Epub 2018 Sep 29.

c Department of Oral Medicine , Stomatology Hospital, School of Medicine, Zhejiang University , Hangzhou , P. R. China.

Biomaterials have been widely used in bone infection and osteomyelitis resulting from their versatile functionalities. As far as we know, the appearance of osteomyelitis was mainly caused by bacteria. Therefore, a biomaterial that can cure bone infection and promote osteogenesis may become an ideal candidate for the treatment of osteomyelitis. Cationic antimicrobial peptides (AMPs) have been proved to have an excellent ability to kill bacteria, fungi, viruses, and parasites. However, the application of AMPs in bone infection and osteomyelitis is quite limited. Here, we designed a new hydrogel that has an inhibitory effect on the proliferation of S. aureus and enhances osteogenesis. RADA16 self-assembling peptide has been applied for AMPs delivery. In this study, we demonstrated that RADA16 could form a stable structure and afford the sustained release of AMPs. The interwoven nanofiber morphology was detected by field emission scanning electron microscopy. The sustained release study revealed that the release of AMPs could be obtained until 28 days. In vitro research showed this new self-assembling hydrogel could promote the proliferation of bone mesenchymal stem cells (BMSCs) and inhibited the growth of S. aureus. More importantly, the results in vivo also proved that RADA16-AMP self-assembling peptide had an excellent effect on bone formation. Our findings implied that we successfully combined RADA16 and AMPs together and laid the foundation for the application of this new hydrogel and open new avenues for biomaterials.
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http://dx.doi.org/10.1080/09205063.2018.1504191DOI Listing
October 2018