Publications by authors named "Tao Cheng"

742 Publications

PUMA facilitates EMI1-promoted cytoplasmic Rad51 ubiquitination and inhibits DNA repair in stem and progenitor cells.

Signal Transduct Target Ther 2021 Mar 31;6(1):129. Epub 2021 Mar 31.

State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

Maintenance of genetic stability via proper DNA repair in stem and progenitor cells is essential for the tissue repair and regeneration, while preventing cell transformation after damage. Loss of PUMA dramatically increases the survival of mice after exposure to a lethal dose of ionizing radiation (IR), while without promoting tumorigenesis in the long-term survivors. This finding suggests that PUMA (p53 upregulated modulator of apoptosis) may have a function other than regulates apoptosis. Here, we identify a novel role of PUMA in regulation of DNA repair in embryonic or induced pluripotent stem cells (PSCs) and immortalized hematopoietic progenitor cells (HPCs) after IR. We found that PUMA-deficient PSCs and HPCs exhibited a significant higher double-strand break (DSB) DNA repair activity via Rad51-mediated homologous recombination (HR). This is because PUMA can be associated with early mitotic inhibitor 1 (EMI1) and Rad51 in the cytoplasm to facilitate EMI1-mediated cytoplasmic Rad51 ubiquitination and degradation, thereby inhibiting Rad51 nuclear translocation and HR DNA repair. Our data demonstrate that PUMA acts as a repressor for DSB DNA repair and thus offers a new rationale for therapeutic targeting of PUMA in regenerative cells in the context of DNA damage.
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http://dx.doi.org/10.1038/s41392-021-00510-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009889PMC
March 2021

Modeling acute erythroid leukemia via CRISPR.

Blood 2021 Mar;137(12):1565-1567

Peking Union Medical College.

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http://dx.doi.org/10.1182/blood.2020010544DOI Listing
March 2021

Single-cell transcriptomics dissects hematopoietic cell destruction and T cell engagement in aplastic anemia.

Blood 2021 Mar 24. Epub 2021 Mar 24.

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Tianjin, China.

Aplastic anemia (AA) is a T cell-mediated autoimmune disorder of the hematopoietic system manifested by severe depletion of the hematopoietic stem and progenitor cells (HSPCs). Nonetheless our understanding of the complex relationship between HSPCs and T cells is still obscure, mainly limited by techniques and the sparsity of HSPCs in the context of bone marrow failure. Here we performed single-cell transcriptome analysis of residual HSPCs and T cells to identify the molecular players from AA patients. We observed that residual HSPCs in AA exhibited lineage-specific alterations in gene expression and transcriptional regulatory networks, indicating a selective disruption of distinct lineage-committed progenitor pools. In particular, HSPCs displayed frequently altered alternative splicing events and skewed patterns of polyadenylation in transcripts related to DNA damage and repair, suggesting a likely role in AA progression to myelodysplastic syndromes. We further identified cell-type-specific ligand-receptor interactions as potential mediators for ongoing HSPCs destruction by T cells. By tracking patients after immunosuppressive therapy (IST), we showed that hematopoiesis remission was incomplete accompanied by IST insensitive interactions between HSPCs and T cells as well as sustained abnormal transcription state. These data collectively constitute the transcriptomic landscape of disrupted hematopoiesis in AA at single-cell resolution, providing new insights into the molecular interactions of engaged T cells with residual HSPCs and render novel therapeutic opportunities for AA.
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http://dx.doi.org/10.1182/blood.2020008966DOI Listing
March 2021

Autobifunctional Mechanism of Jagged Pt Nanowires for Hydrogen Evolution Kinetics via End-to-End Simulation.

J Am Chem Soc 2021 Apr 17;143(14):5355-5363. Epub 2021 Mar 17.

Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon 34141, South Korea.

The extraordinary mass activity of jagged Pt nanowires can substantially improve the economics of the hydrogen evolution reaction (HER). However, it is a great challenge to fully unveil the HER kinetics driven by the jagged Pt nanowires with their multiscale morphology. Herein we present an end-to-end framework that combines experiment, machine learning, and multiscale advances of the past decade to elucidate the HER kinetics catalyzed by jagged Pt nanowires under alkaline conditions. The bifunctional catalysis conventionally refers to the synergistic increase in activity by the combination of two different catalysts. We report that monometals, such as jagged Pt nanowires, can exhibit bifunctional characteristics owing to its complex surface morphology, where one site prefers electrochemical proton adsorption and another is responsible for activation, resulting in a 4-fold increase in the activity. We find that the conventional design guideline that the sites with a 0 eV Gibbs free energy of adsorption are optimal for HER does not hold under alkaline conditions, and rather, an energy between -0.2 and 0.0 eV is shown to be optimal. At the reaction temperatures, the high activity arises from low-coordination-number (≤7) Pt atoms exposed by the jagged surface. Our current demonstration raises an emerging prospect to understand highly complex kinetic phenomena on the nanoscale in full by implementing end-to-end multiscale strategies.
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http://dx.doi.org/10.1021/jacs.0c11261DOI Listing
April 2021

Effects of High and Low Salt Concentrations in Electrolytes at Lithium-Metal Anode Surfaces Using DFT-ReaxFF Hybrid Molecular Dynamics Method.

J Phys Chem Lett 2021 Mar 16;12(11):2922-2929. Epub 2021 Mar 16.

Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, United States.

Due to creating a passivated solid electrolyte interphase (SEI), high concentration (HC) electrolytes demonstrate peculiar physicochemical properties and outstanding electrochemical performance. However, the structures of such SEI remains far from clear. In this work, a ybrid and eactive molecular dynamics (HAIR) scheme is employed to investigate the concentration effect of SEI formation by simulating the reductive degradation reactions of lithium bis(fluorosulfonyl)imide (LiFSI) in 1,3 dioxalane (DOL) electrolytes at concentrations of 1 M, 4 M, and 10 M. The efficient HAIR scheme allows the simulations to reach 1 ns to predict electrolytes' deep products at different concentrations. The simulation findings show that the most critical distinction between HC and its low concentration (LC) analogue is that anion decomposition in HC is much more incomplete when only S-F breaking is observed. These insights are important for the future development of advanced electrolytes by rational design of electrolytes.
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http://dx.doi.org/10.1021/acs.jpclett.1c00279DOI Listing
March 2021

Distribution of ε-Poly-L-lysine Synthetases in Coryneform Bacteria Isolated from Cheese and Human Skin.

Appl Environ Microbiol 2021 Mar 12. Epub 2021 Mar 12.

The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark

ε-poly-L-lysine is a potent antimicrobial produced through fermentation of and used in many Asian countries as a food preservative. It is synthesized and excreted by a special NRPS-like enzyme called Pls. Here we discovered a gene from cheese bacterium that showed high similarity to the Pls from in terms of domain architecture and gene context. By cloning it into with a Pls promoter, we confirmed that its product is indeed ε-poly-L-lysine. A comprehensive sequence analysis suggests that Pls genes are widely spread among coryneform actinobacteria isolated from cheese and human skin; 14 out of 15 isolates and 10 out of 12 isolates contain it in their genomes. This finding raises the possibility that ε-poly-L-lysine as a bioactive secondary metabolite might be produced and play a role in the cheese and skin ecosystems. Every year, microbial contamination causes billions of tons of food wasted and millions of cases of illness. ε-poly-L-lysine has potent, wide spectrum of inhibitory activity and is heat stable and biodegradable. It has been approved for food preservation by an increasing number of countries. ε-poly-L-lysine is produced from the soil bacteria , also a producer of various antibiotic drugs and toxins, and not considered to be a naturally-occurring food component. The frequent finding of in cheese and skin bacteria suggests that ε-poly-L-lysine may naturally exist in cheese and on our skin, and ε-poly-L-lysine producers are not limited to filamentous actinobacteria.
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http://dx.doi.org/10.1128/AEM.01841-20DOI Listing
March 2021

Beam complexity and monitor unit efficiency comparison in two different volumetric modulated arc therapy delivery systems using automated planning.

BMC Cancer 2021 Mar 10;21(1):261. Epub 2021 Mar 10.

Department of Radiation Oncology Physics, Shandong Cancer Hospital and Institute, Cancer Hospital affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China.

Background: To investigate the beam complexity and monitor unit (MU) efficiency issues for two different volumetric modulated arc therapy (VMAT) delivery technologies for patients with left-sided breast cancer (BC) and nasopharyngeal carcinoma (NPC).

Methods: Twelve left-sided BC and seven NPC cases were enrolled in this study. Each delivered treatment plan was optimized in the Pinnacle treatment planning system with the Auto-Planning module for the Trilogy and Synergy systems. Similar planning dose objectives and beam configurations were used for each site in the two different delivery systems to produce clinically acceptable plans. The beam complexity was evaluated in terms of the segment area (SA), segment width (SW), leaf sequence variability (LSV), aperture area variability (AAV), and modulation complexity score (MCS) based on the multileaf collimator sequence and MU. Plan delivery and a gamma evaluation were performed using a helical diode array.

Results: With similar plan quality, the average SAs for the Trilogy plans were smaller than those for the Synergy plans: 55.5 ± 21.3 cm vs. 66.3 ± 17.9 cm (p < 0.05) for the NPC cases and 100.7 ± 49.2 cm vs. 108.5 ± 42.7 cm (p < 0.05) for the BC cases, respectively. The SW was statistically significant for the two delivery systems (NPC: 6.87 ± 1.95 cm vs. 6.72 ± 2.71 cm, p < 0.05; BC: 8.84 ± 2.56 cm vs. 8.09 ± 2.63 cm, p < 0.05). The LSV was significantly smaller for Trilogy (NPC: 0.84 ± 0.033 vs. 0.86 ± 0.033, p < 0.05; BC: 0.89 ± 0.026 vs. 0.90 ± 0.26, p < 0.05). The mean AAV was significantly larger for Trilogy than for Synergy (NPC: 0.18 ± 0.064 vs. 0.14 ± 0.037, p < 0.05; BC: 0.46 ± 0.15 vs. 0.33 ± 0.13, p < 0.05). The MCS values for Trilogy were higher than those for Synergy: 0.14 ± 0.016 vs. 0.12 ± 0.017 (p < 0.05) for the NPC cases and 0.42 ± 0.106 vs. 0.30 ± 0.087 (p < 0.05) for the BC cases. Compared with the Synergy plans, the average MUs for the Trilogy plans were larger: 828.6 ± 74.1 MU and 782.9 ± 85.2 MU (p > 0.05) for the NPC cases and 444.8 ± 61.3 MU and 393.8 ± 75.3 MU (p > 0.05) for the BC cases. The gamma index agreement scores were never below 91% using 3 mm/3% (global) distance to agreement and dose difference criteria and a 10% lower dose exclusion threshold.

Conclusions: The Pinnacle Auto-Planning system can optimize BC and NPC plans to achieve the same plan quality using both the Trilogy and Synergy systems. We found that these two systems resulted in different SAs, SWs, LSVs, AAVs and MCSs. As a result, we suggested that the beam complexity should be considered in the development of further methodologies while optimizing VMAT autoplanning.
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http://dx.doi.org/10.1186/s12885-021-07991-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945217PMC
March 2021

Effectiveness and safety of Liuhedan for treating acute pancreatitis: A protocol for systematic review and meta analysis.

Medicine (Baltimore) 2021 Feb;100(8):e24863

Department of Emergency Medicine.

Background: Liuhedan is a famous traditional Chinese medicine (TCM) formula used to treat acute pancreatitis (AP) in China. However, there is no systematic reviews for the evidence and the therapeutic effectiveness and safety of Liuhedan for treating AP. The aim of this study is to summarize previous evidence, assessing the efficacy and safety of Liuhedan in the treatment of AP.

Methods: We will search the EMBASE, WANFANG DATA, Web of Knowledge, CNKI, PubMed, ClinicalTrials.gov and Cochrane Library from inception to June 30, 2021 to retrieve relevant studies using the search strategy: ("Liuhedan" OR "Liuhe Pill" OR "Liu-He-Dan") AND ("pancreatitis" OR "pancreatitides"). Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic.

Results: This study assessed the efficiency and safety of Liuhedan for treating acute pancreatitis.

Conclusions: This study will provide reliable evidence-based evidence for the clinical application of Liuhedan for treating AP.

Ethics And Dissemination: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.
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http://dx.doi.org/10.1097/MD.0000000000024863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909230PMC
February 2021

Effectiveness and safety of proton pump inhibitors for treating acute pancreatitis: A protocol for systematic review and meta analysis.

Medicine (Baltimore) 2021 Feb;100(8):e24808

Emergency Department.

Background: Previous studies have showed that anti-acid therapy with proton pump inhibitors (PPIs) can inhibit pancreatic secretion and it may be used in treating acute pancreatitis (AP). But at present, there is no systematic reviews for the evidence and the therapeutic effectiveness and safety of anti-acid therapy with PPIs in AP were not unclear. Therefore, we will undertake a systematic review of the literature to summarize previous evidence regarding this topic, in order to clarify the effectiveness and safety of anti-acid therapy with PPIs in AP.

Methods: We will search the EMBASE, WANFANG DATA, Web of Knowledge, China National Knowledge Infrastructure, PubMed, ClinicalTrials.gov and Cochrane Library from inception to June 30,2021 to retrieve relevant studies using the search strategy: ("Proton pump inhibitors" OR "PPI" OR "PPIs" OR "Omeprazole" OR "Tenatoprazole" OR "Pantoprazole" OR "acid suppression therapy" OR "acid suppression drugs") AND ("pancreatitis" OR "pancreatitides"). Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic.

Results: This study assessed the efficiency and safety of proton pump inhibitors for treating acute pancreatitis.

Conclusions: This study will provide reliable evidence-based evidence for the clinical application of PPIs for treating AP.

Ethics And Dissemination: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.
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http://dx.doi.org/10.1097/MD.0000000000024808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909174PMC
February 2021

COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.

Cell 2021 04 3;184(7):1895-1913.e19. Epub 2021 Feb 3.

Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing 100871, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China. Electronic address:

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.
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http://dx.doi.org/10.1016/j.cell.2021.01.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857060PMC
April 2021

Vitronectin-activated αvβ3 and αvβ5 integrin signalling specifies haematopoietic fate in human pluripotent stem cells.

Cell Prolif 2021 Apr 3;54(4):e13012. Epub 2021 Mar 3.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.

Objectives: Vitronectin (VTN) has been widely used for the maintenance and expansion of human pluripotent stem cells (hPSCs) as feeder-free conditions. However, the effect of VTN on hPSC differentiation remains unclear. Here, we investigated the role of VTN in early haematopoietic development of hPSCs.

Materials And Methods: A chemically defined monolayer system was applied to study the role of different matrix or basement membrane proteins in haematopoietic development of hPSCs. The role of integrin signalling in VTN-mediated haematopoietic differentiation was investigated by integrin antagonists. Finally, small interfering RNA was used to knock down integrin gene expression in differentiated cells.

Results: We found that the haematopoietic differentiation of hPSCs on VTN was far more efficient than that on Matrigel that is also often used for hPSC culture. VTN promoted the fate determination of endothelial-haematopoietic lineage during mesoderm development to generate haemogenic endothelium (HE). Moreover, we demonstrated that the signals through αvβ3 and αvβ5 integrins were required for VTN-promoted haematopoietic differentiation. Blocking αvβ3 and αvβ5 integrins by the integrin antagonists impaired the development of HE, but not endothelial-to-haematopoietic transition (EHT). Finally, both αvβ3 and αvβ5 were confirmed acting synergistically for early haematopoietic differentiation by knockdown the expression of αv, β3 or β5.

Conclusion: The established VTN-based monolayer system of haematopoietic differentiation of hPSCs presents a valuable platform for further investigating niche signals involved in human haematopoietic development.
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http://dx.doi.org/10.1111/cpr.13012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016644PMC
April 2021

Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms.

Cell Stem Cell 2021 Mar 22;28(3):502-513.e6. Epub 2021 Feb 22.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China. Electronic address:

The implications of stem cell heterogeneity for disease pathogenesis and therapy are poorly defined. JAK2V617F myeloproliferative neoplasms (MPNs), harboring the same mutation in hematopoietic stem cells (HSCs), display diverse phenotypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These chronic malignant disorders are ideal models to analyze the pathological consequences of stem cell heterogeneity. Single-cell gene expression profiling with parallel mutation detection demonstrated that the megakaryocyte (Mk)-primed HSC subpopulation expanded significantly with enhanced potential in untreated individuals with JAK2V617F ET, driven primarily by the JAK2 mutation and elevated interferon signaling. During treatment, mutant HSCs were targeted preferentially in the Mk-primed HSC subpopulation. Interestingly, homozygous mutant HSCs were forced to re-enter quiescence, whereas their heterozygous counterparts underwent apoptosis. This study provides important evidence for the association of stem cell heterogeneity with the pathogenesis and therapeutic response of a malignant disease.
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http://dx.doi.org/10.1016/j.stem.2021.01.018DOI Listing
March 2021

TWIST1 preserves hematopoietic stem cell function via CACNA1B/Ca2+/mitochondria axis.

Blood 2021 Feb 22. Epub 2021 Feb 22.

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

Mitochondria of hematopoietic stem cells (HSCs) play crucial roles in regulating cell fate and preserving HSC functionality and survival. However, the mechanism underlying its regulation remains poorly understood. Here, we identify transcription factor TWIST1 as a novel regulator of HSC maintenance through modulating mitochondrial function. We demonstrate that Twist1 deletion results in a significantly decreased lymphoid-biased (Ly-biased) HSC frequency, markedly reduced HSC dormancy and self-renewal capacities, and skewed myeloid differentiation in steady-state hematopoiesis. Twist1-deficient HSCs are more compromised in tolerance of irradiation and 5-fluorouracil-induced stresses, and exhibit typical phenotypes of senescence. Mechanistically, Twist1 deletion induces transactivation of voltage-gated calcium channel (VGCC) Cacna1b which exhausts Ly-biased HSCs, impairs genotoxic hematopoietic recovery, and enhances mitochondrial calcium levels, metabolic activity, and reactive oxygen species production. Suppression of VGCC by a calcium channel blocker largely rescues the phenotypic and functional defects in Twist1-deleted HSCs under both steady-state and stress conditions. Collectively, our data, for the first time, characterize TWIST1 as a critical regulator of HSC function acting through the CACNA1B/Ca2+/mitochondria axis, and highlight the importance of Ca2+ in HSC maintenance. These observations provide new insights into the mechanisms for the control of HSC fate.
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http://dx.doi.org/10.1182/blood.2020007489DOI Listing
February 2021

Efficiency of free thyroxine in predicting severity and mortality of patients with acute pancreatitis: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Feb;100(7):e24809

Emergency Department.

Background: Previous studies suggest that free thyroxine may be used as a severity indicator of patients with acute pancreatitis (AP) in emergency department, helping determine the differential care of AP. However, there are no systematic reviews and the association between free thyroxine and AP is still not completely understood. Therefore, we will undertake a systematic review of the literature to summarize previous evidence regarding this topic, in order to clarify whether free thyroxine can help us pick out the mild AP cases.

Methods: : We will search the EMBASE, Web of Knowledge, PubMed, ClinicalTrials.gov, and Cochrane Library from inception to Mar 2021 to retrieve relevant studies using the search strategy: ("free thyroxine") AND (pancreatitis OR pancreatitides). Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic.

Results: : This study proved the efficiency of free thyroxine in predicting the severity of patients with AP.

Conclusions: : This study will provide reliable evidence-based evidence for the clinical application of free thyroxine predicting the severity of patients with AP.

Ethics And Dissemination: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.
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http://dx.doi.org/10.1097/MD.0000000000024809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899895PMC
February 2021

Efficiency of red cell distribution width in predicting severity and mortality of patients with acute pancreatitis: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Feb;100(6):e24658

Emergency Department.

Background: Previous studies have showed that red cell distribution width (RDW) may be an inflammatory status, and it may be used to predict prognosis of acute pancreatitis (AP). However, there are no systematic reviews for the evidence, and the association between RDW and AP is still not completely understood. Therefore, we will undertake a systematic review of the literature to summarize previous evidence regarding this topic, in order to clarify the value of RDW predicting prognosis of patients with AP.

Methods: We will search EMBASE, Web of Knowledge, PubMed, ClinicalTrials.gov and Cochrane Library from their inception to Mar 2021 to retrieve relevant studies. Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic.

Results: This study proved the Efficiency of RDW in predicting mortality and severity of patients with AP. And provided easy method for clinical evaluation for AP patients.

Conclusions: The findings of this systematic review will show the value of RDW predicting prognosis of patients with AP.

Ethics And Dissemination: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.
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http://dx.doi.org/10.1097/MD.0000000000024658DOI Listing
February 2021

Selective CO Electrochemical Reduction Enabled by a Tricomponent Copolymer Modifier on a Copper Surface.

J Am Chem Soc 2021 Feb 11;143(7):2857-2865. Epub 2021 Feb 11.

Joint Center for Artificial Photosynthesis and The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.

Electrochemical CO reduction over Cu could provide value-added multicarbon hydrocarbons and alcohols. Despite recent breakthroughs, it remains a significant challenge to design a catalytic system with high product selectivity. Here we demonstrate that a high selectivity of ethylene (55%) and C products (77%) could be achieved by a highly modular tricomponent copolymer modified Cu electrode, rivaling the best performance using other modified polycrystalline Cu foil catalysts. Such a copolymer can be conveniently prepared by a ring-opening metathesis polymerization, thereby offering a new degree of freedom for tuning the selectivity. Control experiments indicate all three components are essential for the selectivity enhancement. A surface characterization showed that the incorporation of a phenylpyridinium component increased the film robustness against delamination. It was also shown that its superior performance is not due to a morphology change of the Cu underneath. Molecular dynamics (MD) simulations indicate that a combination of increased local CO concentration, increased porosity for gas diffusion, and the local electric field effect together contribute to the increased ethylene and C product selectivity.
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http://dx.doi.org/10.1021/jacs.0c12478DOI Listing
February 2021

Single-cell transcriptomes of peripheral blood cells indicate and elucidate severity of COVID-19.

Sci China Life Sci 2021 Feb 4. Epub 2021 Feb 4.

State Key Laboratory of Experimental Hematology and National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

The blood and immune system of coronavirus disease 2019 (COVID-19) infected patients are dysfunctional, and numerous studies have been conducted to resolve their characteristics and pathogenic mechanisms. Nevertheless, the variations of immune responses along with disease severity have not been comprehensively documented. Here, we profiled the single-cell transcriptomes of 96,313 peripheral blood mononuclear cells (PBMCs) derived from 12 COVID-19 patients (including four moderate, four severe and four critical cases) and three healthy donors. We showed that proliferative CD8 effector T cells with declined immune functions and cytotoxicity accumulated in the critical stage. By contrast, the quantity of natural killer (NK) cells was significantly reduced, while they exhibited enhanced immune activities. Notably, a gradually attenuated responseto COVID-19 along with disease severity was observed in monocytes, in terms of cellular composition, transcriptional discrepancy and transcription factor regulatory network. Furthermore, we identified immune cell-type dependent cytokine signatures distinguishing the severity of COVID-19 patients. In addition, cell interactions between CD8 effector T/NK cells and monocytes mediated by inflammatory cytokines were enhanced in moderate and severe stages, but weakened in critical cases. Collectively, our work uncovers the cellular and molecular players underlying the disordered and heterogeneous immune responses associated with COVID-19 severity, which could provide valuable insights for the treatment of critical COVID-19 patients.
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http://dx.doi.org/10.1007/s11427-020-1880-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872720PMC
February 2021

Variational-LSTM autoencoder to forecast the spread of coronavirus across the globe.

PLoS One 2021 28;16(1):e0246120. Epub 2021 Jan 28.

Department of Civil, Environmental and Geomatic Engineering, Centre for Transport Studies (CTS), University College London (UCL), London, United Kingdom.

Modelling the spread of coronavirus globally while learning trends at global and country levels remains crucial for tackling the pandemic. We introduce a novel variational-LSTM Autoencoder model to predict the spread of coronavirus for each country across the globe. This deep Spatio-temporal model does not only rely on historical data of the virus spread but also includes factors related to urban characteristics represented in locational and demographic data (such as population density, urban population, and fertility rate), an index that represents the governmental measures and response amid toward mitigating the outbreak (includes 13 measures such as: 1) school closing, 2) workplace closing, 3) cancelling public events, 4) close public transport, 5) public information campaigns, 6) restrictions on internal movements, 7) international travel controls, 8) fiscal measures, 9) monetary measures, 10) emergency investment in health care, 11) investment in vaccines, 12) virus testing framework, and 13) contact tracing). In addition, the introduced method learns to generate a graph to adjust the spatial dependences among different countries while forecasting the spread. We trained two models for short and long-term forecasts. The first one is trained to output one step in future with three previous timestamps of all features across the globe, whereas the second model is trained to output 10 steps in future. Overall, the trained models show high validation for forecasting the spread for each country for short and long-term forecasts, which makes the introduce method a useful tool to assist decision and policymaking for the different corners of the globe.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246120PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842932PMC
February 2021

The DFT-ReaxFF Hybrid Reactive Dynamics Method with Application to the Reductive Decomposition Reaction of the TFSI and DOL Electrolyte at a Lithium-Metal Anode Surface.

J Phys Chem Lett 2021 Feb 27;12(4):1300-1306. Epub 2021 Jan 27.

Institute of Functional Nano and Soft Materials, Soochow University, Suzhou 215123, China.

The high energy density and suitable operating voltage make rechargeable lithium ion batteries (LIBs) promising candidates to replace such conventional energy storage devices as nonrechargeable batteries. However, the large-scale commercialization of LIBs is impeded significantly by the degradation of the electrolyte, which reacts with the highly reactive lithium metal anode. Future improvement of the battery performance requires a knowledge of the reaction mechanism that is responsible for the degradation and formation of the solid-electrolyte interphase (SEI). In this work, we develop a hybrid computational scheme, , denoted , to accelerate Quantum Mechanics-based reaction dynamics (QM-MD or AIMD, for ab initio RD) simulations. The HAIR scheme extends the time scale accessible to AIMD by a factor of 10 times through interspersing reactive force field (ReaxFF) simulations between the AIMD parts. This enables simulations of the initial chemical reactions of SEI formation, which may take 1 ns, far too long for AIMD. We apply the HAIR method to the bis(trifluoromethanesulfonyl)imide (TFSI) electrolyte in 1,3-dioxolane (DOL) solvent at the Li metal electrode, demonstrating that HAIR reproduces the initial reactions of the electrolyte (decomposition of TFSI) previously observed in AIMD simulation while also capturing solvent reactions (DOL) that initiate by ring-opening to form such stable products as CO, CHO, and CH, as observed experimentally. These results demonstrate that the HAIR scheme can significantly increase the time scale for reactive MD simulations while retaining the accuracy of AIMD simulations. This enables a full atomistic description of the formation and evolution of SEI.
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http://dx.doi.org/10.1021/acs.jpclett.0c03720DOI Listing
February 2021

High incidence of MYD88 and KMT2D mutations in Chinese with chronic lymphocytic leukemia.

Leukemia 2021 Jan 22. Epub 2021 Jan 22.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Blood Diseases Hospital & Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

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http://dx.doi.org/10.1038/s41375-021-01124-5DOI Listing
January 2021

Crossover between the adiabatic and nonadiabatic electron transfer limits in the Landau-Zener model.

Nat Commun 2021 01 19;12(1):456. Epub 2021 Jan 19.

Department of Chemistry, Jinan University, 601 Huang-Pu Avenue West, Guangzhou, 510632, China.

The semiclassical models of nonadiabatic transition were proposed first by Landau and Zener in 1932, and have been widely used in the study of electron transfer (ET); however, experimental demonstration of the Landau-Zener formula remains challenging to observe. Herein, employing the Hush-Marcus theory, thermal ET in mixed-valence complexes {[Mo]-(ph)-[Mo]} (n = 1-3) has been investigated, spanning the nonadiabatic throughout the adiabatic limit, by analysis of the intervalence transition absorbances. Evidently, the Landau-Zener formula is valid in the adiabatic regime in a broader range of conditions than the theoretical limitation known as the narrow avoided-crossing. The intermediate system is identified with an overall transition probability (κ) of ∼0.5, which is contributed by the single and the first multiple passage. This study shows that in the intermediate regime, the ET kinetic results derived from the adiabatic and nonadiabatic formalisms are nearly identical, in accordance with the Landau-Zener model. The obtained insights help to understand and control the ET processes in biological and chemical systems.
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http://dx.doi.org/10.1038/s41467-020-20557-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815917PMC
January 2021

HDAC inhibitors improve CRISPR-mediated HDR editing efficiency in iPSCs.

Sci China Life Sci 2021 Jan 6. Epub 2021 Jan 6.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

Genome-edited human induced pluripotent stem cells (iPSCs) hold great promise for therapeutic applications. However, low editing efficiency has hampered the applications of CRISPR-Cas9 technology in creating knockout and homology-directed repair (HDR)-edited iPSC lines, particularly for silent genes. This is partially due to chromatin compaction, inevitably limiting Cas9 access to the target DNA. Among the six HDAC inhibitors we examined, vorinostat, or suberoylanilide hydroxamic acid (SAHA), led to the highest HDR efficiency at both open and closed loci, with acceptable toxicity. HDAC inhibitors equally increased non-homologous end joining (NHEJ) editing efficiencies (∼50%) at both open and closed loci, due to the considerable HDAC inhibitor-mediated increase in Cas9 and sgRNA expression. However, we observed more substantial HDR efficiency improvement at closed loci relative to open chromatin (2.8 vs. 1.1-fold change). These studies provide a new strategy for HDR-editing of silent genes in iPSCs.
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http://dx.doi.org/10.1007/s11427-020-1855-4DOI Listing
January 2021

Integrated decoding hematopoiesis and leukemogenesis using single-cell sequencing and its medical implication.

Cell Discov 2021 Jan 5;7(1). Epub 2021 Jan 5.

Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China.

Single-cell RNA sequencing provides exciting opportunities to unbiasedly study hematopoiesis. However, our understanding of leukemogenesis was limited due to the high individual differences. Integrated analyses of hematopoiesis and leukemogenesis potentially provides new insights. Here we analyzed ~200,000 single-cell transcriptomes of bone marrow mononuclear cells (BMMCs) and its subsets from 23 clinical samples. We constructed a comprehensive cell atlas as hematopoietic reference. We developed counterpart composite index (CCI; available at GitHub: https://github.com/pengfeeei/cci) to search for the healthy counterpart of each leukemia cell subpopulation, by integrating multiple statistics to map leukemia cells onto reference hematopoietic cells. Interestingly, we found leukemia cell subpopulations from each patient had different healthy counterparts. Analysis showed the trajectories of leukemia cell subpopulations were similar to that of their healthy counterparts, indicating that developmental termination of leukemia initiating cells at different phases leads to different leukemia cell subpopulations thus explained the origin of leukemia heterogeneity. CCI further predicts leukemia subtypes, cellular heterogeneity, and cellular stemness of each leukemia patient. Analyses of leukemia patient at diagnosis, refractory, remission and relapse vividly presented dynamics of cell population during leukemia treatment. CCI analyses showed the healthy counterparts of relapsed leukemia cells were closer to the root of hematopoietic tree than that of other leukemia cells, although single-cell transcriptomic genetic variants and haplotype tracing analyses showed the relapsed leukemia cell were derived from an early minor leukemia cell population. In summary, this study developed a unified framework for understanding leukemogenesis with hematopoiesis reference, which provided novel biological and medical implication.
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http://dx.doi.org/10.1038/s41421-020-00223-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788081PMC
January 2021

Dynamics and competition of CRISPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing.

Nucleic Acids Res 2021 01;49(2):969-985

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.

Investigations of CRISPR gene knockout editing profiles have contributed to enhanced precision of editing outcomes. However, for homology-directed repair (HDR) in particular, the editing dynamics and patterns in clinically relevant cells, such as human iPSCs and primary T cells, are poorly understood. Here, we explore the editing dynamics and DNA repair profiles after the delivery of Cas9-guide RNA ribonucleoprotein (RNP) with or without the adeno-associated virus serotype 6 (AAV6) as HDR donors in four cell types. We show that editing profiles have distinct differences among cell lines. We also reveal the kinetics of HDR mediated by the AAV6 donor template. Quantification of T50 (time to reach half of the maximum editing frequency) indicates that short indels (especially +A/T) occur faster than longer (>2 bp) deletions, while the kinetics of HDR falls between NHEJ (non-homologous end-joining) and MMEJ (microhomology-mediated end-joining). As such, AAV6-mediated HDR effectively outcompetes the longer MMEJ-mediated deletions but not NHEJ-mediated indels. Notably, a combination of small molecular compounds M3814 and Trichostatin A (TSA), which potently inhibits predominant NHEJ repairs, leads to a 3-fold increase in HDR efficiency.
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http://dx.doi.org/10.1093/nar/gkaa1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826255PMC
January 2021

Human umbilical cord-derived mesenchymal stem cell therapy ameliorates lupus through increasing CD4+ T cell senescence via MiR-199a-5p/Sirt1/p53 axis.

Theranostics 2021 1;11(2):893-905. Epub 2021 Jan 1.

Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008 China.

: Although human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation has been proved to be an effective therapeutic approach to treat systemic lupus erythematosus (SLE), the detailed underlying mechanisms are not fully understood. Transferring miRNAs is one mean by which MSCs communicate with surrounding cells. Sirt1 is a NAD-dependent deacetylase that protects against cell senescence by deacetylating p53. Here we aimed to explore whether hUC-MSCs affected senescence of splenic CD4+ T cells through regulating Sirt1/p53 via miRNA in the MRL/ lupus mouse model. : The effects of hUC-MSCs on lupus syndrome and senescence pathways in MRL/ mice and were determined. The functional roles of miR-199a-5p in splenic CD4+ T cell senescence were studied by miRNA mimic or inhibitor MRL mice were injected with miR-199a-5p agomir to evaluate the effects of miR-199a-5p on splenic CD4+ T cell senescence and disease : We showed that hUC-MSCs transplantation ameliorated lupus symptoms and increased senescence of splenic CD4+ T cells through Sirt1/p53 signaling via miR-199a-5p in MRL/ mice. Moreover, systemic delivery of miR-199a-5p in MRL/ mice increased splenic CD4+ T-cell senescence, mimicking the therapeutic effects of transplanted hUC-MSCs. : We have identified miR-199a-5p as one of the mechanisms employed by hUC-MSCs to alleviate lupus disease associated pathologies in MRL/ mice, which is attributable for promoting splenic CD4+ T cell senescence through Sirt1/p53 pathway.
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http://dx.doi.org/10.7150/thno.48080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738872PMC
January 2021

Incidence and risk factors of delirium after percutaneous coronary intervention in individuals hospitalised for acute myocardial infarction: protocol for a systematic review and meta-analysis.

BMJ Open 2020 12 30;10(12):e044564. Epub 2020 Dec 30.

Intensive Care Unit, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 519000, China

Introduction: Delirium in the postoperative period is a wide-reaching problem that affects important clinical outcomes. The incidence and risk factors of delirium in individuals with acute myocardial infarction (AMI) after primary percutaneous coronary intervention (PCI) has not been completely determined and no relevant systematic review and meta-analysis of incidence or risk factors exists. Hence, we aim to conduct a systematic review and meta-analysis to ascertain the incidence and risk factors of delirium among AMI patients undergoing PCI.

Methods And Analyses: We will undertake a comprehensive literature search among PubMed, EMBASE, Cochrane Library, PsycINFO, CINAHL and Google Scholar from their inception to the search date. Prospective cohort and cross-sectional studies that described the incidence or at least one risk factor of delirium will be eligible for inclusion. The primary outcome will be the incidence of postoperative delirium. The quality of included studies will be assessed using a risk of bias tool for prevalence studies and the Cochrane guidelines. Heterogeneity of the estimates across studies will be assessed. Incidence and risk factors associated with delirium will be extracted. Incidence data will be pooled. Each risk factor reported in the included studies will be recorded together with its statistical significance; narrative and meta-analytical approaches will be employed. The systematic review and meta-analysis will be presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Ethics And Dissemination: This proposed systematic review and meta-analysis is based on published data, and thus there is no requirement for ethics approval. The study will provide an up to date and accurate incidence and risk factors of delirium after PCI among patients with AMI, which is necessary for future research in this area. The findings of this study will be disseminated through publication in a peer-reviewed journal.

Prospero Registration Number: CRD42020184388.
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http://dx.doi.org/10.1136/bmjopen-2020-044564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780515PMC
December 2020

Trifluorinated Keto-Enol Tautomeric Switch in Probing Domain Rotation of a G Protein-Coupled Receptor.

Bioconjug Chem 2021 Jan 30;32(1):99-105. Epub 2020 Dec 30.

Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida 33620, United States.

Conformational dynamics and transitions of biologically active molecules are pivotal for understanding the physiological responses they elicit. In the case of receptor activation, there are major implications elucidating disease mechanisms and drug discovery innovation. Yet, incorporation of these factors into drug screening systems remains challenging in part due to the lack of suitable approaches to include them. Here, we present a novel strategy to probe the GPCR domain rotation by utilizing the fluorine signal variability of a trifluorinated keto-enol (TFKE) chemical equilibrium. The method takes advantage of the high sensitivity of the TFKE tautomerism toward microenvironmental changes resulting from receptor conformational transitions upon ligand binding. We validated the method using the adenosine AR receptor as a model system in which the TFKE was attached to two sites exhibiting opposing motions upon ligand binding, namely, V229C on transmembrane domain VI (TM6) and A289C on TM7. Our results demonstrated that the TFKE switch was an excellent reporter for the domain rotation and could be used to study the conformational transition and dynamics of relative domain motions. Although further studies are needed in order to establish a quantitative relationship between the rotational angle and the population distribution of different components in a particular system, the research presented here provides a foundation for its application in studying receptor domain rotation and dynamics, which could be useful in drug screening efforts.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00670DOI Listing
January 2021