Publications by authors named "Fengchao Wang"

160 Publications

CD63 acts as a functional marker in maintaining hematopoietic stem cell quiescence through supporting TGFβ signaling in mice.

Cell Death Differ 2021 Aug 6. Epub 2021 Aug 6.

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.

Hematopoietic stem cell (HSC) fate is tightly controlled by various regulators, whereas the underlying mechanism has not been fully uncovered due to the high heterogeneity of these populations. In this study, we identify tetraspanin CD63 as a novel functional marker of HSCs in mice. We show that CD63 is unevenly expressed on the cell surface in HSC populations. Importantly, HSCs with high CD63 expression (CD63) are more quiescent and have more robust self-renewal and myeloid differentiation abilities than those with negative/low CD63 expression (CD63). On the other hand, using CD63 knockout mice, we find that loss of CD63 leads to reduced HSC numbers in the bone marrow. In addition, CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity, accompanied by increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations demonstrate that CD63 is required to sustain TGFβ signaling activity through its interaction with TGFβ receptors I and II, thereby playing an important role in regulating the quiescence of HSCs. Collectively, our data not only reveal a previously unrecognized role of CD63 but also provide us with new insights into HSC heterogeneity.
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http://dx.doi.org/10.1038/s41418-021-00848-2DOI Listing
August 2021

Hydrophilicity gradient in covalent organic frameworks for membrane distillation.

Nat Mater 2021 Jul 22. Epub 2021 Jul 22.

Frontiers Science Center for High Energy Material, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, P. R. China.

Desalination can help to alleviate the fresh-water crisis facing the world. Thermally driven membrane distillation is a promising way to purify water from a variety of saline and polluted sources by utilizing low-grade heat. However, membrane distillation membranes suffer from limited permeance and wetting owing to the lack of precise structural control. Here, we report a strategy to fabricate membrane distillation membranes composed of vertically aligned channels with a hydrophilicity gradient by engineering defects in covalent organic framework films by the removal of imine bonds. Such functional variation in individual channels enables a selective water transport pathway and a precise liquid-vapour phase change interface. In addition to having anti-fouling and anti-wetting capability, the covalent organic framework membrane on a supporting layer shows a flux of 600 l m h with 85 °C feed at 16 kPa absolute pressure, which is nearly triple that of the state-of-the-art membrane distillation membrane for desalination. Our results may promote the development of gradient membranes for molecular sieving.
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http://dx.doi.org/10.1038/s41563-021-01052-wDOI Listing
July 2021

Reprogramming Glial Cells into Functional Neurons for Neuro-regeneration: Challenges and Promise.

Neurosci Bull 2021 Jul 20. Epub 2021 Jul 20.

State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China.

The capacity for neurogenesis in the adult mammalian brain is extremely limited and highly restricted to a few regions, which greatly hampers neuronal regeneration and functional restoration after neuronal loss caused by injury or disease. Meanwhile, transplantation of exogenous neuronal stem cells into the brain encounters several serious issues including immune rejection and the risk of tumorigenesis. Recent discoveries of direct reprogramming of endogenous glial cells into functional neurons have provided new opportunities for adult neuro-regeneration. Here, we extensively review the experimental findings of the direct conversion of glial cells to neurons in vitro and in vivo and discuss the remaining issues and challenges related to the glial subtypes and the specificity and efficiency of direct cell-reprograming, as well as the influence of the microenvironment. Although in situ glial cell reprogramming offers great potential for neuronal repair in the injured or diseased brain, it still needs a large amount of research to pave the way to therapeutic application.
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http://dx.doi.org/10.1007/s12264-021-00751-3DOI Listing
July 2021

Anomalously low friction of confined monolayer water with a quadrilateral structure.

J Chem Phys 2021 Jun;154(22):224508

CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, CAS Center for Excellence in Complex System Mechanics, University of Science and Technology of China, Hefei 230027, China.

In this work, we explored how the structure of monolayer water confined between two graphene sheets is coupled to its dynamic behavior. Our molecular dynamics simulations show that there is a remarkable interrelation between the friction of confined water with two walls and its structure under extreme confinement. When the water molecules formed a regular quadrilateral structure, the friction coefficient is dramatically reduced. Such a low-friction coefficient can be attributed to the formation of long-range ordered hydrogen bond network, which not only decreases the structure corrugation in the direction perpendicular to the walls but also promotes the collective motion of the confined water. The regular quadrilateral structure can be formed only if the number density of confined water falls within a certain range. Higher number density results in larger structure corrugations, which increases the friction, while smaller number density leads to an irregular hydrogen bond network in which the collective motion cannot play the role. We demonstrated that there are four distinct stages in the diagram of the friction coefficient vs the number density of confined water. This research clearly established the connection between the dynamic characteristics of confined monolayer water and its structure, which is beneficial to further understand the mechanism of the high-speed water flow through graphene nanocapillaries observed in recent experiments.
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http://dx.doi.org/10.1063/5.0053361DOI Listing
June 2021

De novo generation of macrophage from placenta-derived hemogenic endothelium.

Dev Cell 2021 Jul 30;56(14):2121-2133.e6. Epub 2021 Jun 30.

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Macrophages play pivotal roles in immunity, hematopoiesis, and tissue homeostasis. In mammals, macrophages have been shown to originate from yolk-sac-derived erythro-myeloid progenitors and aorta-gonad-mesonephros (AGM)-derived hematopoietic stem cells. However, whether macrophages can arise from other embryonic sites remains unclear. Here, using single-cell RNA sequencing, we profile the transcriptional landscape of mouse fetal placental hematopoiesis. We uncover and experimentally validate that a CD44 subpopulation of placental endothelial cells (ECs) exhibits hemogenic potential. Importantly, lineage tracing using the newly generated Hoxa13 reporter line shows that Hoxa13-labeled ECs can produce placental macrophages, named Hofbauer cell (HBC)-like cells. Furthermore, we identify two subtypes of HBC-like cells, and cell-cell interaction analysis identifies their potential roles in angiogenesis and antigen presentation, separately. Our study provides a comprehensive understanding of placental hematopoiesis and highlights the placenta as a source of macrophages, which has important implications for both basic and translational research.
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http://dx.doi.org/10.1016/j.devcel.2021.06.005DOI Listing
July 2021

Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development.

Cell Death Dis 2021 06 3;12(6):574. Epub 2021 Jun 3.

Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China.

Sphingosine phosphate lyase 1 (SGPL1) is a highly conserved enzyme that irreversibly degrades sphingosine-1-phosphate (S1P). Sgpl1-knockout mice fail to develop germ cells, resulting in infertility. However, the molecular mechanism remains unclear. The results of the present study showed that SGPL1 was expressed mainly in granulosa cells, Leydig cells, spermatocytes, and round spermatids. Sgpl1 deletion led to S1P accumulation in the gonads. In the ovary, S1P decreased natriuretic peptide receptor 2 (NPR2) activity in granulosa cells and inhibited early follicle growth. In the testis, S1P increased the levels of cyclin-dependent kinase inhibitor 1A (p21) and apoptosis in Leydig cells, thus resulting in spermatogenesis arrest. These results indicate that Sgpl1 deletion increases intracellular S1P levels, resulting in the arrest of female and male germ cell development via different signaling pathways.
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http://dx.doi.org/10.1038/s41419-021-03848-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175456PMC
June 2021

A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin-induced corpus luteum regression.

Elife 2021 May 24;10. Epub 2021 May 24.

National Institute of Biological Sciences, Beijing, China.

Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knock-in mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.
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http://dx.doi.org/10.7554/eLife.67409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143796PMC
May 2021

IP-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion.

Nat Commun 2021 04 28;12(1):2461. Epub 2021 Apr 28.

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

COP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1-CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2 mice with partially disrupted binding of IP, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP-assisted CSN-COP1 competition. Deregulation of the IP-CSN-CRL4-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.
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http://dx.doi.org/10.1038/s41467-021-22941-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080631PMC
April 2021

Neutrophils-derived Spink7 as one safeguard against experimental murine colitis.

Biochim Biophys Acta Mol Basis Dis 2021 06 13;1867(6):166125. Epub 2021 Mar 13.

Institute of Combined Injury, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China. Electronic address:

The uncontrolled abnormal intestinal immune responses play important role in eliciting inflammatory bowel disease (IBD), yet the molecular events regulating intestinal inflammation during IBD remain poorly understood. Here, we describe an endogenous, homeostatic pattern that controls inflammatory responses in experimental murine colitis. We show that Spink7 (serine peptidase inhibitor, kazal type 7), the ortholog of human SPINK7, is significantly upregulated in dextran sodium sulfate (DSS)-induced murine colitis model. Spink7-deficient mice showed highly susceptible to experimental colitis characterized by enhanced weight loss, shorter colon length, higher disease activity index and increased colonic tissue destruction. Bone marrow reconstitution experiments demonstrated that expression of Spink7 in the immune compartment makes main contribution to its protective role in colitis. What's more, neutrophils are the primary sources of Spink7 in experimental murine colitis. Loss of Spink7 leads to augmented productions of multiple chemokines and cytokines in colitis. In summary, this study identifies neutrophils-derived endogenous Spink7-mediated control of chemokines/cytokines production as a molecular mechanism contributing to inflammation resolution during colitis.
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http://dx.doi.org/10.1016/j.bbadis.2021.166125DOI Listing
June 2021

Rapid Analysis for via Microchip Capillary Electrophoresis.

Sensors (Basel) 2021 Feb 13;21(4). Epub 2021 Feb 13.

Institute of Photonics and Bio-Medicine, Graduate School of Science, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.

() is one of the most common pathogens for nosocomial and community infections, which is closely related to the occurrence of pyogenic and toxic diseases in human beings. In the current study, a lab-built microchip capillary electrophoresis (microchip CE) system was employed for the rapid determination of , while a simple-to-use space domain internal standard (SDIS) method was carried out for the reliable quantitative analysis. The precision, accuracy, and reliability of SDIS were investigated in detail. Noted that these properties could be elevated in SDIS compared with traditional IS method. Remarkably, the PCR products of gene could be identified and quantitated within 80 s. The theoretical detection limit could achieve a value of 0.066 ng/μL, determined by the using SDIS method. The current work may provide a promising detection strategy for the high-speed and highly efficient analysis of pathogens in the fields of food safety and clinical diagnosis.
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http://dx.doi.org/10.3390/s21041334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917630PMC
February 2021

A bispecific antibody targeting GPC3 and CD47 induced enhanced antitumor efficacy against dual antigen-expressing HCC.

Mol Ther 2021 04 9;29(4):1572-1584. Epub 2021 Jan 9.

National Institute of Biological Sciences, 7 Science Park Road, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address:

Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen, yet anti-GPC3 therapies have achieved only minimal clinical progress. CD47 is a ubiquitously expressed innate immune checkpoint that promotes evasion of tumors from immune surveillance. Given both the specific expression of GPC3 in HCC and the known phagocytosis inhibitory effect of CD47 in liver cancer, we hypothesized that a bispecific antibody (BsAb) that co-engages with GPC3 and CD47 may offer excellent antitumor efficacy with minimal toxicity. Here, we generated a novel BsAb: GPC3/CD47 biAb. With the use of both in vitro and in vivo assays, we found that GPC3/CD47 biAb exerts strong antitumor activity preferentially against dual antigen-expressing tumor cells. In hCD47/human signal regulatory protein alpha (hCD47/hSIRPα) humanized mice, GPC3/CD47 biAb had an extended serum half-life without causing systemic toxicity. Importantly, GPC3/CD47 biAb induced enhanced Fc-mediated effector functions to dual antigen-expressing HCC cells in vitro, and both macrophages and neutrophils are required for its strong efficacy against xenograft HCC tumors. Notably, GPC3/CD47 biAb outperformed monotherapies and a combination therapy with anti-CD47 and anti-GPC3 monoclonal antibodies (mAbs) in a xenograft HCC model. Our study illustrates a strategy for improving HCC treatment by boosting innate immune responses and presents new insights to inform antibody design for the future development of innovative immune therapies.
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http://dx.doi.org/10.1016/j.ymthe.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058486PMC
April 2021

Potential roles of exosome non‑coding RNAs in cancer chemoresistance (Review).

Oncol Rep 2021 02 8;45(2):439-447. Epub 2020 Dec 8.

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.

Multiple studies have demonstrated chemoresistance in multiple types of tumor, which limits the effectiveness of cancer treatments. Chemoresistance often contributes to cancer relapse. Non‑coding RNAs, are a group of regulatory RNAs, that are involved in tumor drug resistance. Exosomes, membranous vesicles secreted by cells, are reported to mediate cell‑to‑cell communication, including in cancer. Furthermore, exosomal non‑coding RNAs have been reported to mediate chemoresistance via exchange of biological information. In the present review, the main roles of exosomal non‑coding RNAs, including micro(mi) RNAs, long non‑coding (lnc) RNAs, and circular (circ) RNAs in cancer are described and their potential roles in chemoresistance in various types of cancer are also discussed.
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http://dx.doi.org/10.3892/or.2020.7887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757100PMC
February 2021

A generalized examination of capillary force balance at contact line: On rough surfaces or in two-liquid systems.

J Colloid Interface Sci 2021 Mar 30;585:320-327. Epub 2020 Nov 30.

CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, CAS Center for Excellence in Complex System Mechanics, University of Science and Technology of China, Hefei 230027, China. Electronic address:

We investigate the capillary force balance at the contact line on rough solid surfaces and in two-liquid systems. Our results confirm that solid-liquid interactions perpendicular to the interface have a significant influence on the lateral component of the capillary force exerted on the contact line. Surface roughness of the solid substrate reduces the mobility of liquid and alters how the perpendicular solid-liquid interactions transfer into a force acting parallel to the interface. A quantitative relation between surface roughness and the transfer strategy is proposed. Moreover, when a liquid is in coexistence with another immiscible liquid on a solid, the capillary forces exerted on liquids of both sides are involved in our theoretical model. The contact angle can be predicted by calculating three interfacial tensions. These arguments are then verified by molecular dynamics simulations. Our findings set up the generalized theoretical framework for the capillary force balance at the contact line and broaden its application in more realistic scenarios.
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http://dx.doi.org/10.1016/j.jcis.2020.11.100DOI Listing
March 2021

Casein kinase 1G2 suppresses necroptosis-promoted testis aging by inhibiting receptor-interacting kinase 3.

Elife 2020 11 18;9. Epub 2020 Nov 18.

National Institute of Biological Sciences, Beijing, China.

Casein kinases are a large family of intracellular serine/threonine kinases that control a variety of cellular signaling functions. Here we report that a member of casein kinase 1 family, casein kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting kinase 3, RIPK3, thereby attenuating RIPK3-mediated necroptosis. The binding of CSNK1G2 to RIPK3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and premature aging of their testis, a phenotype that was rescued by either double knockout of the gene or feeding the animal with a RIPK1 kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIPK3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIPK3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.
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http://dx.doi.org/10.7554/eLife.61564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673785PMC
November 2020

Coagulopathy as a Prodrome of Cytokine Storm in COVID-19-Infected Patients.

Front Med (Lausanne) 2020 23;7:572989. Epub 2020 Oct 23.

Department of Laboratory Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.

The rapid coronavirus disease 2019 (COVID-19) pandemic has hit hard on the world and causes panic since the virus causes serious infectious respiratory illness and easily leads to severe conditions such as immune system overactivation or cytokine storm. Due to the limited knowledge on the course of infection of this coronavirus and the lack of an effective treatment for this fatal disease, mortality remains high. The emergence of a cytokine storm in patients with a severe condition has been reported as the top reason of the death of patients with COVID-19 infection. However, the causative mechanism of cytokine storm remains elusive. Thus, we aim to observe the association of coagulopathy (D-dimer) with cytokine (i.e., IL-6) and CT imaging in COVID-19-infected patients. In this retrospective observational study, we systematically analyzed the comprehensive clinical laboratory data of COVID-19-positive patients in different illness groups of mild, moderate, and severe conditions according to the Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition). tests and chi-square tests were used for two-group comparisons. One-way ANOVA was used for three-group comparisons. Pearson and Spearman correlation coefficients of the D-dimer level with IL-6 and CT imaging were computed at baseline. With regular liquid biopsy approach, D-dimer, IL-6, and neutrophil-to-lymphocyte ratio were recorded repeatedly with a time curve to investigate disease progression, along with CT imaging, and other indicators. All the 64 patients were clinically evaluated and classified into three groups of mild (32 cases), moderate (23 cases), and severe (nine cases) conditions. The D-dimer level positively correlated with IL-6 ( = 0.5) at baseline when the COVID-19-infected patients were admitted. In addition, we observed that D-dimer rises earlier than the cytokine storm represented by IL-6 surge, which suggests that coagulopathy might act as a trigger to potentiate a cytokine storm. Integrated analysis revealed a positive correlation of coagulopathy with cytokine storm in COVID-19-infected patients; the D-dimer rises early, which indicates that coagulopathy acts as a prodrome of cytokine storm. Coagulopathy can be used to monitor early cytokine storm in COVID-19-infected patients.
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http://dx.doi.org/10.3389/fmed.2020.572989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645068PMC
October 2020

Serum Interleukin-6 Concentrations and the Severity of COVID-19 Pneumonia: A Retrospective Study at a Single Center in Bengbu City, Anhui Province, China, in January and February 2020.

Med Sci Monit 2020 Nov 11;26:e926941. Epub 2020 Nov 11.

Department of Clinical Laboratory Science, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland).

BACKGROUND At present, the relationships among COVID-19 disease progression, patient prognosis, and immune status are unclear. This single-center retrospective study evaluated the correlation between serum interleukin-6 (IL-6) levels at admission with the severity of COVID-19 pneumonia, as determined by admission to the intensive Care Unit (ICU). MATERIAL AND METHODS Patients admitted to The First Affiliated Hospital of Bengbu Medical College in Bengbu City, Anhui Province, China, in January and February 2020 for COVID-19 pneumonia were enrolled in this study. COVID-19 infection was confirmed by the detection of SARS-CoV-2 nucleic acid in throat swab samples using real-time fluorescent reverse transcription PCR. Serum IL-6 concentrations at admission were measured by ELISA. Correlations between serum IL-6 concentrations and ICU admission due to the development of severe COVID-19 pneumonia were evaluated. RESULTS This study enrolled 68 patients with novel coronavirus pneumonia. IL-6 concentrations were significantly higher in patients with more severe than less severe COVID-19 pneumonia. Eight of 40 patients with severe COVID-19 pneumonia became critically ill and required ICU admission. IL-6 concentrations were significantly higher in patients with severe COVID-19 pneumonia who were than who were not treated in the ICU. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.816 (P<0.01), indicating that IL-6 was prognostic of disease severity in patients with COVID-19 pneumonia. CONCLUSIONS Serum IL-6 concentration is closely associated with the severity of COVID-19. Continuous monitoring of IL-6 has clinical value in evaluating patient condition.
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http://dx.doi.org/10.12659/MSM.926941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670831PMC
November 2020

RNF219 interacts with CCR4-NOT in regulating stem cell differentiation.

J Mol Cell Biol 2020 10;12(11):894-905

School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.

Regulation of RNA stability plays a crucial role in gene expression control. Deadenylation is the initial rate-limiting step for the majority of RNA decay events. Here, we show that RING finger protein 219 (RNF219) interacts with the CCR4-NOT deadenylase complex. RNF219-CCR4-NOT exhibits deadenylation activity in vitro. RNA-seq analyses identify some of the 2-cell-specific genes and the neuronal genes significantly downregulated upon RNF219 knockdown, while upregulated after depletion of the CCR4-NOT subunit CNOT10 in mouse embryonic stem (ES) cells. RNF219 depletion leads to impaired neuronal lineage commitment during ES cell differentiation. Our study suggests that RNF219 is a novel interacting partner of CCR4-NOT and required for maintenance of ES cell pluripotency.
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http://dx.doi.org/10.1093/jmcb/mjaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883825PMC
October 2020

Zika Virus Infection Leads to Variable Defects in Multiple Neurological Functions and Behaviors in Mice and Children.

Adv Sci (Weinh) 2020 Sep 2;7(18):1901996. Epub 2020 Aug 2.

State Key Laboratory of Molecular Developmental Biology CAS Center for Excellence in Brain Science and Intelligence Technology School of Future Technology Institute of Genetics and Developmental Biology Chinese Academy of Sciences Beijing 100101 China.

Zika virus (ZIKV) has evolved into a global health threat because of its causal link to congenital Zika syndrome. ZIKV infection of pregnant women may cause a spectrum of abnormalities in children. In the studies in Brazil, a large cohort of children with perinatal exposure to ZIKV is followed, and a spectrum of neurodevelopmental abnormalities is identified. In parallel, it is demonstrated that infection of the mouse neonatal brain by a contemporary ZIKV strain instead of an Asian ancestral strain can cause microcephaly and various abnormal neurological functions. These include defects in social interaction and depression, impaired learning and memory, in addition to severe motor defects, which are present in adult mice as well as in the prospective cohort of children. Importantly, although mouse brains infected later after birth do not have apparent abnormal brain structure, those mice still show significant impairments of visual cortical functions, circuit organization, and experience-dependent plasticity. Thus, the study suggests that special attention should be paid to all children born to ZIKV infected mothers for screening of abnormal behaviors and sensory function during childhood.
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http://dx.doi.org/10.1002/advs.201901996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509663PMC
September 2020

NTCP Deficiency Causes Gallbladder Abnormalities in Mice and Human Beings.

Cell Mol Gastroenterol Hepatol 2021 9;11(3):831-839. Epub 2020 Sep 9.

National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. Electronic address:

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http://dx.doi.org/10.1016/j.jcmgh.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851344PMC
September 2020

Genome transfer for the prevention of female infertility caused by maternal gene mutation.

J Genet Genomics 2020 06 21;47(6):311-319. Epub 2020 Jun 21.

Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. Electronic address:

Poor oocyte quality is associated with early embryo developmental arrest and infertility. Maternal gene plays crucial roles in the regulation of oocyte maturation, and its mutation is a common cause of female infertility. However, how to improve oocyte quality and develop effective therapy for maternal gene mutation remains elusive. Here, we use Zar1 as an example to assess the feasibility of genome transfer to cure maternal gene mutation-caused female infertility. We first discover that cytoplasmic deficiency primarily leads to Zar1-null embryo developmental arrest by disturbing maternal transcript degradation and minor zygotic genome activation (ZGA) during the maternal-zygotic transition. We next perform genome transfer at the oocyte (spindle transfer or polar body transfer) and zygote (early pronuclear transfer or late pronuclear transfer) stages to validate the feasibility of preventing Zar1 mutation-caused infertility. We finally demonstrate that genome transfer either at the oocyte or at the early pronuclear stage can support normal preimplantation embryo development and produce live offspring. Moreover, those pups grow to adulthood and show normal fertility. Therefore, our findings provide an effective basis of therapies for the treatment of female infertility caused by maternal gene mutation.
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http://dx.doi.org/10.1016/j.jgg.2020.06.002DOI Listing
June 2020

A Vagal-NTS Neural Pathway that Stimulates Feeding.

Curr Biol 2020 10 20;30(20):3986-3998.e5. Epub 2020 Aug 20.

National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China. Electronic address:

A fundamental question of physiology is how gut-brain signaling stimulates appetite. While many studies have emphasized the importance of vagal afferents to the brain in inducing satiation, little is known about whether and how the vagal-mediated gut-brain pathway senses orexigenic signals and stimulates feeding. Here, we identified a previously uncharacterized population of fasting-activated catecholaminergic neurons in the nucleus of the solitary tract (NTS). After characterizing the anatomical complexity among NTS catecholaminergic neurons, we surprisingly found that activation of NTS epinephrine (E) neurons co-expressing neuropeptide Y (NPY) stimulated feeding, whereas activation of NTS norepinephrine (NE) neurons suppressed feeding. Monosynaptic tracing/activation experiments then showed that these NTS neurons receive direct vagal afferents from nodose neurons. Moreover, activation of the vagal→NPY/E neural circuit stimulated feeding. Our study reveals an orexigenic role of the vagal→NTS pathway in controlling feeding, thereby providing important insights about how gut-brain signaling regulates feeding behavior.
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http://dx.doi.org/10.1016/j.cub.2020.07.084DOI Listing
October 2020

SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation.

Science 2020 08;369(6506):984-988

Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P. R. China.

Germinal center (GC) responses potentiate the generation of follicular regulatory T (T) cells. However, the molecular cues driving T cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (T) cells and T-B cell border-enriched fibroblastic reticular cells, is developmentally required for T cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing T cells as a distinct T cell population that develops after SOSTDC1 T cells and loses the ability to help B cells for antibody production. Notably, ablation in T cells results in substantially reduced T cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT-β-catenin axis and facilitates T cell differentiation.
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http://dx.doi.org/10.1126/science.aba6652DOI Listing
August 2020

SRC-3 Functions as a Coactivator of T-bet by Regulating the Maturation and Antitumor Activity of Natural Killer Cells.

Cancer Immunol Res 2020 09 19;8(9):1150-1162. Epub 2020 Jun 19.

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.

Natural killer (NK)-cell development and maturation is a well-organized process. The steroid receptor coactivator 3 (SRC-3) is a regulator of the hematopoietic and immune systems; however, its role in NK cells is poorly understood. Here, SRC-3 displayed increased nuclear translocation in NK cells during terminal differentiation and upon inflammatory cytokine stimulation. Targeted deletion of SRC-3 altered normal NK-cell distribution and compromised NK-cell maturation. SRC-3 deficiency led to significantly impaired NK-cell functions, especially their antitumor activity. The expression of several critical T-bet target genes, including , and , but not T-bet itself, was markedly decreased in NK cells in the absence of SRC-3. There was a physiologic interaction between SRC-3 and T-bet proteins, where SRC-3 was recruited by T-bet to regulate the transcription of the aforementioned genes. Collectively, our findings unmask a previously unrecognized role of SRC-3 as a coactivator of T-bet in NK-cell biology and indicate that targeting SRC-3 may be a promising strategy to increase the tumor surveillance function of NK cells.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0181DOI Listing
September 2020

Deficiency Inhibits Microglial Activation and Alleviates Ischemia-Induced Brain Injury.

Aging Dis 2020 May 9;11(3):523-535. Epub 2020 May 9.

2The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China.

Neuroinflammation plays a critical role in ischemia-induced brain injury. Mib2, an E3 ubiquitin ligase, has been reported to regulate Notch signaling and participate in the peripheral immune system. However, the roles of Mib2 in the nervous system are not well characterized. In this study, we show that Mib2 is involved in lipopolysaccharide (LPS)- and oxygen-glucose deprivation (OGD)-induced microglial activation. Mechanistically, Mib2 interacts with the IKK complex and regulates the activation of NF-κB signaling, thus modulating Notch1 transcription in the microglia. Furthermore, we generated a microglia-specific knockout mice and found that microglia-specific deletion of significantly alleviates ischemia-induced neuroinflammation and brain injury. Taken together, our results reveal a critical role of Mib2 in microglial activation and ischemia-induced brain injury, thus providing a potential target for the treatment of stroke.
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http://dx.doi.org/10.14336/AD.2019.0807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220279PMC
May 2020

In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model.

Brain 2020 05;143(5):1350-1367

Tsinghua-Peking Joint Center for Life Science, Beijing, China.

Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.
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http://dx.doi.org/10.1093/brain/awaa076DOI Listing
May 2020

E2F1 Regulates Adipocyte Differentiation and Adipogenesis by Activating ICAT.

Cells 2020 04 21;9(4). Epub 2020 Apr 21.

Department of Animal Science, Texas A&M University, College Station, TX 77843, USA.

Wnt/β-catenin is a crucial repressor of adipogenesis. We have shown that E2 promoter binding factor 1 (E2F1) suppresses Wnt/β-catenin activity through transactivation of β-catenin interacting protein 1 (CTNNBIP1), also known as inhibitor of β-catenin and TCF4 (ICAT) in human colorectal cancers. However, it remains unknown whether ICAT is required for E2F1 to promote differentiation by inhibiting β-catenin activity in pre-adipocytes. In the present study, we found that 1-methyl-3-isobutylxanthine, dexamethasone, and insulin (MDI)-induced differentiation and lipid accumulation in 3T3-L1 pre-adipocytes was reversed by activation of β-catenin triggered by CHIR99021, a GSK3β inhibitor. Intriguingly, we observed a reduced protein level of E2F1 and ICAT at a later stage of pre-adipocytes differentiation. Importantly, overexpression of ICAT in 3T3-L1 pre-adipocytes markedly promote the adipogenesis and partially reversed the inhibitory effect of CHIR99021 on MDI-induced adipogenesis and lipid accumulation by regulating adipogenic regulators and Wnt/β-catenin targets. Moreover, pre-adipocytes differentiation induced by MDI were markedly inhibited in siE2F1 or siICAT transfected 3T3-L1 cells. Gene silencing of ICAT in the E2F1 overexpressed adipocytes also inhibited the adipogenesis. These data indicated that E2F1 is a metabolic regulator with an ability to promote pre-adipocyte differentiation by activating ICAT, therefore represses Wnt/β-catenin activity in 3T3-L1 cells. We also demonstrated that ICAT overexpression did not affect oleic acid-induced lipid accumulation at the surface of Hela and HepG2 cells. In conclusion, we show that E2F1 is a critical regulator with an ability to promote differentiation and adipogenesis by activating ICAT in pre-adipocytes.
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http://dx.doi.org/10.3390/cells9041024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225968PMC
April 2020

Microscopic Origin of Capillary Force Balance at Contact Line.

Phys Rev Lett 2020 Mar;124(12):125502

CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, CAS Center for Excellence in Complex System Mechanics, University of Science and Technology of China, Hefei 230027, China.

We investigate the underlying mechanism of capillary force balance at the contact line. In particular, we offer a novel approach to describe and quantify the capillary force on the liquid in coexistence with its vapor phase, which is crucial in wetting and spreading dynamics. Its relation with the interface tension is elucidated. The proposed model is verified by our molecular dynamics simulations over a wide contact angle range. Differences in capillary forces are observed in evaporating droplets on homogeneous and decorated surfaces. Our findings not only provide a theoretical insight into capillary forces at the contact line, but also validate Young's equation based on a mechanical interpretation.
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http://dx.doi.org/10.1103/PhysRevLett.124.125502DOI Listing
March 2020

Megakaryocytes promote bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1.

Theranostics 2020 12;10(5):2229-2242. Epub 2020 Jan 12.

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.

: The hematopoietic system and skeletal system have a close relationship, and megakaryocytes (MKs) may be involved in maintaining bone homeostasis. However, the exact role and underlying mechanism of MKs in bone formation during steady-state and stress conditions are still unclear. : We first evaluated the bone phenotype with MKs deficiency in bone marrow by using c-Mpl-deficient mice and MKs-conditionally deleted mice. Then, osteoblasts (OBs) proliferation and differentiation and CD31Emcn tube formation were assessed. The expression of growth factors related to bone formation in MKs was detected by RNA-sequencing and enzyme-linked immunosorbent assays (ELISAs). Mice with specific depletion of TGF-β1 in MKs were used to further verify the effect of MKs on osteogenesis and angiogenesis. Finally, MKs treatment of irradiation-induced bone injury was tested in a mouse model. : We found that MKs deficiency significantly impaired bone formation. Further investigations revealed that MKs could promote OBs proliferation and differentiation, as well as CD31Emcn vessels formation, by secreting high levels of TGF-β1. Consistent with these findings, mice with specific depletion of TGF-β1 in MKs displayed significantly decreased bone mass and strength. Importantly, treatment with MKs or thrombopoietin (TPO) substantially attenuated radioactive bone injury in mice by directly or indirectly increasing the level of TGF-β1 in bone marrow. MKs-derived TGF-β1 was also involved in suppressing apoptosis and promoting DNA damage repair in OBs after irradiation exposure. : Our findings demonstrate that MKs contribute to bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1, which may offer a potential therapeutic strategy for the treatment of irradiation-induced osteoporosis.
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http://dx.doi.org/10.7150/thno.40559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019172PMC
April 2021

Correlation Between von Hippel-Lindau Gene Expression and Tumor SUVmax and Survival Prognosis in Hepatocellular Carcinoma.

Med Sci Monit 2020 Feb 20;26:e920473. Epub 2020 Feb 20.

Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China (mainland).

BACKGROUND We investigated the relationship between the 18F-FDG PET/CT metabolic parameter SUVmax in primary hepatocellular carcinoma (HCC) and expression of von Hippel-Lindau (VHL), as well as its effect on HCC survival prognosis. MATERIAL AND METHODS We retrospectively analyzed data for 62 HCC patients who received 18F-FDG PET/CT before surgery at the First Affiliated Hospital of Bengbu Medical College from June 2013 to June 2018 (42 males, 20 females; median age 62 years). No treatment was performed prior to the examination. The relationship between preoperative 18F-FDG PET/CT metabolic parameters, clinical pathology, and disease prognosis was analyzed. RESULTS SUVmax was significantly different in varying HCC pathological grades, and with tumor length, lymph node metastasis, portal vein tumor thrombus, and distant metastasis (p<0.05). SUVmax was significantly higher in the shorter patient survival group (p<0.05). 18F-FDG uptake was correlated with expression of glucose transporter 1 and VHL in tumor tissues (correlation coefficients 0.476 and 0.565, respectively; both p<0.05). Negative expression of VHL suggested poor tumor differentiation and poor prognosis, but no correlation was observed with patient age, sex, tumor length, lymph node metastasis, or distant metastasis. The survival time of patients with low VHL expression was significantly shorter than that of patients with positive VHL expression (p=0.02). CONCLUSIONS VHL expression in primary HCC has a significant correlation with SUVmax, and negative VHL expression predicts a worse clinical prognosis.
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http://dx.doi.org/10.12659/MSM.920473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050478PMC
February 2020

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3-phosphoinositides.

J Pineal Res 2020 Apr 11;68(3):e12637. Epub 2020 Mar 11.

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.

Melatonin (MT), endogenously secreted by the pineal gland, is closely related to multiple biological processes; however, its effect on thrombopoiesis is still not well illustrated. Here, we demonstrate that MT administration can elevate peripheral platelet levels. Analysis of different stages in thrombopoiesis reveals that MT has the capacity to promote the expansion of CD34 and CD41 cells, and accelerate proplatelet formation (PPF) and platelet production. Furthermore, in vivo experiments show that MT has a potential therapeutic effect on radiation-induced thrombocytopenia. The underlying mechanism suggests that both extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling are involved in the processes of thrombopoiesis facilitated by MT. Interestingly, in addition to the direct regulation of Akt signaling by its upstream phosphoinositide 3-kinase (PI3K), ERK1/2 signaling is also regulated by PI3K via its effector, dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1), in megakaryocytes after MT treatment. Moreover, the expression level of DAPP1 during megakaryocyte differentiation is closely related to the activation of ERK1/2 and Akt at different stages of thrombopoiesis. In conclusion, our data suggest that MT treatment can promote thrombopoiesis, which is modulated by the DAPP1-orchestrated activation of ERK1/2 and Akt signaling.
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http://dx.doi.org/10.1111/jpi.12637DOI Listing
April 2020
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