Publications by authors named "Jian Zheng"

799 Publications

Differential Effects of Prostaglandin D Signaling on Macrophages and Microglia in Murine Coronavirus Encephalomyelitis.

mBio 2021 Sep 7:e0196921. Epub 2021 Sep 7.

Department of Microbiology and Immunology, University of Iowagrid.214572.7, Iowa City, Iowa, USA.

Microglia and macrophages initiate and orchestrate the innate immune response to central nervous system (CNS) virus infections. Microglia initiate neurotropic coronavirus clearance from the CNS, but the role of infiltrating macrophages is not well understood. Here, using mice lacking cell-specific expression of DP1, the receptor for prostaglandin D (PGD), we delineate the relative roles of PGD signaling in microglia and macrophages in murine coronavirus-infected mice. We show that the absence of PGD/DP1 signaling on microglia recapitulated the suboptimal immune response observed in global DP1 mice. Unexpectedly, the absence of the DP1 receptor on macrophages had an opposite effect, resulting in enhanced activation and more rapid virus clearance. However, microglia are still required for disease resolution, even when macrophages are highly activated, in part because they are required for macrophage recruitment to sites of infection. Together, these results identify key differences in the effects of PGD/DP1 signaling on microglia and macrophages and illustrate the complex relationship between the two types of myeloid cells. Current understanding about the roles of microglia versus macrophages in viral encephalitis is limited. We previously showed that the signaling of a single prostaglandin, PGD, through its DP1 receptor on myeloid cells is critical for optimal immune responses in infected mice. Here, we demonstrate that the specific ablation of the DP1 receptor on macrophages and microglia had markedly different effects on outcomes. DP1 macrophages exhibited greater phagocytic properties than controls, resulting in enhanced kinetics of virus clearance, while DP1 absence on microglia resulted in increased lethality. Microglia were still required for protection, even when DP1 was not expressed on macrophages. These results suggest that therapeutic strategies directed at specific myeloid subsets in the brain may be useful in the context of viral infections.
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http://dx.doi.org/10.1128/mBio.01969-21DOI Listing
September 2021

Correction to: Serum levels of miR-21-5p and miR-339-5p associate with occupational trichloroethylene hypersensitivity syndrome.

J Occup Med Toxicol 2021 Aug 11;16(1):31. Epub 2021 Aug 11.

Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China.

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http://dx.doi.org/10.1186/s12995-021-00315-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359055PMC
August 2021

[Study on Irradiation Uniformity of Array Blue LED in Jaundice Treatment Box].

Zhongguo Yi Liao Qi Xie Za Zhi 2021 Jul;45(4):376-379

Zhejiang Institute of Medical Device Testing, Hangzhou, 310018.

The uniformity of blue LED array in jaundice treatment box is improved. The mathematical model of illumination uniformity algorithm for inner and outer LED arrays layout is established. Taking the actual size of blue light board in jaundice treatment box as an example, the optimal illumination uniformity with best LED arrays layout are obtained through programming iteration and simulation verification. The uniformity of blue light LED improved 42.9 % comparing with tradition LED arrays.
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http://dx.doi.org/10.3969/j.issn.1671-7104.2021.04.005DOI Listing
July 2021

N6-methyladenosine-mediated upregulation of WTAPP1 promotes WTAP translation and Wnt signaling to facilitate pancreatic cancer progression.

Cancer Res 2021 Aug 6. Epub 2021 Aug 6.

State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center

Pseudogenes may play important roles in cancer. Here, we explore the mechanism and function of a pseudogene WTAPP1 in the progress of pancreatic ductal adenocarcinoma (PDAC). WTAPP1 RNA was significantly elevated in PDAC and was associated with poor prognosis in patients. Overexpression of WTAPP1 RNA promoted PDAC proliferation and invasiveness in vitro and in vivo. Mechanistically, N6-methyladenosine (m6A) modification stabilized WTAPP1 RNA via CCHC-type zinc finger nucleic acid binding protein (CNBP), resulting in increased levels of WTAPP1 RNA in PDAC cells. Excessive WTAPP1 RNA bound its protein-coding counterpart WT1 associated protein (WTAP) mRNA and recruited more EIF3 translation initiation complex to promote WTAP translation. Increased WTAP protein enhanced the activation of Wnt signaling and provoked the malignant phenotypes of PDAC. Decreasing WTAPP1 RNA significantly suppressed the in vivo growth and metastasis of PDAC cell lines and patient-derived xenografts. These results indicate that m6A-mediated increases in WTAPP1 expression promotes PDAC progression and thus may serve as a therapeutic target.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0494DOI Listing
August 2021

NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization.

Oncogene 2021 Aug 3. Epub 2021 Aug 3.

State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

5-Methylcytosine (mC) is a posttranscriptional RNA modification participating in many critical bioprocesses, but its functions in human cancer remain unclear. Here, by detecting the transcriptome-wide mC profiling in esophageal squamous cell carcinoma (ESCC), we showed increased mC methylation in ESCC tumors due to the overexpressed mC methyltransferase NSUN2. Aberrant expression of NSUN2 was positively regulated by E2F Transcription Factor 1 (E2F1). High NSUN2 levels predicted poor survival of ESCC patients. Moreover, silencing NSUN2 suppressed ESCC tumorigenesis and progression in Nsun2 knockout mouse models. Mechanistically, NSUN2 induced mC modification of growth factor receptor-bound protein 2 (GRB2) and stabilized its mRNA, which was mediated by a novel mC mediator, protein lin-28 homolog B (LIN28B). Elevated GRB2 levels increased the activation of PI3K/AKT and ERK/MAPK signalling. These results demonstrate that NSUN2 enhances the initiation and progression of ESCC via mC-LIN28B dependent stabilization of GRB2 transcript, providing a promising epitranscriptomic-targeted therapeutic strategy for ESCC.
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http://dx.doi.org/10.1038/s41388-021-01978-0DOI Listing
August 2021

The development of - as anti-SARS-CoV-2 nanobody drug candidates.

Elife 2021 08 2;10. Epub 2021 Aug 2.

Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, United States.

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), , from a camelid nanobody phage display library. Structural data showed that bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor angiotensin-converting enzyme 2 (ACE2). The lead drug candidate possessing an Fc tag () bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of c documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, may contribute to the battle against COVID-19.
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http://dx.doi.org/10.7554/eLife.64815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354634PMC
August 2021

Management of Clinically Involved Lateral Lymph Node Metastasis in Locally Advanced Rectal Cancer: A Radiation Dose Escalation Study.

Front Oncol 2021 16;11:674253. Epub 2021 Jul 16.

Department of Radiation Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Patients with lateral lymph nodes (LLNs) metastasis are not effectively treated with neoadjuvant chemoradiotherapy. This study aimed to compare the efficacy of three neoadjuvant therapeutic regimens, namely, chemotherapy, chemoradiotherapy, and chemoradiotherapy with a dose boost of LLNs, and to identify the optimal approach for treating LLNs metastasis of locally advanced rectal cancer.

Methods: A total of 202 patients with baseline LLNs metastasis (short axis ≥5 mm) and treated with neoadjuvant treatment, followed by radical surgery from 2011 to 2019, were enrolled. The short axis of the LLNs on baseline and restaging MRI were recorded. Survival outcomes were compared.

Results: In the booster subgroup, shrinkage of LLNs was significantly greater than in the neoadjuvant chemotherapy and chemoradiotherapy subgroups (0.001), without increasing radiation related side effects ( 0.121). For patients with baseline LLNs of short axis ≥5 mm in the booster subgroup, the response rate (short axis <5 mm on restaging MRI) was 72.9%, significantly higher than patients in the neoadjuvant chemotherapy subgroup (48.9%, = 0.007) and higher than for patients in the neoadjuvant chemoradiotherapy group (65.0%), but there was no statistical difference ( = 0.411). The 3-year local recurrence and lateral local recurrence rates were both 2.3% in the dose booster group, which were lower than those of the other two subgroups (local recurrence: 0.001; lateral local recurrence: 0.001). The short axis of lateral lymph nodes (≥5 and <5 mm) on restaging MRI was an independent risk factor for prognosis (0.05).

Conclusion: Radiation dose boost is an effective way of increasing the response rate and decreasing recurrence rates. The restaging LLNs with short axis ≥5 mm is a predictor of poor prognosis.
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http://dx.doi.org/10.3389/fonc.2021.674253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322741PMC
July 2021

Classification of microcalcification clusters in digital breast tomosynthesis using ensemble convolutional neural network.

Biomed Eng Online 2021 Jul 28;20(1):71. Epub 2021 Jul 28.

Department of Medical Imaging, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China.

Background: The classification of benign and malignant microcalcification clusters (MCs) is an important task for computer-aided diagnosis (CAD) of digital breast tomosynthesis (DBT) images. Influenced by imaging method, DBT has the characteristic of anisotropic resolution, in which the resolution of intra-slice and inter-slice is quite different. In addition, the sharpness of MCs in different slices of DBT is quite different, among which the clearest slice is called focus slice. These characteristics limit the performance of CAD algorithms based on standard 3D convolution neural network (CNN).

Methods: To make full use of the characteristics of the DBT, we proposed a new ensemble CNN, which consists of the 2D ResNet34 and the anisotropic 3D ResNet to extract the 2D focus slice features and 3D contextual features of MCs, respectively. Moreover, the anisotropic 3D convolution is used to build 3D ResNet to avoid the influence of DBT anisotropy.

Results: The proposed method was evaluated on 495 MCs in DBT images of 275 patients, which are collected from our collaborative hospital. The area under the curve (AUC) of receiver operating characteristic (ROC) and accuracy of classifying benign and malignant MCs using decision-level ensemble strategy were 0.8837 and 82.00%, which were significantly higher than the experimental results of 2D ResNet34 (AUC: 0.8264, ACC: 76.00%) and anisotropic 3D ResNet (AUC: 0.8455, ACC: 76.00%). Compared with the results of 3D features classification in the radiomics, the AUC of the deep learning method with decision-level ensemble strategy was improved by 0.0435, and the F1 score was improved from 79.37 to 85.71%. More importantly, the sensitivity increased from 78.13 to 84.38%, and the specificity increased from 66.67 to 77.78%, which effectively reduced the false positives of diagnosis CONCLUSION: The results fully prove that the ensemble CNN can effectively integrate 2D features and 3D features, improve the classification performance of benign and malignant MCs in DBT, and reduce the false positives.
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http://dx.doi.org/10.1186/s12938-021-00908-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317331PMC
July 2021

Measurement of density profile and fluctuations using a multi-channel terahertz solid-state interferometer system on Keda Torus eXperiment (KTX).

Rev Sci Instrum 2021 May;92(5):053514

University of Science and Technology of China, Hefei, Anhui 230026, China.

A five-chord interferometer based on terahertz solid state sources has been successfully installed on the Keda Torus eXperiment (KTX), a reversed field pinch machine. The optical design has been carefully optimized for the uniform distribution of beam light to fully use the limited power source (∼2 mW). By setting the telescopic mirror unit, the beam waist is located in the center of the vacuum vessel and its diameter is in the range of the Rayleigh length. The beam width across the plasma area is improved to ∼20 mm to minimize crosstalk and beam energy loss. After careful beam alignment, the phase noise for each channel can reach 0.004π. The radial profiles of electron density on the KTX are inverted, and density fluctuation associated with instabilities is shown based on the forward-scattering signals.
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http://dx.doi.org/10.1063/5.0043864DOI Listing
May 2021

Compact broadband Compton spectroscopy used for intense laser-driven gamma rays.

Rev Sci Instrum 2021 May;92(5):053546

CAS Key Laboratory of Geospace Environment and Department of Engineering and Applied Physics, University of Science and Technology of China, Hefei, Anhui 230026, China.

A compact broadband Compton spectrometer is designed to measure the continuous spectrum of gamma-ray sources driven by an intense laser. The incident gamma rays are converted into electrons in low-Z materials by Compton scattering. Produced by a pair of stepped magnets, a weaker-front-stronger-rear nonuniform magnetic field in the electron magnetic spectrometer is used to spectrally resolve the scattered electrons, leading to a broadband gamma-ray spectral coverage of 2-20 MeV in a compact volume. Flat imaging-plate detectors are placed near the focused imaging points of the magnetic spectrometer to record the dispersed electrons, thereby achieving an optimal spectral resolution of 6%-13% in the energy range of 3-20 MeV. The spectrometer is used successfully to measure the gamma-ray spectrum generated by the high-energy electron beams produced by a femtosecond-laser-driven wakefield.
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http://dx.doi.org/10.1063/5.0028098DOI Listing
May 2021

Angelica sinensis polysaccharide (ASP) attenuates diosbulbin-B (DB)-induced hepatotoxicity through activating the MEK/ERK pathway.

Bioengineered 2021 Dec;12(1):3516-3524

Department of Gastrointestinal Surgical Ward, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.

Diosbulbin-B (DB) is a promising therapeutic drug for cancer treatment; however, DB-induced hepatotoxicity seriously limits its clinical utilization. Based on this, the present study investigated whether the extract, angelica sinensis polysaccharide (ASP), was effective to attenuate DB-induced cytotoxicity in hepatocytes. The primary hepatocytes were isolated from rats and cultured , which were subsequently treated with high-dose DB (100 μM) and ASP (12 μg/ml) to establish the DB-induced hepatotoxicity models. MTT assay and flow cytometry (FCM) were performed to evaluate cell viability, and the results showed that high-dose DB-induced cell apoptosis and inhibition of proliferation were reversed by co-treating cells with ASP, which were supported by our Western Blot assay data that ASP upregulated Cyclin D1 and CDK2 to abrogate high-dose DB-induced cell cycle arrest. In addition, ASP exerted its regulating effects on cell autophagy, and we found that ASP increased LC3B-II/I ratio and Atg5, but decreased p62 to activate the autophagy flux. Of note, the MEK/ERK pathway could be activated by ASP in the DB-treated hepatocytes, and the protective effects of ASP on high-dose DB-induced hepatocyte death were abolished by co-treating cells with the autophagy inhibitor (3-methyladenine, 3-MA) and MEK/ERK selective inhibitor (SCH772984). Moreover, blockage of the MEK/ERK pathway suppressed cell autophagy in the hepatocytes co-treated with ASP and high-dose DB. Taken together, this study illustrated that ASP activated the MEK/ERK pathway mediated autophagy to suppress high-dose DB-induced hepatotoxicity.
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http://dx.doi.org/10.1080/21655979.2021.1950280DOI Listing
December 2021

Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease.

J Med Chem 2021 07 2;64(14):10047-10058. Epub 2021 Jul 2.

Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States.

A series of nondeuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally constrained cyclohexane moiety was synthesized and found to potently inhibit severe acute respiratory syndrome coronavirus-2 3CL protease in biochemical and cell-based assays. Several of the inhibitors were also found to be nanomolar inhibitors of Middle East respiratory syndrome coronavirus 3CL protease. The corresponding latent aldehyde bisulfite adducts were found to be equipotent to the precursor aldehydes. High-resolution cocrystal structures confirmed the mechanism of action and illuminated the structural determinants involved in binding. The spatial disposition of the compounds disclosed herein provides an effective means of accessing new chemical space and optimizing pharmacological activity. The cellular permeability of the identified inhibitors and lack of cytotoxicity warrant their advancement as potential therapeutics for COVID-19.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276672PMC
July 2021

Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.

Proc Natl Acad Sci U S A 2021 07;118(29)

Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506;

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.
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http://dx.doi.org/10.1073/pnas.2101555118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307543PMC
July 2021

Design of a New Acoustic Logging While Drilling Tool.

Sensors (Basel) 2021 Jun 26;21(13). Epub 2021 Jun 26.

ChangQing Branch of CNPC Logging, Xi'an 710075, China.

To obtain qualified logging while drilling (LWD) data, a new acoustic LWD tool was designed. Its overall design is introduced here, including the physical construction, electronic structure, and operation flowchart. Thereafter, core technologies adopted in this tool are presented, such as dominant exciting wave bands of dipole source, a sine wave pulse excitation circuit, broadband impedance matching, and an intellectualized active reception transducer. Lastly, we tested this tool in the azimuthal anisotropy module well, calibration well, and normal well, working in the model of the cable, sliding eye, and logging while drilling. Experiments showed that the core technologies achieved ideal results and that the LWD tool obtained qualified data.
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http://dx.doi.org/10.3390/s21134385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272091PMC
June 2021

LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling.

Nat Commun 2021 06 22;12(1):3830. Epub 2021 Jun 22.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

The molecular mechanism underlying pancreatic ductal adenocarcinoma (PDAC) malignancy remains unclear. Here, we characterize a long intergenic non-coding RNA LINC00842 that plays a role in PDAC progression. LINC00842 expression is upregulated in PDAC and induced by high concentration of glucose via transcription factor YY1. LINC00842 binds to and prevents acetylated PGC-1α from deacetylation by deacetylase SIRT1 to form PGC-1α, an important transcription co-factor in regulating cellular metabolism. LINC00842 overexpression causes metabolic switch from mitochondrial oxidative catabolic process to fatty acid synthesis, enhancing the malignant phenotypes of PDAC cells. High LINC00842 levels are correlated with elevated acetylated- PGC-1α levels in PDAC and poor patient survival. Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target.
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http://dx.doi.org/10.1038/s41467-021-23904-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219694PMC
June 2021

β3-adrenoceptor activation exhibits a dual effect on behaviors and glutamate receptor function in the prefrontal cortex.

Behav Brain Res 2021 Aug 19;412:113417. Epub 2021 Jun 19.

School of Life Sciences, Nanchang University, Nanchang, 330031, China. Electronic address:

β-adrenoceptor (β-AR), especially the β1- and β2-AR subtypes, is known to participate in stress-related behavioral changes. Recently, SR58611A, a brain-penetrant β3-AR agonist, exhibits anxiolytic- and antidepressant-like effects. In this study, we sought to study the role of SR58611A in behavioral changes and its potential cellular and molecular mechanism in the prefrontal cortex (PFC). We found that rats with SR58611A (1 mg/kg) enhanced PFC-mediated recognition memory, whereas administration of higher dosage of SR58611A (20 mg/kg) caused hyperlocomotion, and exhibited an impairment effect on recognition memory. Electrophysiological data also indicated that SR58611A (1 mg/kg) selectively enhanced NMDA receptor-mediated excitatory postsynaptic currents (EPSC) through interacting with norepinephrine (NE) system and activating β3-AR, whereas higher dosage of SR58611A (20 mg/kg) reduced both AMPA receptor- and NMDA receptor-mediated EPSC. SR58611A-induced different effects on EPSC linked with the change of the surface expression quantity of NMDA receptor and/or AMPA receptor subunits. Synaptosomal-associated protein 25 (SNAP-25), which is a key soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein involved in incorporation of NMDA receptor to postsynaptic membrane, contributed to SR58611A (1 mg/kg)-induced enhancement of recognition memory and NMDA receptor function. Moreover, SR58611A (1 mg/kg) could rescue repeated stress-induced defect of both recognition memory and NMDA receptor function through a SNAP-25-dependent mechanism. These results provide a potential mechanism underlying the cognitive-enhancing effects of SR58611A (1 mg/kg).
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http://dx.doi.org/10.1016/j.bbr.2021.113417DOI Listing
August 2021

Oncologic and survival outcomes in elderly patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy and total mesorectal excision.

Jpn J Clin Oncol 2021 Aug;51(9):1391-1399

Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.

Background: The efficacy of the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer in elderly patients has not been established.

Methods: A total of 3096 locally advanced rectal cancer patients who received neoadjuvant chemotherapy, along with neoadjuvant chemoradiotherapy and total mesorectal excision, with or without adjuvant chemotherapy, between January 2010 and December 2018, were studied retrospectively. Patients were divided into elderly (>75 years) and younger (≤75 years) groups, and propensity score matching was used to balance a potentially confounding clinical bias. Overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and local recurrence-free survival rates for the two groups were compared. Hazard ratios (HR) with 95% confidence intervals (CI) for different clinicopathological variables were calculated to determine predictors of 3-year overall survival.

Results: Mean follow-up was 39.0 (range, 5-140) months. The overall 3-year overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates were 86.1, 87.6, 80.0, 82.4 and 95.4%, respectively. Only 3-year overall survival rates differed significantly between the elderly (77.2%) and younger (88.9%) groups (P = 0.01). Cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates did not differ significantly between the two groups. Significant negative independent prognostic factors for 3-year overall survival were age >75 years (HR = 2.016, 95% CI 1.157-23.511, P = 0.01) and high pathologic TNM stage (yp stage III, P < 0.001).

Conclusion: For elderly locally advanced rectal cancer patients who have good health and performance status, the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision can result in disease-related survival rates and oncological outcomes similar to those experienced by younger patients. The decision to use this treatment approach in elderly patients should not be based solely on chronological age.
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http://dx.doi.org/10.1093/jjco/hyab095DOI Listing
August 2021

Long noncoding RNA SNHG3 promotes glioma tumorigenesis by sponging miR-485-5p to upregulate LMX1B expression.

Kaohsiung J Med Sci 2021 Jun 21. Epub 2021 Jun 21.

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.

LIM homeobox transcription factor 1-beta (LMX1B) has recently been found to be highly expressed in advanced gliomas and is associated with poor survival. However, the regulatory molecular mechanism of LMX1B expression in gliomas remains unclear. In this study, bioinformatics analysis showed that miR-485-5p may be the potential upstream regulator of LMX1B, and long noncoding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) may function as a competitive endogenous RNA to sponge miR-485-5p. In addition, the expression of SNHG3 and LMX1B in advanced glioma tissues was significantly upregulated, while the expression of miR-485-5p was significantly downregulated. SNHG3 overexpression reduced the expression of miR-485-5p; increased the expression of LMX1B; and promoted the proliferation, migration, and invasion of glioma cells. In contrast, miR-485-5p overexpression reduced the expression of LMX1B and inhibited cell proliferation, migration, and invasion. The luciferase reporter assay and RNA immunoprecipitation assay further confirmed the interaction between SNHG3 and miR-485-5p and between miR-485-5p and LMX1B. In addition, subcutaneous and orthotropic xenograft models confirmed that lncRNA SNHG3 silencing or miR-485-5p overexpression significantly reduced the growth of glioma xenografts and prolonged survival time. These results indicate that lncRNA SNHG3 can regulate the expression of LMX1B by sponging miR-485-5p, thereby promoting the proliferation, migration, and invasion of glioma cells. This study provides the first evidence that the SNHG3/miR-485-5p/LMX1B axis is involved in glioma tumorigenesis and highlights the potential of SNHG3 and miR-485-5p as therapeutic targets for glioma.
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http://dx.doi.org/10.1002/kjm2.12411DOI Listing
June 2021

Associations between clinical characteristics and tumor response to neoadjuvant chemoradiotherapy in rectal cancer.

Cancer Med 2021 07 15;10(14):4832-4843. Epub 2021 Jun 15.

Department of Radiation Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Following standard neoadjuvant chemoradiotherapy and total mesorectal excision, some patients with locally advanced rectal cancer achieve good response (pathological T0-2N0), while others show nonresponse (pathological T3-4N0 or node-positive). To date, the clinicopathological predictors of good response and the necessity of adjuvant chemotherapy treatment (ACT) in good responders remain unclear. In this retrospective study, clinicopathological characteristics were surveyed to investigate the correlation with good response; furthermore, a propensity score matching (PSM) model was designed to balance the confounding factors between good responders treated with ACT or observation. A total of 2255 patients were enrolled, including 1069 good responders and 1186 nonresponders. The results of the survival analysis showed a good response predicted a better 3-year prognosis (p < 0.001). The logistic regression analysis showed less advanced T and N stages (T3 vs. T4; N0 vs. N1-2), more neoadjuvant chemotherapy (nCT) cycles (≥4 vs. 1-3), and delayed surgery (≥8 weeks vs. <8 weeks) were independent predictors of a good response (p < 0.05). Especially, patients treated with both more nCT cycles and a delay in surgery included the greatest number of good responders (p < 0.001). For good responders, after PSM (1:3), 235 observation cases were matched to 705 ACT cases. As compared with observation, ACT had no greater impact on prognosis analysis (p > 0.05). In conclusion, more cycles of nCT and a delay in surgery predicted a better response, and the delivery of ACT might be omitted in good responders.
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http://dx.doi.org/10.1002/cam4.4051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290248PMC
July 2021

Middle East respiratory syndrome coronavirus Spike protein variants exhibit geographic differences in virulence.

Proc Natl Acad Sci U S A 2021 06;118(24)

Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242;

Human Middle East respiratory syndrome (MERS) cases were detected primarily in the Middle East before a major outbreak occurred in South Korea in 2015. The Korean outbreak was initiated by a single infected individual, allowing studies of virus evolution in the absence of further MERS-CoV introduction into human populations. In contrast, MERS is primarily a camel disease on the Arabian Peninsula and in Africa, with clinical disease in humans only in the former location. Previous work identified two mutations in the South Korean MERS-CoV, D510G and I529T on the Spike (S) protein, that led to impaired binding to the receptor. However, whether these mutations affected virulence is unknown. To address this question, we constructed isogenic viruses expressing mutations found in the S protein from Korean isolates and showed that isogenic viruses carrying the Korean MERS-CoV mutations, D510G or I529T, were attenuated in mice, resulting in greater survival, less induction of inflammatory cytokines, and less severe lung injury. In contrast, isogenic viruses expressing S proteins from African isolates were nearly fully virulent; other studies showed that West African camel isolates carry mutations in MERS-CoV accessory proteins, which may limit human transmission. These data indicate that following a single-point introduction of the virus, MERS-CoV S protein evolved rapidly in South Korea to adapt to human populations, with consequences on virulence. In contrast, the mutations in S proteins of African isolates did not change virulence, indicating that S protein variation likely does not play a major role in the lack of camel-to-human transmission in Africa.
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http://dx.doi.org/10.1073/pnas.2102983118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214665PMC
June 2021

Glycosylation of Siglec15 promotes immunoescape and tumor growth.

Am J Cancer Res 2021 15;11(5):2291-2302. Epub 2021 May 15.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University Guangzhou 510655, Guangdong, China.

Siglec15 is a recently characterized immunosuppressive transmembrane protein, which expresses in various types of solid tumors and promotes cancer development. Several studies reported that Siglec15 is a prognostic biomarker of cancer patients, and targeting Siglec15 may be a promising strategy for cancer therapy. However, the regulation of Siglec15 function remains unclear. Here we show that the immunosuppression activity of Siglec15 is largely modulated by N-glycosylation. Through mass spectrum and site mutation analysis, we identified that Siglec15 was extensively glycosylated at N172 (N173 for mouse) in cancer cells. Meanwhile, Siglec15 N172Q had a similar molecular weight with PNGase-F-treated Siglec15, suggesting N172 as the only one glycosylation residue. In xenograft model, glycosylation deficiency of Siglec15 reduced tumor growth in C57BL/6 mice, but had no impact in nude mice, indicating the requirement of N-glycosylation for immunosuppressive function of Siglec15. Furthermore, colorectal cancer patients with high Siglec15 expression had a poor response to neoadjuvant chemo-radiotherapy and short survival time. Interestingly, removal of N-glycosylation enhances the detection of Siglec15, which may be employed in the prediction of immunotherapy response. Together, our results disclose a pivotal role of glycosylated Siglec15 in tumor immune escape, which may be a therapeutic target for cancer immunotherapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167674PMC
May 2021

Coronavirus-specific antibody production in middle-aged mice requires phospholipase A2G2D.

J Clin Invest 2021 06;131(11)

Department of Microbiology and Immunology and.

Worse outcomes occur in aged compared with young populations after infections with respiratory viruses, including pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), and are associated with a suboptimal lung milieu ("inflammaging"). We previously showed that a single inducible phospholipase, PLA2G2D, is associated with a proresolving/antiinflammatory response in the lungs, and increases with age. Survival was increased in naive Pla2g2d-/- mice infected with SARS-CoV resulting from augmented respiratory dendritic cell (rDC) activation and enhanced priming of virus-specific T cells. Here, in contrast, we show that intranasal immunization provided no additional protection in middle-aged Pla2g2d-/- mice infected with any of the 3 pathogenic human coronaviruses because virtually no virus-specific antibodies or follicular helper CD4+ T (Tfh) cells were produced. Using MERS-CoV-infected mice, we found that these effects did not result from T or B cell intrinsic factors. Rather, they resulted from enhanced, and ultimately, pathogenic rDC activation, as manifested most prominently by enhanced IL-1β expression. Wild-type rDC transfer to Pla2g2d-/- mice in conjunction with partial IL-1β blockade reversed this defect and resulted in increased virus-specific antibody and Tfh responses. Together, these results indicate that PLA2G2D has an unexpected role in the lungs, serving as an important modulator of rDC activation, with protective and pathogenic effects in respiratory coronavirus infections and immunization, respectively.
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http://dx.doi.org/10.1172/JCI147201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266207PMC
June 2021

Effect of circular RNA, mmu_circ_0000296, on neuronal apoptosis in chronic cerebral ischaemia via the miR-194-5p/Runx3/Sirt1 axis.

Cell Death Discov 2021 May 29;7(1):124. Epub 2021 May 29.

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.

Chronic cerebral ischaemia (CCI) is a common pathological disorder, which is associated with various diseases, such as cerebral arteriosclerosis and vascular dementia, resulting in neurological dysfunction. As a type of non-coding RNA, circular RNA is involved in regulating the occurrence and development of diseases, such as ischaemic brain injury. Here, we found that HT22 cells and hippocampus treated with CCI had low expression of circ_0000296, Runx3, Sirt1, but high expression of miR-194-5p. Overexpression of circ_0000296, Runx3, Sirt1, and silenced miR-194-5p significantly inhibited neuronal apoptosis induced by CCI. This study demonstrated that circ_0000296 specifically bound to miR-194-5p; miR-194-5p bound to the 3'UTR region of Runx3 mRNA; Runx3 directly bound to the promoter region of Sirt1, enhancing its transcriptional activity. Overexpression of circ_0000296 by miR-194-5p reduced the negative regulatory effect of miR-194-5p on Runx3, promoted the transcriptional effect of Runx3 on Sirt1, and inhibited neuronal apoptosis induced by CCI. mmu_circ_0000296 plays an important role in regulating neuronal apoptosis induced by CCI through miR-194-5p/Runx3/Sirt1 pathway.
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http://dx.doi.org/10.1038/s41420-021-00507-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164632PMC
May 2021

Glioma glycolipid metabolism: MSI2-SNORD12B-FIP1L1-ZBTB4 feedback loop as a potential treatment target.

Clin Transl Med 2021 05;11(5):e411

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.

Abnormal energy metabolism, including enhanced aerobic glycolysis and lipid synthesis, is a well-established feature of glioblastoma (GBM) cells. Thus, targeting the cellular glycolipid metabolism can be a feasible therapeutic strategy for GBM. This study aimed to evaluate the roles of MSI2, SNORD12B, and ZBTB4 in regulating the glycolipid metabolism and proliferation of GBM cells. MSI2 and SNORD12B expression was significantly upregulated and ZBTB4 expression was significantly low in GBM tissues and cells. Knockdown of MSI2 or SNORD12B or overexpression of ZBTB4 inhibited GBM cell glycolipid metabolism and proliferation. MSI2 may improve SNORD12B expression by increasing its stability. Importantly, SNORD12B increased utilization of the ZBTB4 mRNA transcript distal polyadenylation signal in alternative polyadenylation processing by competitively combining with FIP1L1, which decreased ZBTB4 expression because of the increased proportion of the 3' untranslated region long transcript. ZBTB4 transcriptionally suppressed the expression of HK2 and ACLY by binding directly to the promoter regions. Additionally, ZBTB4 bound the MSI promoter region to transcriptionally suppress MSI2 expression, thereby forming an MSI2/SNORD12B/FIP1L1/ZBTB4 feedback loop to regulate the glycolipid metabolism and proliferation of GBM cells. In conclusion, MSI2 increased the stability of SNORD12B, which regulated ZBTB4 alternative polyadenylation processing by competitively binding to FIP1L1. Thus, the MSI2/SNORD12B/FIP1L1/ZBTB4 positive feedback loop plays a crucial role in regulating the glycolipid metabolism of GBM cells and provides a potential drug target for glioma treatment.
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http://dx.doi.org/10.1002/ctm2.411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114150PMC
May 2021

Two Enhancers Regulate Genes Expression During Retinoic Acid-Induced Early Embryonic Stem Cells Differentiation Through Long-Range Chromatin Interactions.

Stem Cells Dev 2021 Jul 24;30(13):683-695. Epub 2021 May 24.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.

Homeobox B cluster () genes play important roles in retinoic acid (RA)-induced early embryonic stem cells (ESCs) differentiation. Knowledge of regulation network of is important to further unveil the mechanism of ESCs differentiation. In this study, we identified two enhancers that were activated by RA treatment and 4C data showed long-range interactions between genes and the two enhancers. CRISPR/Cas9-mediated individual or compound deletion of the two enhancers significantly inhibits gene expression, and transcriptome analysis revealed that RA-induced early ESCs differentiation was blocked in the enhancer KO cells. We propose new mechanism by which two enhancers regulate gene expression by different regulation modes during RA-induced early ESCs differentiation through long-range chromatin interactions.
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http://dx.doi.org/10.1089/scd.2021.0020DOI Listing
July 2021

Role of bronchoalveolar lavage fluid and serum interleukin-27 in the diagnosis of smear-negative pulmonary tuberculosis.

Medicine (Baltimore) 2021 May;100(20):e25821

Department of Respiratory and Critical Care Medicine.

Background: To evaluate the value of interleukin (IL)-27 measured in serum and bronchoalveolar lavage fluid (BALF) for the diagnosis of smear-negative pulmonary tuberculosis (TB).

Methods: This was a prospective study of patients planned to undergo bronchoscopy at Wuxi No.5 People's Hospital between January 2017 and September 2018. The patients were grouped as the TB and control groups. BALF and serum IL-27 were measured by ELISA. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value and calculate the optimal cutoff values.

Results: There were 40 patients in the control group and 87 in the TB group. In the TB group, 20 had positive sputum smear results and 67 were negative. The area under the ROC curve (AUC) of BALF IL-27 for pulmonary TB was 0.897 (95% CI: 0.830-0.944) (P < .001). The AUC of serum IL-27 for pulmonary TB was 0.703 (95% CI: 0.616-0.781) (P < .001). In patients with negative sputum smear results, the AUCs of BALF IL-27 and serum IL-27 for pulmonary TB was 0.882 (95% confidence interval [CI]: 0.805-0.936) (P < .001) and 0.679 (95% CI: 0.601-0.782) (P < .001), respectively.

Conclusions: BALF IL-27 can be used for the diagnosis of pulmonary TB, particularly in those with a negative sputum smear result. Serum IL-27 could be an auxiliary method for TB screening.
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http://dx.doi.org/10.1097/MD.0000000000025821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137093PMC
May 2021

Serum levels of miR-21-5p and miR-339-5p associate with occupational trichloroethylene hypersensitivity syndrome.

J Occup Med Toxicol 2021 May 17;16(1):19. Epub 2021 May 17.

Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China.

Background: Trichloroethylene (TCE) hypersensitivity syndrome (THS) is a dose-independent and potentially life-threatening disease. In this study, we sought to identify THS-related miRNAs and evaluate its potential clinical value.

Methods: Serum samples of five patients and five matched TCE contacts were used for screening differential miRNAs. Another 34 patients and 34 matched TCE contacts were used for verifying significantly differential miRNAs with SYBR™ Green PCR and MGB PCR. The diagnostic model based on these miRNAs was established via the support vector machine (SVM) algorithm. Correlation between differential miRNAs and liver function was analyzed via the Spearman correlation test.

Results: A total of 69 miRNAs was found to be differentially expressed. MiR-21-5p and miR-339-5p were verified to have significant higher expressions in patients. The sensitivity, specificity and accuracy of disease model were 100, 75 and 86%, respectively. The two miRNAs showed significant correlations with liver function.

Conclusion: These findings suggested that miRNAs profiles in serum of THS patients had changed significantly, and miR-21-5p and miR-339-5p were associated with THS.
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http://dx.doi.org/10.1186/s12995-021-00308-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127200PMC
May 2021

Physiological and transcriptomic analyses characterized high temperature stress response mechanisms in Sorbus pohuashanensis.

Sci Rep 2021 May 12;11(1):10117. Epub 2021 May 12.

School of Landscape Architecture, Beijing University of Agriculture, Beijing, 102206, China.

Sorbus pohuashanensis (Hance) Hedl. is a Chinese native alpine tree species, but the problem of introducing S. pohuashanensis to low altitude areas has not been solved. In this study, we aimed to explore the molecular regulatory network of S. pohuashanensis in response to high-temperature stress using RNA-Sequencing technology and physiological and biochemical determination. Based on transcriptomic data, we obtained 1221 genes (752 up-regulated and 469 down-regulated) that were differentially expressed during 8 h 43℃ treatment and candidate genes were related to calcium signaling pathway, plant hormone signal transduction, heat shock factors, chaperones, ubiquitin mediated proteolysis, cell wall modification, ROS scavenging enzymes, detoxification and energy metabolism. The analysis of high temperature response at the physiological level and biochemical level were performed. The chlorophyll fluorescence parameters of leaf cells decreased, the content of osmotic regulators increased, and the activity of ROS scavenging enzymes decreased. The molecular regulatory network of S. pohuashanensis in response to high-temperature stress was preliminarily revealed in this study, which provides fundamental information improving introducing methods and discovering heat-tolerant genes involved in high-temperature stress in this species and provides a reference for other plants of the genus Sorbus.
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http://dx.doi.org/10.1038/s41598-021-89418-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115228PMC
May 2021

Usefulness of New Shear Wave Elastography Technique for Noninvasive Assessment of Liver Fibrosis in Patients with Chronic Hepatitis B: A Prospective Multicenter Study.

Ultraschall Med 2021 Apr 28. Epub 2021 Apr 28.

Department of Ultrasound, Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Purpose:  To explore the usefulness of liver stiffness measurements (LSMs) by sound touch elastography (STE) and sound touch quantification (STQ) in chronic hepatitis B (CHB) patients for staging fibrosis.

Methods:  This prospective multicenter study recruited normal volunteers and CHB patients between May 2018 and October 2019. The volunteers underwent LSM by STE and supersonic shear imaging (SSI) or by STQ and acoustic radiation force impulse imaging (ARFI). CHB patients underwent liver biopsy and LSM by both STE/STQ. The areas under the receiver operating characteristic curves (AUCs) for staging fibrosis were calculated.

Results:  Overall, 97 volunteers and 524 CHB patients were finally eligible for the study. The successful STE and STQ measurement rates were both 100 % in volunteers and 99.4 % in CHB patients. The intraclass correlation coefficients (ICCs) for the intra-observer stability of STE and STQ (0.94; 0.90) were similar to those of SSI and ARFI (0.95; 0.87), respectively. STE and STQ showed better accuracy than the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) (AUC: 0.87 vs 0.86 vs 0.73 vs 0.77) in staging cirrhosis. However, both STE and STQ were not superior to APRI and FIB-4 in staging significant fibrosis (AUC: 0.76 vs 0.73 vs 0.70 vs 0.71, all P-values > 0.05).

Conclusion:  STE and STQ are convenient techniques with a reliable LSM value. They have a similar diagnostic performance and are superior to serum biomarkers in staging cirrhosis in CHB patients.
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http://dx.doi.org/10.1055/a-1376-6734DOI Listing
April 2021

Eicosanoid signaling as a therapeutic target in middle-aged mice with severe COVID-19.

bioRxiv 2021 Apr 21. Epub 2021 Apr 21.

Coronavirus disease 2019 (COVID-19) is especially severe in aged populations . Resolution of the COVID-19 pandemic has been advanced by the recent development of SARS-CoV-2 vaccines, but vaccine efficacy is partly compromised by the recent emergence of SARS-CoV-2 variants with enhanced transmissibility . The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially in aged populations. Here, we describe the isolation of a new set of highly virulent mouse-adapted viruses and use them to test a novel therapeutic drug useful in infections of aged animals. Initially, we show that many of the mutations observed in SARS-CoV-2 during mouse adaptation (at positions 417, 484, 501 of the spike protein) also arise in humans in variants of concern (VOC) . Their appearance during mouse adaptation indicates that immune pressure is not required for their selection. Similar to the human infection, aged mice infected with mouse-adapted SARS-CoV-2 develop more severe disease than young mice. In murine SARS, in which severity is also age-dependent, we showed that elevated levels of an eicosanoid, prostaglandin D2 (PGD ) and of a phospholipase, PLA G2D, contributed to poor outcomes in aged mice . Using our virulent mouse-adapted SARS-CoV-2, we show that infection of middle-aged mice lacking expression of DP1, a PGD receptor, or PLA G2D are protected from severe disease. Further, treatment with a DP1 antagonist, asapiprant, protected aged mice from a lethal infection. DP1 antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, and demonstrates that the PLA G2D-PGD /DP1 pathway is a useful target for therapeutic interventions. (Words: 254).
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http://dx.doi.org/10.1101/2021.04.20.440676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077574PMC
April 2021
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