Publications by authors named "Xiaowen Liu"

381 Publications

Cysteine Metabolism in Tumor Redox Homeostasis.

Curr Med Chem 2022 Aug 17. Epub 2022 Aug 17.

Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443003, P.R. China.

Cysteine (Cys) is a semi-essential nutrient amino acid, which plays an important role in cells through endogenous production and various transport systems. Intracellular Cys can be used as a precursor of protein synthesis to maintain cell homeostasis and is used to generate sulfur-containing substances, including glutathione (GSH), hydrogen sulfide (H2S), and taurine. There have been quite a few reports that Cys is related to tumor occurrence and development, and its level is closely related to tumor proliferation, invasion, and metastasis. Moreover, it helps in maintaining the tumor redox balance and increasing drug resistance. This review aims to summarize the production and metabolism of Cys and its role in tumors, with special emphasis on the potential therapeutic value of Cys in tumors to improve the quality of life of cancer patients.
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http://dx.doi.org/10.2174/0929867329666220817141227DOI Listing
August 2022

Optimization of protein-level tandem mass tag (TMT) labeling conditions in complex samples with top-down proteomics.

Anal Chim Acta 2022 Aug 7;1221:340037. Epub 2022 Jun 7.

Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73019, USA. Electronic address:

Isobaric chemical tag labels (e.g., iTRAQ and TMT) have been extensively utilized as a standard quantification approach in bottom-up proteomics, which provides high multiplexing capacity and enables MS2-level quantification while not complicating the MS1 scans. We recently demonstrated the feasibility of intact protein TMT labeling for the identification and quantification with top-down proteomics of smaller intact proteoforms (<35 kDa) in complex biological samples through the removal of large proteins prior to labeling. Still, the production of side products during TMT labeling (i.e., incomplete labeling or labeling of unintended residues) complicated the analysis of complex protein samples. In this study, we systematically evaluated the protein-level TMT labeling reaction parameters, including TMT-to-protein mass ratio, pH/concentration of quenching buffer, protein concentration, reaction time, and reaction buffer. Our results indicated that: (1) high TMT-to-protein mass ratio (e.g., 8:1, 4:1), (2) high pH/concentration of quenching buffer (pH > 9.1, final hydroxylamine concentration >0.3%), and (3) high protein concentration (e.g., > 1.0 μg/μL) resulted in optimal labeling efficiency and minimized production of over/underlabeled side products. >90% labeling efficiency was achieved for E. coli cell lysate after optimization of protein-level TMT labeling conditions. In addition, a double labeling approach was developed for efficiently labeling limited biological samples with low concentrations. This research provides practical guidance for efficient TMT labeling of complex intact protein samples, which can be readily adopted in the high-throughput quantification top-down proteomics.
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http://dx.doi.org/10.1016/j.aca.2022.340037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371347PMC
August 2022

mRNA vaccines induce rapid antibody responses in mice.

NPJ Vaccines 2022 Aug 1;7(1):88. Epub 2022 Aug 1.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

mRNA vaccines can be developed and produced quickly, making them prime candidates for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. Thus, we sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first compared the immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA (4 µg/mouse), but not DNA (50 µg/mouse), immunization. Comparing innate responses hours post immunization, the mRNA vaccine induced increased levels of IL-5, IL-6, and MCP-1 cytokines which maybe promoting humoral responses downstream. We then evaluated the immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines of the same HIV-1 envelope antigen in mice. Again, induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Thus, eliciting rapid humoral immunity may be a unique and advantageous property of mRNA vaccines for controlling infectious disease outbreaks.
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http://dx.doi.org/10.1038/s41541-022-00511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340693PMC
August 2022

Quantum Linear System Algorithm for General Matrices in System Identification.

Entropy (Basel) 2022 Jun 29;24(7). Epub 2022 Jun 29.

College of Information and Communication, National University of Defense Technology, Xi'an 710006, China.

Solving linear systems of equations is one of the most common and basic problems in classical identification systems. Given a coefficient matrix and a vector , the ultimate task is to find the solution such that Ax=b. Based on the technique of the singular value estimation, the paper proposes a modified quantum scheme to obtain the quantum state |x⟩ corresponding to the solution of the linear system of equations in O(κ2rpolylog(mn)/ϵ) time for a general m×n dimensional , which is superior to existing quantum algorithms, where κ is the condition number, is the rank of matrix and ϵ is the precision parameter. Meanwhile, we also design a quantum circuit for the homogeneous linear equations and achieve an exponential improvement. The coefficient matrix in our scheme is a sparsity-independent and non-square matrix, which can be applied in more general situations. Our research provides a universal quantum linear system solver and can enrich the research scope of quantum computation.
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http://dx.doi.org/10.3390/e24070893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323527PMC
June 2022

Dexamethasone Sensitizes Acute Monocytic Leukemia Cells to Ara-C by Upregulating FKBP51.

Front Oncol 2022 4;12:888695. Epub 2022 Jul 4.

Department of Central Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, China.

In this study, we demonstrated that the expression of FK506 binding protein 51 (FKBP51) is upregulated in acute monocytic leukemia (AML-M5) cells by dexamethasone and aimed to investigate the possible effects of FKBP51 on the growth and cytarabine sensitivity of AML-M5 cells. THP-1 and U937cells were used to establish AML-M5 cell models with FKBP51 overexpression and knockdown, respectively. Cell proliferation, apoptosis and response to cytarabine were investigated by cell cycle, CCK-8 and Flow cytometry analyses. The mice experiment was conducted to detect the role of FKBP51 on AML-M5 cells proliferation and antileukemia effect of Ara-C/Dexamethasone co-therapy . Western blots were employed to determine protein expression levels. FKBP51 upregulation significantly attenuated THP-1 cell proliferation and sensitized the cells to cytarabine treatment which was further enhanced by dexamethasone. These effects were indicated by decreases in cell viability, S-G2/M phase cell cycle distribution, cytarabine 50% inhibitory concentration (IC50) values and increases in apoptosis and were supported by decreased phosphorylation levels of AKT, GSK3β and FOXO1A and decreased levels of BCL-2 and increased levels of P21 and P27. In contrast, FKBP51 knockdown led to excessive U937 cell proliferation and cytarabine resistance, as indicated by increased cell viability and S-G2/M phase cell cycle distribution, decreased apoptosis, increased phosphorylation levels of AKT, GSK3β and FOXO1A, and increased BCL-2 and decreased P21 and P27 expression. In addition, an AKT inhibitor blocked cell cycle progression and reduced cell viability in all groups of cells. Furthermore, SAFit2, a specific FKBP51 inhibitor, increased U937 cell viability and cytarabine resistance as well as AKT phosphorylation. In conclusion, FKBP51 decelerates proliferation and improves the cytarabine sensitivity of AML-M5 cells by inhibiting AKT pathways, and dexamethasone in combination with Ara-C improves the chemosensitivity of AML-M5.
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http://dx.doi.org/10.3389/fonc.2022.888695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9290766PMC
July 2022

Erratum: General method to stabilize mesophilic proteins in hyperthermal water.

iScience 2022 Jul 29;25(7):104662. Epub 2022 Jun 29.

[This corrects the article DOI: 10.1016/j.isci.2021.102503.].
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http://dx.doi.org/10.1016/j.isci.2022.104662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254118PMC
July 2022

Metastasis Related Epithelial-Mesenchymal Transition Signature Predicts Prognosis and Response to Immunotherapy in Gastric Cancer.

Front Immunol 2022 13;13:920512. Epub 2022 Jun 13.

Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Increasing evidence has revealed the effect of epithelial-mesenchymal transition (EMT) on tumor microenvironment and cancer treatment. However, an EMT-based signature to predict the prognosis and therapeutic effect in gastric cancer (GC) has rarely been established.

Methods: Differentially expressed genes (DEGs) between paired primary gastric and ovarian metastatic tumors were identified through comparative RNA-seq analysis, followed by the construction of metastasis-related EMT signature (MEMTS) based on DEGs and EMT gene set. Then, both The Cancer Genome Atlas (TCGA) cohort and the Asian Cancer Research Group (ACRG) cohort were analyzed to explore the potential association between MEMTS and prognosis in GC. Samsung Medical Center (SMC) cohort and two individual immunotherapy treatment cohorts, including Kim cohort and Hugo cohort, were utilized to evaluate the predictive value of MEMTS on the response to adjuvant therapy and immunotherapy, respectively. Finally, the potential association of MEMTS with tumor environment and immune escape mechanisms was investigated.

Results: High MEMTS predicted a poor prognosis in patients with GC. Patients with low MEMTS potentially gained more benefits from adjuvant chemoradiotherapy than those with high MEMTS. MEMTS reliably predicted the response to immunotherapy in GC (area under the curve = 0.896). MEMTS was significantly associated with cancer-associated fibroblasts and stromal score in the aspect of the tumor microenvironment.

Conclusion: MEMTS serves as a potential biomarker to predict the prognosis and response to adjuvant therapy and immunotherapy in GC. MEMTS-based evaluation of individual tumors enables personalized treatment for GC patients in the future.
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http://dx.doi.org/10.3389/fimmu.2022.920512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234207PMC
June 2022

A study protocol of a randomized phase II trial of perioperative chemoimmunotherapy verses perioperative chemoimmunotherapy plus preoperative chemoradiation for locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma: the NeoRacing study.

BMC Cancer 2022 Jun 28;22(1):710. Epub 2022 Jun 28.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China.

Background: Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC.

Methods: Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy.

Discussion: The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety.

Trial Registration: ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12885-022-09786-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9238164PMC
June 2022

Genome-Wide Reassortment Analysis of Influenza A H7N9 Viruses Circulating in China during 2013-2019.

Viruses 2022 06 9;14(6). Epub 2022 Jun 9.

Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.

Reassortment with the H9N2 virus gave rise to the zoonotic H7N9 avian influenza virus (AIV), which caused more than five outbreak waves in humans, with high mortality. The frequent exchange of genomic segments between H7N9 and H9N2 has been well-documented. However, the reassortment patterns have not been described and are not yet fully understood. Here, we used phylogenetic analyses to investigate the patterns of intersubtype and intrasubtype/intralineage reassortment across the eight viral segments. The H7N9 virus and its progeny frequently exchanged internal genes with the H9N2 virus but rarely with the other AIV subtypes. Before beginning the intrasubtype/intralineage reassortment analyses, five Yangtze River Delta (YRD A-E) and two Pearl River Delta (PRD A-B) clusters were divided according to the HA gene phylogeny. The seven reset segment genes were also nomenclatured consistently. As revealed by the tanglegram results, high intralineage reassortment rates were determined in waves 2-3 and 5. Additionally, the clusters of PB2 c05 and M c02 were the most dominant in wave 5, which could have contributed to the onset of the largest H7N9 outbreak in 2016-2017. Meanwhile, a portion of the YRD-C cluster (HP H7N9) inherited their PB2, PA, and M segments from the co-circulating YRD-E (LP H7N9) cluster during wave 5. Untanglegram results revealed that the reassortment rate between HA and NA was lower than HA with any of the other six segments. A multidimensional scaling plot revealed a robust genetic linkage between the PB2 and PA genes, indicating that they may share a co-evolutionary history. Furthermore, we observed relatively more robust positive selection pressure on HA, NA, M2, and NS1 proteins. Our findings demonstrate that frequent reassortment, particular reassorted patterns, and adaptive mutations shaped the H7N9 viral genetic diversity and evolution. Increased surveillance is required immediately to better understand the current state of the HP H7N9 AIV.
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http://dx.doi.org/10.3390/v14061256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230085PMC
June 2022

Amino Acid Mutations in Hemagglutinin-Neuraminidase Enhance the Virulence and Pathogenicity of the Genotype III Newcastle Disease Vaccine Strain After Intravenous Inoculation.

Front Vet Sci 2022 27;9:890657. Epub 2022 May 27.

Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.

Newcastle disease virus (NDV), the causative agent that generally causes severe disease in poultry, continues to mutate and has thus evolved into 21 genotypes. We previously isolated a velogenic genotype III NDV JS/7/05/Ch that evolved from the vaccine strain Mukteswar, accompanying by amino acid mutations in Hemagglutinin-Neuraminidase (HN). Here, we sought to investigate the role of the mutant HN protein in NDV virulence. The HN genes of Mukteswar and JS/7/05/Ch were replaced reciprocally via reverse genetics, yielding two recombinant viruses rJS/MHN and rMu/JHN, respectively. rMu/JHN, in which the endogenous HN protein was replaced with the HN protein of JS/7/05/Ch, had a higher intravenous pathogenicity index (IVPI) value in chickens. Moreover, dual aa mutations (A494D and E495K from JS/7/05/Ch-type HN) were introduced into the HN protein of Mukteswar to generate the recombinant virus rMukHN494+495. This virus showed an equivalent IVPI value to that of rJS/7/05/Ch (generated from parental JS/7/05/Ch via reverse genetics). and assays further showed that A494D and E495K in HN induced antigenic changes, a higher replication level and a more intense inflammatory response. Taken together, these findings indicate that aa mutations in HN are crucial for the virulence of the genotype III Newcastle disease (ND) vaccine strain after intravenous inoculation. Our study further highlights that close surveillance is needed to monitor the genetic variation of ND vaccine strains.
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http://dx.doi.org/10.3389/fvets.2022.890657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9196742PMC
May 2022

Top-Down Mass Spectrometry Data Analysis Using TopPIC Suite.

Methods Mol Biol 2022 ;2500:83-103

Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, USA.

With the advances of mass spectrometry (MS) techniques, top-down MS-based proteomics has gained increasing attention because of its advantages over bottom-up MS in studying complex proteoforms. TopPIC Suite is a widely used software package for top-down MS-based proteoform identification and quantification. Here, we present the methods for top-down MS data analysis using TopPIC Suite.
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http://dx.doi.org/10.1007/978-1-0716-2325-1_8DOI Listing
January 2022

Intranasal Immunization with a Recombinant Avian Paramyxovirus Serotypes 2 Vector-Based Vaccine Induces Protection against H9N2 Avian Influenza in Chicken.

Viruses 2022 04 28;14(5). Epub 2022 Apr 28.

Animal Infectious Disease Laboratory, School of Veterinary Medicine, Yangzhou University, Yangzhou 225000, China.

Commercial inactivated vaccines against H9N2 avian influenza (AI) have been developed in China since 1990s and show excellent immunogenicity with strong HI antibodies. However, currently approved vaccines cannot meet the clinical demand for a live-vectored vaccine. Newcastle disease virus (NDV) vectored vaccines have shown effective protection in chickens against H9N2 virus. However, preexisting NDV antibodies may affect protective efficacy of the vaccine in the field. Here, we explored avian paramyxovirus serotype 2 (APMV-2) as a vector for developing an H9N2 vaccine via intranasal delivery. APMV-2 belongs to the same genus as NDV, distantly related to NDV in the phylogenetic tree, based on the sequences of Fusion (F) and hemagglutinin-neuraminidase (HN) gene, and has low cross-reactivity with anti-NDV antisera. We incorporated hemagglutinin (HA) of H9N2 into the junction of P and M gene in the APMV-2 genome by being flanked with the gene start, gene end, and UTR of each gene of APMV-2-T4 to generate seven recombinant APMV-2 viruses rAPMV-2/HAs, rAPMV-2-NPUTR-HA, rAPMV-2-PUTR-HA, rAPMV-2-FUTR-HA, rAPMV-2-HNUTR-HA, rAPMV-2-LUTR-HA, and rAPMV-2-MUTR-HA, expressing HA. The rAPMV-2/HAs displayed similar pathogenicity compared with the parental APMV-2-T4 virus and expressed HA protein in infected CEF cells. The NP-UTR facilitated the expression and secretion of HA protein in cells infected with rAPMV-2-NPUTR-HA. Animal studies demonstrated that immunization with rAPMV-2-NPUTR-HA elicited effective H9N2-specific antibody (6.14 ± 1.2 log2) responses and conferred complete immune protection to prevent viral shedding in the oropharyngeal and cloacal swabs from chickens challenged with H9N2 virus. This study suggests that our recombinant APMV-2 virus is safe and immunogenic and can be a useful tool in the combat of H9N2 outbreaks in chicken.
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http://dx.doi.org/10.3390/v14050918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144924PMC
April 2022

Construction of ovarian metastasis-related immune signature predicting prognosis of gastric cancer patients.

Cancer Med 2022 May 27. Epub 2022 May 27.

Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Ovarian metastasis (OM) results in poor survival of gastric cancer (GC) patients. While immunotherapy has emerged as a promising approach for late-stage GC, validated immune-related prognostic signatures still remain in need. In this study, we constructed an ovarian metastasis- and immune-related prognostic signature (OMIRPS), characterized the molecular and immune features of OMIRPS-categorized subgroups and predicted their potential response to immunotherapy.

Methods: Three individual cohorts were used to construct and evaluate OMIRPS: RNA-seq of matched primary GC and OM from Fudan University Shanghai Cancer Center (FUSCC) (discovery cohort, n = 4), The Cancer Genome Atlas (TCGA) (training cohort, n = 544) and GSE84437 (validation cohort, n = 433). Differentially expressed genes (DEGs) identified between primary GC and OM and immune-related genes (IRGs) from the ImmPort and InnateDB databases were used to identify immune-related prognostic hub genes, which were further used to construct OMIRPS by using LASSO regression analysis. Prognosis, molecular characteristics, immune features, and differential immunotherapy efficacy between different OMIRPS subgroups were analyzed.

Results: Functional analyses of DEGs revealed the significance of immune-related signatures and pathways in the OM. Immune-related prognostic hub genes including TNFRSF18, CARD11, BCL11B, NRP1, BNIP3L, and ATF3 were utilized to construct OMIRPS, which was identified as an independent prognostic factor. Comprehensive analyses unveiled the distinctive molecular and immune characteristics of OMIRPS-high and -low subgroup in regard to enriched pathways, mutation rate, tumor mutation burden, microsatellite instability status, infiltrated immune cell, immune exclusion score, and the prediction of immunotherapy efficacy. Additionally, OMIRPS was associated with Immune Subtypes with borderline significance.

Conclusions: RNA-seq of paired primary and ovarian metastatic tumors unveiled the significance of immune-related pathways and tumor immune microenvironment in OM. OMIRPS served as a promising biomarker to predict the prognosis of GC patients and distinguish the molecular features, immune characteristics, and efficacy of immunotherapy between different subgroups.
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http://dx.doi.org/10.1002/cam4.4857DOI Listing
May 2022

Evaluation of Machine Learning Models for Proteoform Retention and Migration Time Prediction in Top-Down Mass Spectrometry.

J Proteome Res 2022 07 26;21(7):1736-1747. Epub 2022 May 26.

Tulane Center for Biomedical Informatics and Genomics, Tulane University, New Orleans, Louisiana 70112, United Staes.

Reversed-phase liquid chromatography (RPLC) and capillary zone electrophoresis (CZE) are two primary proteoform separation methods in mass spectrometry (MS)-based top-down proteomics. Proteoform retention time (RT) prediction in RPLC and migration time (MT) prediction in CZE provide additional information for accurate proteoform identification and quantification. While existing methods are mainly focused on peptide RT and MT prediction in bottom-up MS, there is still a lack of methods for proteoform RT and MT prediction in top-down MS. We systematically evaluated eight machine learning models and a transfer learning method for proteoform RT prediction and five models and the transfer learning method for proteoform MT prediction. Experimental results showed that a gated recurrent unit (GRU)-based model with transfer learning achieved a high accuracy ( = 0.978) for proteoform RT prediction and that the GRU-based model and a fully connected neural network model obtained a high accuracy of = 0.982 and 0.981 for proteoform MT prediction, respectively.
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http://dx.doi.org/10.1021/acs.jproteome.2c00124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250612PMC
July 2022

Deepm5C: A deep-learning-based hybrid framework for identifying human RNA N5-methylcytosine sites using a stacking strategy.

Mol Ther 2022 Aug 6;30(8):2856-2867. Epub 2022 May 6.

Tulane Center for Biomedical Informatics and Genomics, Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA. Electronic address:

As one of the most prevalent post-transcriptional epigenetic modifications, N5-methylcytosine (m5C) plays an essential role in various cellular processes and disease pathogenesis. Therefore, it is important accurately identify m5C modifications in order to gain a deeper understanding of cellular processes and other possible functional mechanisms. Although a few computational methods have been proposed, their respective models have been developed using small training datasets. Hence, their practical application is quite limited in genome-wide detection. To overcome the existing limitations, we propose Deepm5C, a bioinformatics method for identifying RNA m5C sites throughout the human genome. To develop Deepm5C, we constructed a novel benchmarking dataset and investigated a mixture of three conventional feature-encoding algorithms and a feature derived from word-embedding approaches. Afterward, four variants of deep-learning classifiers and four commonly used conventional classifiers were employed and trained with the four encodings, ultimately obtaining 32 baseline models. A stacking strategy is effectively utilized by integrating the predicted output of the optimal baseline models and trained with a one-dimensional (1D) convolutional neural network. As a result, the Deepm5C predictor achieved excellent performance during cross-validation with a Matthews correlation coefficient and an accuracy of 0.697 and 0.855, respectively. The corresponding metrics during the independent test were 0.691 and 0.852, respectively. Overall, Deepm5C achieved a more accurate and stable performance than the baseline models and significantly outperformed the existing predictors, demonstrating the effectiveness of our proposed hybrid framework. Furthermore, Deepm5C is expected to assist community-wide efforts in identifying putative m5Cs and to formulate the novel testable biological hypothesis.
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http://dx.doi.org/10.1016/j.ymthe.2022.05.001DOI Listing
August 2022

Pan-cancer analysis reveals RIPK2 predicts prognosis and promotes immune therapy resistance via triggering cytotoxic T lymphocytes dysfunction.

Mol Med 2022 05 4;28(1):47. Epub 2022 May 4.

Department of Gastric Surgery, Fudan University Shanghai Cancer Center, 200030, Shanghai, China.

Background: Receptor-interacting protein kinase 2 (RIPK2, also known as RIP2) was reported to be associated with bacterial infections as well as inflammatory responses. However, the role of RIPK2 in prognosis and immunotherapy response is yet to be elucidated in human pan-cancer.

Methods: In this study, we investigated the expression, gene alteration landscape and prognostic value of RIPK2 in 33 cancers through various databases including Ualcan, cBioportal and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Then, the correlation between RIPK2 and immune infiltration, immune score, stromal score, and ESTIMATE score was investigated in the Cancer Genome Atlas (TCGA) and tumor immune estimation resource (TIMER) databases. Independent cohorts were utilized to explore the role of RIPK2 in tumor immunotherapy response. Furthermore, Gene set enrichment analysis (GSEA) was conducted to explore the mechanisms by which RIPK2 regulates immune therapy resistance. Single-cell RNA-seq datasets were used to analyze the expression level of RIPK2 on different immune cells. Moreover, CellMiner database was used to explore the relationship between RIPK2 expression with drug response.

Result: Compared with normal tissue, tumor tissue had a higher expression level of RIPK2 in various cancers. Survival analysis showed that high expression of RIPK2 associated with poor prognosis in numerous cancers. RIPK2 was found to promote a series of immune cell infiltration and B cells, macrophages, and neutrophils were significantly positively correlated with the expression of RIPK2. Moreover, RIPK2 affected immune score, stromal score and ESTIMATE score for a wide range of cancers. In the vast majority of 33 cancers, gene co-expression analysis showed that RIPK2 was positively correlated with the expression of immune checkpoint markers, such as PDCD1 (PD-1), CD274 (PD-L1), CTLA4 and TIGIT. RIPK2 aggravated cytotoxic T lymphocyte (CTL) dysfunction and related to the poor efficacy of immune checkpoint blockade in skin cutaneous melanoma (SKCM) and kidney renal clear cell carcinoma (KIRC). High expression of RIPK2 promoted innate immunotherapy resistance and adaptive immunotherapy resistance through IL-6/JAK/STAT3 signaling, interferon-gamma response, and interferon-alpha response pathway.

Conclusions: These results confirmed that RIPK2 could serve as a prognostic biomarker and promoted immune therapy resistance via triggering cytotoxic T lymphocytes dysfunction.
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http://dx.doi.org/10.1186/s10020-022-00475-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066895PMC
May 2022

[Scanning electron microscope of the human nasal septum].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2022 May;36(5):335-337;342

Department of Otorhinolaryngology Head and Neck Surgery,Lanzhou University Second Hospital,Lanzhou,730000,China.

Explore the significance of ultrastructural differences in tissue engineering, 3D printing, and rhinoplasty. 32 specimens (8 vomers, 8 perpendicular plates of ethmoid bone, 8 maxillary nasal crests, and 8 septal cartilage) of the nasal septum from patients with a nasal deviated septum and chronic sinusitis undergoing septoplasty were selected and examined using scanning electron microscopy. The nasal septum of patients of different ages behaves similarly under the scanning electron microscope, and the bones of different parts of the nasal septum have similarities and differences. By observing the scanning electron micrograph of the nasal septum and analyzing the surface ultrastructure, it provides important information for the development of tissue engineering, assists in the refined modeling of 3D printing technology, and provides more ideal restoration materials for clinical operations.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2022.05.002DOI Listing
May 2022

Capturing 3D Chromatin Maps of Human Primary Monocytes: Insights From High-Resolution Hi-C.

Front Immunol 2022 3;13:837336. Epub 2022 Mar 3.

Department of Central Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Although the variation in chromatin architecture during adaptive immune responses has been thoroughly investigated, the 3D landscape of innate immunity is still unknown. Herein, chromatin regulation and heterogeneity among human primary monocytes were investigated. Peripheral blood was collected from two healthy persons and two patients with systemic lupus erythematosus (SLE), and CD14 monocytes were selected to perform Hi-C, RNA-seq, ATAC-seq and ChIP-seq analyses. Raw data from the THP1 cell line Hi-C library were used for comparison. For each sample, we constructed three Hi-C libraries and obtained approximately 3 billion paired-end reads in total. Resolution analysis showed that more than 80% of bins presented depths greater than 1000 at a 5 kb resolution. The constructed high-resolution chromatin interaction maps presented similar landscapes in the four individuals, which showed significant divergence from the THP1 cell line chromatin structure. The variability in chromatin interactions around HLA-D genes in the HLA complex region was notable within individuals. We further found that the CD16-encoding gene () is located at a variable topologically associating domain (TAD) boundary and that chromatin loop dynamics might modulate CD16 expression. Our results indicate both the stability and variability of high-resolution chromatin interaction maps among human primary monocytes. This work sheds light on the potential mechanisms by which the complex interplay of epigenetics and spatial 3D architecture regulates chromatin in innate immunity.
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http://dx.doi.org/10.3389/fimmu.2022.837336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8927851PMC
May 2022

Compressive sensing based parameter estimation for free-space continuous-variable quantum key distribution.

Opt Express 2022 Feb;30(5):8075-8091

In satellite-based free-space continuous-variable QKD (CV-QKD), the parameter estimation for the atmospheric channel fluctuations due to the turbulence effects and attenuation is crucial for analyzing and improving the protocol performance. However, the partial key data usually need to be sacrificed for the parameter estimation leading to the secret key reduction and the possible information leakage, especially when the channel is varying. In this paper, compressive sensing (CS) theory is applied to free-space CV-QKD to achieve the channel parameter estimation with small amount of key data sacrifice and low computational complexity. According to CS theory, the possibility of the sparse representation for free-space channel is analyzed and the two types of sparse reconstruction models for the channel parameters are constructed combining with the stability of the sub-channels. The most part of key data for parameter estimation is saved by using the model constructed by the variables in the quantum signals, while all the key data can be saved and be used to generate the secret key by using the model constructed by the second-order statistics of the variables. Thus, the methods can generate more secret key, improve the secret key rate, and be well adapted for the cases with the limited communication time since fewer or no key data (variables) is sacrificed for parameter estimation. Finally, simulation results are given to verify the effectiveness of the proposed methods.
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http://dx.doi.org/10.1364/OE.447526DOI Listing
February 2022

Analysis of GJB2 Gene Mutations in 1330 Deafness Cases of Major Ethnic Groups in Northwest China.

Inquiry 2022 Jan-Dec;59:469580211055571

Department of Otolaryngology-Head and Neck Surgery, 74713Lanzhou University Second Hospital, Lanzhou, China.

: The gene is the most common deafness gene, and epidemic characteristics have obvious racial specificity. Our study aimed to investigate the prevalence and ethnic specificity of the gene in deafness in major ethnic groups in Northwest China, evaluate the value of molecular screening for deafness in minority populations, and explore the strategies and methods for genetic diagnosis. : Ethics approval was obtained to collect 1330 cases of moderate to very severe nonsyndromic sensorineural deafness in northwestern China. The mutation characteristics of ethnic minorities were analyzed and compared with those of 464 patients with nonsyndromic sensorineural deafness among ethnic Han in the northwestern from research group by Sequence Scanner V25.0. Then, we analyzed the ethnic specificity of the mutations. : A total of 15 sequence changes were detected in 1330 minority patients. The study showed that the allele frequency in Tibetan patients was significantly lower than that in Hui and Dongxiang patients, that in Uygur patients was significantly lower than that in Han and Hui patients, and that in Kazak and Tibetan patients was significantly lower than that in Han patients, and the differences between other ethnic groups were not statistically significant. Each ethnic group has a unique gene mutation spectrum, and its hotspot mutation distribution has its own characteristics, with c.235delC, c.109 G > A, c.299-300delAT, and c.35delG being common. : It has been confirmed that gene mutation has a high prevalence in patients with nonsyndromic sensorineural hearing loss in Northwest China. Each ethnic group has a unique mutation spectrum for the gene, which is related to its genetic background. It is necessary to develop a corresponding gene diagnosis strategy according to the hotspot mutations and mutation spectrum of each ethnic group.
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http://dx.doi.org/10.1177/00469580211055571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891923PMC
April 2022

Treatments of Differential Item Functioning: A Comparison of Four Methods.

Educ Psychol Meas 2022 Apr 10;82(2):225-253. Epub 2021 May 10.

University of Connecticut, Storrs, CT, USA.

Test fairness is critical to the validity of group comparisons involving gender, ethnicities, culture, or treatment conditions. Detection of differential item functioning (DIF) is one component of efforts to ensure test fairness. The current study compared four treatments for items that have been identified as showing DIF: deleting, ignoring, multiple-group modeling, and modeling DIF as a secondary dimension. Results of this study provide indications about which approach could be applied for items showing DIF for a wide range of testing environments requiring reliable treatment.
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http://dx.doi.org/10.1177/00131644211012050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850764PMC
April 2022

Effects of HA2 154 deglycosylation and NA V202I mutation on biological property of H5N6 subtype avian influenza virus.

Vet Microbiol 2022 Mar 22;266:109353. Epub 2022 Jan 22.

Animal Infectious Diseases Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009, China; Jiangsu Key Laboratory of Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, China. Electronic address:

In recent years, clade 2.3.4.4 H5N6 subtype avian influenza virus (AIV) has been predominantly prevalent in poultry flocks in China. During our AIV surveillance in 2018-2019, 6 circulating strains of H5N6 that possess the natural loss of glycosylation site 154 due to N154D mutation in HA2 protein were isolated. In particular, 5 strains simultaneously carried the V202I mutation in NA protein. Based on the paired backbone H5N6 viruses Y6 and RY6, which just diverged in the glycosylation status at site 158 in HA1 protein, 8 reassortants of rY6-154 N/202 V, rY6-154D/202 V, rY6-154 N/202I and rY6-154D/202I plus rRY6-154 N/202 V, rRY6-154D/202 V, rRY6-154 N/202I and rRY6-154D/202I were constructed with different variation patterns at site 154 in HA2 and site 202 in NA. By determining those reassortants in growth performance on cells, plaque-forming ability, heat and low pH stability, and pathogenicity in mammals, the results showed that HA2 N154D and NA V202I could singly or jointly change the viral biological properties both in vitro and in vivo. Additionally, the effect of HA mutation was significantly more robust than that of NA, and the resulting increasing or reducing impact was closely related to the glycosylation at HA1 site 158. The present study provided a reference for further parsing the relevant mechanism of the functional match between HA and NA proteins of the influenza virus.
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http://dx.doi.org/10.1016/j.vetmic.2022.109353DOI Listing
March 2022

Different modes of cochlear implantation in children: A comparative study on hearing and speech rehabilitation effects.

J Laryngol Otol 2022 Jan 28:1-23. Epub 2022 Jan 28.

Department of Otolaryngology-Head and Neck Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu Province & Health Commission of Gansu Province, Lanzhou, Gansu Province.

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http://dx.doi.org/10.1017/S0022215122000263DOI Listing
January 2022

Esmolol to Treat the Hemodynamic Effects of Septic Shock: A Randomized Controlled Trial.

Shock 2022 04;57(4):508-517

Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Introduction: Septic shock is often characterized by tachycardia and a hyperdynamic hemodynamic profile. Use of the beta antagonist esmolol has been proposed as a therapy to lower heart rate, thereby improving diastolic filling time and improving cardiac output, resulting in a reduction in vasopressor support.

Methods: We conducted a two-center, open-label, randomized, Phase II trial comparing esmolol to placebo in septic shock patients with tachycardia. The primary endpoint was improvement in hemodynamics as measured by the difference in norepinephrine equivalent dose (NED) between groups at 6 hours after initiation of study drug. Secondary outcomes included assessing differences in inflammatory biomarkers and oxygen consumption (VO2).

Results: A total of 1,122 patients were assessed for eligibility and met inclusion criteria; 42 underwent randomization, and 40 received study interventions (18 in the esmolol arm and 22 in the usual care arm). The mean NED at 6 h was 0.30 ± 0.17 mcg/kg/min in the esmolol arm compared to 0.21 ± 0.19 in the standard care arm (P = 0.15). There was no difference in number of shock free days between the esmolol (2, IQR 0, 5) and control groups (2.5, IQR 0, 6) (P = 0.32). There were lower levels of C-reactive protein at 12 and 24 h in the esmolol arm, as well as a statistically significant difference in trend over time between groups. There were no differences in terms of IL-4, IL-6, IL-10, and TNFα. Among a subset who underwent VO2 monitoring, there was decreased oxygen consumption in the esmolol patients; the mean difference between groups at 24 h was -2.07 mL/kg/min (95% CI -3.82, -0.31) (P = 0.02), with a significant difference for the trend over time (P < 0.01).

Conclusion: Among patients with septic shock, infusion of esmolol did not improve vasopressor requirements or time to shock reversal. Esmolol was associated with decreased levels of C-reactive protein over 24 h.

Trial Registration: www.clinicaltrials.gov. Registered February 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02369900.
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http://dx.doi.org/10.1097/SHK.0000000000001905DOI Listing
April 2022

Clinical characteristics and allergen detection of perioperative anaphylaxis: a 12-year retrospective analysis from an anesthesia clinic in China.

Perioper Med (Lond) 2022 Jan 21;11(1). Epub 2022 Jan 21.

Department of Anesthesiology, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100029, China.

Background: Anaphylaxis during anesthesia is a rare but often a potentially life-threatening event for patients. Identifying culprit agents responsible for anaphylaxis is of great important for avoiding potential re-exposure to allergens, but it poses great challenge for anesthetists. This retrospective study aimed to analyze the culprits of patients with a history of perioperative anaphylaxis referred to an anesthesia allergy clinic in China, and to evaluate the role of allergy diagnostic tests in clinical practice.

Methods: A total of 145 patients (102 female/43 male) who attended the Anesthesia Allergy Clinic for allergen detection between 1 January 2009 and 31 December 2020 were reviewed retrospectively. Clinical characteristics, results of allergy diagnostic tests including skin, and/or basophil activation tests, and the incidence of repeat anaphylaxis after use of recommended alternative anesthetics were obtained.

Results: Of these 145 patients, 109 patients (75.2%, 74 females/35 males) were determined to experience perioperative anaphylaxis. The most common presenting clinical feature was cardiovascular manifestations (n = 63, 57.8%). According to diagnostic work up, the most common causative agents for perioperative anaphylaxis were neuromuscular blocking agents (n = 35, 32.1%). After diagnostic work up, 52 patients underwent repeat anesthesia. None of these patients experienced recurrent anaphylaxis.

Conclusions: This study suggests that neuromuscular blocking agents are the main cause of perioperative anaphylaxis. For patients with perioperative anaphylaxis, allergy diagnostic tests are essential to identify causative agents, and to find suitable alternative drugs for the future planning of subsequent anesthetics.
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http://dx.doi.org/10.1186/s13741-021-00234-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8781513PMC
January 2022

Phylogenetic and phenotypic characterization of two novel clade 2.3.2.1 H5N2 subtype avian influenza viruses from chickens in China.

Infect Genet Evol 2022 03 5;98:105205. Epub 2022 Jan 5.

Animal Infectious Diseases Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, China. Electronic address:

The extended co-circulation of H5 subtype highly pathogenic avian influenza (HPAI) viruses and H9N2 low pathogenic avian influenza (LPAI) viruses has inevitably facilitated gene reassortment between the two subtypes in fields. And, novel reassortant H5NX viruses harboring partial or even whole sets of H9N2 internal genes have continuously been detected, such as clade 2.3.4.4 H5N2 or H5N6 reassortants. Here, we report two novel H5N2 subtype HPAI isolates of HF9 and QY5 from chickens in live poultry markets during routine surveillance in 2018. Phylogenetic analysis showed that those two H5N2 strains both possessed the HA genes from clade 2.3.2.1e of H5N1 viruses but all the other seven gene segments consistently from the endemic S genotype of H9N2 subtype viruses. Further analysis revealed that HF9 and QY5 differed only in six sites including K353R, A588T and T661I in PB2, I682V and L704S in PB1 plus G631S in PA at the amino acid level. A chicken regression experiment confirmed that both HF9 and QY5 were lethal infection to all tested chickens via contact transmission. Moreover, those two isolates could immediately replicate in mice lungs without adaptation. However, mortality rate of those two variants were distinct in mice model, HF9 with 100% but QY5 with just 20% at the infection dosage of 10EID per mouse. We suppose that the phenotypic difference may probably be attributed to the amino acid substitutions in the polymerase genes between the two isolates that constitute of a subject of further ongoing research.
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http://dx.doi.org/10.1016/j.meegid.2022.105205DOI Listing
March 2022

Spatiotemporal Associations and Molecular Evolution of Highly Pathogenic Avian Influenza A H7N9 Virus in China from 2017 to 2021.

Viruses 2021 12 15;13(12). Epub 2021 Dec 15.

Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.

Highly pathogenic (HP) H7N9 avian influenza virus (AIV) emerged in China in 2016. HP H7N9 AIV caused at least 33 human infections and has been circulating in poultry farms continuously since wave 5. The genetic divergence, geographic patterns, and hemagglutinin adaptive and parallel molecular evolution of HP H7N9 AIV in China since 2017 are still unclear. Here, 10 new strains of HP H7N9 AIVs from October 2019 to April 2021 were sequenced. We found that HP H7N9 was primarily circulating in Northern China, particularly in the provinces surrounding the Bohai Sea (Liaoning, Hebei, and Shandong) since wave 6. Of note, HP H7N9 AIV phylogenies exhibit a geographical structure compatible with high levels of local transmission after unidirectional rapid geographical expansion towards the north of China in 2017. In addition, we showed that two major subclades were continually expanding with the viral population size undergoing a sharp increase after 2018 with an obvious seasonal tendency. Notably, the hemagglutinin gene showed signs of parallel evolution and positive selection. Our research sheds light on the current epidemiology, evolution, and diversity of HP H7N9 AIV that can help prevent and control the spreading of HP H7N9 AIV.
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http://dx.doi.org/10.3390/v13122524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705967PMC
December 2021
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