Publications by authors named "Xuefeng Wang"

1,009 Publications

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Assessment of patient based real-time quality control on comparative assays for common clinical analytes.

J Clin Lab Anal 2022 Aug 10:e24651. Epub 2022 Aug 10.

Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background: It is critical for laboratories to conduct multianalyzer comparisons as a part of daily routine work to strengthen the quality management of test systems. Here, we explored the application of patient-based real-time quality controls (PBRTQCs) on comparative assays to monitor the consistency among clinical laboratories.

Methods: The present study included 11 commonly tested analytes that were detected using three analyzers. PBRTQC procedures were set up with exponentially weighted moving average (EWMA) algorithms and evaluated using the AI-MA artificial intelligence platform. Comparative assays were carried out on serum samples, and patient data were collected. Patients were divided into total patient (TP), inpatient (IP), and outpatient (OP) groups.

Results: Optimal PBRTQC protocols were evaluated and selected with appropriate truncation limits and smoothing factors. Generally, similar comparative assay performance was achieved using both the EWMA and median methods. Good consistency between the results from patients' data and serum samples was obtained, and unacceptable bias was detected for alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) when using analyzer C. Categorizing patients' data and applying specific groups for comparative assays could significantly improve the performance of PBRTQCs. When monitoring the inter- and intraanalyzer stability on a daily basis, EWMA was superior in detecting very small quality-related changes with lower false-positive alarms.

Conclusions: We found that PBRTQCs have the potential to efficiently assess multianalyzer comparability. Laboratories should be aware of population variations concerning both analytes and analyzers to build more suitable PBRTQC protocols.
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http://dx.doi.org/10.1002/jcla.24651DOI Listing
August 2022

Identification, structure, and caseinolytic properties of milk-clotting proteases from Moringa oleifera flowers.

Food Res Int 2022 Sep 30;159:111598. Epub 2022 Jun 30.

College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China; Yunnan Engineering Technology Research Center for Processing of Livestock Products, Kunming 650201, Yunnan, China. Electronic address:

The protein extract of Moringa oleifera flowers is reported to have milk-clotting activity (MCA), but information regarding its protease is unclear. In this study, two milk-clotting proteases (MoFP 12 and MoFP 13) with molecular weights of 42.304 kDa and 31.741 kDa, respectively, were isolated and identified from M. oleifera flowers using liquid chromatography-mass spectrometry (LC-MS/MS). Bioinformatics analysis showed that these two milk-clotting proteases were primarily involved in hydrolase activity and catabolic process, and exhibited hydrophilicity. The secondary structure of MoFP 12 consisted of 43.65% helix, 13.23% strand, and 43.12% coil, and MoFP 13 consisted of 26.51% helix, 20.14% strand, and 53.35% coil. The proteases were stable in the pH range of 5.0 to 8.0 and showed their maximum MCA at 70℃. Additionally, by investigating the effect of proteases on caseins, κ-casein (CN) was observed to preferentially be hydrolyzed by the two proteases, followed by α-CN, and to a lesser extent β-CN. These findings revealed the main milk-clotting proteases in M. oleifera flowers and its milk-clotting properties, indicating its potential for application in the dairy and food sectors, especially in the cheese-making industry.
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http://dx.doi.org/10.1016/j.foodres.2022.111598DOI Listing
September 2022

Performance comparison of RGB and multispectral vegetation indices based on machine learning for estimating SPAD values under different shade conditions.

Front Plant Sci 2022 22;13:928953. Epub 2022 Jul 22.

Institute of Forest Resource Information Techniques, Chinese Academy of Forestry, Beijing, China.

Reasonable cultivation is an important part of the protection work of endangered species. The timely and nondestructive monitoring of chlorophyll can provide a basis for the accurate management and intelligent development of cultivation. The image analysis method has been applied in the nutrient estimation of many economic crops, but information on endangered tree species is seldom reported. Moreover, shade control, as the common seedling management measure, has a significant impact on chlorophyll, but shade levels are rarely discussed in chlorophyll estimation and are used as variables to improve model accuracy. In this study, 2-year-old seedlings of tropical and endangered were taken as the research object, and the SPAD value was used to represent the relative chlorophyll content. Based on the performance comparison of RGB and multispectral (MS) images using different algorithms, a low-cost SPAD estimation method combined with a machine learning algorithm that is adaptable to different shade conditions was proposed. The SPAD values changed significantly at different shade levels ( < 0.01), and 50% shade in the orthographic direction was conducive to chlorophyll accumulation in seedling leaves. The coefficient of determination ( ), root mean square error (RMSE), and average absolute percent error (MAPE) were used as indicators, and the models with dummy variables or random effects of shade greatly improved the goodness of fit, allowing better adaption to monitoring under different shade conditions. Most of the RGB and MS vegetation indices (VIs) were significantly correlated with the SPAD values, but some VIs exhibited multicollinearity (variance inflation factor (VIF) > 10). Among RGB VIs, RGRI had the strongest correlation, but multiple VIs filtered by the Lasso algorithm had a stronger ability to interpret the SPAD data, and there was no multicollinearity (VIF < 10). A comparison of the use of multiple VIs to estimate SPAD indicated that Random forest (RF) had the highest fitting ability, followed by Support vector regression (SVR), linear mixed effect model (LMM), and ordinary least squares regression (OLR). In addition, the performance of MS VIs was superior to that of RGB VIs. The of the optimal model reached 0.9389 for the modeling samples and 0.8013 for the test samples. These findings reinforce the effectiveness of using VIs to estimate the SPAD value of under different shade conditions based on machine learning and provide a reference for the selection of image data sources.
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http://dx.doi.org/10.3389/fpls.2022.928953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355326PMC
July 2022

Beclin1 Deficiency Suppresses Epileptic Seizures.

Front Mol Neurosci 2022 22;15:807671. Epub 2022 Jul 22.

Chongqing Key Laboratory of Neurology, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Epilepsy is a common disease of the nervous system. Autophagy is a degradation process involved in epilepsy, and in turn, seizures can activate autophagy. Beclin1 plays a critical role in autophagy and participates in numerous physiological and pathological processes. However, the mechanism underlying the effect of Beclin1 on epilepsy remains unclear. In this study, we detected increased expression of Beclin1 in brain tissues from patients with temporal lobe epilepsy (TLE). Heterozygous disruption of decreased susceptibility to epilepsy and suppressed seizure activity in two mouse epilepsy models. We further illustrated for the first time that heterozygous disruption of suppresses excitatory synaptic transmission, which may be caused by a decreased dendritic spine density. These findings suggest for the first time that the regulation of Beclin1 may serve as a strategy for antiepileptic therapy. In addition, Beclin1 participates in synaptic transmission, and the development of dendritic spines may be a biological function of Beclin1 independent of its role in autophagy.
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http://dx.doi.org/10.3389/fnmol.2022.807671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354790PMC
July 2022

2H-MoS/CoO nanohybrid with type I nitroreductase-mimicking activity for the electrochemical assays of nitroaromatic compounds.

Anal Chim Acta 2022 Aug 23;1221:340078. Epub 2022 Jun 23.

Materials Genome Institute, Shanghai University, Shanghai, 200444, China. Electronic address:

A type I nitroreductase-mimicking nanocatalyst based on 2H-MoS/CoO nanohybrids for trace nitroaromatic compounds detection is reported in this work. For the preparation of nanocatalyst, ultrathin CoO nanoflakes array was in-situ grown onto 2H-MoS nanosheets forming three-dimensional (3D) nanohybrid with large specific surface area as well as abundant active sites. The as-prepared nanocatalyst shows a specific affinity as well as high catalytic activity towards nitroaromatic compounds. Given the favorable nitroreductase-mimicking catalytic activity of 2H-MoS/CoO nanohybrid, a sensitive and efficient electrochemical microsensor has been constructed for the detection of 2, 4, 6-trinitrotoluene (TNT). Under optimized conditions, the microsensor displayed sensitive response from μM to pM levels with a limit of detection (LOD) of 1 pM. We further employed photoelectron spectroscopy (XPS) analysis and high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method to identify the nitroreductase-mimicking mechanism of 2H-MoS/CoO nanohybrids towards 2, 4, 6- TNT. It was found that the abundant oxygen vacancies in ultrathin CoO nanoflakes played an essential role in determining its catalytic performance. Moreover, the developed MoS/CoO nanozyme has a lower Michaelis-Menten constant (k) than that of nature nitroreductase demonstrating a good enzymatic affinity towards its substrates, and further generating a high catalytic activity. This research not only proposed a new type of nanozyme, but also developed a portable electrochemical microsensor for the detection of 2, 4, 6-TNT.
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http://dx.doi.org/10.1016/j.aca.2022.340078DOI Listing
August 2022

MC4R Deficiency Causes Dysregulation of Postsynaptic Excitatory Synaptic Transmission as a Crucial Culprit for Obesity.

Diabetes 2022 Aug 4. Epub 2022 Aug 4.

State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

Melanocortin-4 receptor (MC4R) in paraventricular nucleus in hypothalamus (PVH) shows bidirectional characterization in modulating food intake and energy homeostasis. Here, we demonstrated that MC4R knock down (MC4R KD) in PVH could attenuate AMPA receptor (AMPAR) mediated postsynaptic responses by altering AMPAR GluA1 subunit phosphorylation via protein kinase A (PKA) dependent signaling cascade and simultaneously lead to rapid body weight gain. Further, PKA knock down (PKA KD) in PVH engendered similar electrophysiological and behavioral phenotypes as MC4R KD mice. Importantly, we observed that the reduction of AMPAR GluA1 expression not only led to attenuated synaptic responses but also caused body weight gain, suggesting that the aberration of synaptic responses may be one of the crucial pathogeny for obesity. Our study provided the synaptic and molecular explanations of how body weight is regulated by MC4R in PVH.
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http://dx.doi.org/10.2337/db22-0162DOI Listing
August 2022

Imbalance of Th17, Treg, and helper innate lymphoid cell in the peripheral blood of patients with rheumatoid arthritis.

Clin Rheumatol 2022 Aug 4. Epub 2022 Aug 4.

Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, China.

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease involving a variety of immune cells, including adaptive T and B cells and innate lymphoid cells (ILCs). Understanding the pathogenic role of these immune cells in RA provides new insights into the intervention and treatment of RA.

Methods: A total of 86 patients with RA (RA group) and 50 healthy controls (HC) were included in the study. The immune cells of CD4, CD19 B, NK, Th17, Treg, ILCs, and their subsets (i.e., ILC1s, ILC2s, and ILC3s) were characterized in peripheral blood mononuclear cells by flow cytometry. Cytokines (i.e., IFN-γ, IL-4, IL-10, IL-17A, IL-22, and IL-33) in sera were detected using ELISA. The above immune cells and cytokines were analyzed in patients with different disease activity status and positive ( +) or negative ( -) rheumatoid factor (RF)/anti-citrullinated protein antibodies (ACPA).

Results: Patients with RA had higher percentages of CD4 T, CD19 B, Th17, ILC2s, and ILC3s and lower percentages of Treg and ILC1s than HC. Patients with RA had elevated levels of IFN-γ, IL-4, IL-17A, and IL-22 and decreased level of IL-10. Compared with HC, patients with high disease activity had higher percentages of Th17, ILC2s, and ILC3s; lower percentages of ILC1s; and lower level of IL-10. The percentage of Treg cells in remission, low, moderate, and high disease activities decreased, whereas the level of IL-17A increased compared with HC. Furthermore, RF or ACPA patients exhibited elevated percentages of CD19 B, ILC2s, and ILC3s and had decreased percentage of ILC1s and Treg cells than HC. The percentage of Th17 cells increased in RF/ACPA and RF/ACPA patients. However, the above immune cells between RF or ACPA positive and negative patients were not significantly different.

Conclusion: Th17, Treg, and ILC subset dysregulations are present in patients with RA but may not be associated with conventionally defined seropositive RF and ACPA. Key Points • Th17, Treg, and ILC subset dysregulations are present in patients with RA but may reflect inflammation rather than specific diseases and stages. • No difference for the distribution of Th17, Treg, and ILC subsets between RF and RF patients and between ACPA and ACPA patients. The screening spectrum of RF and ACPA serology should be expanded to elucidate the role of immune cells in RA pathogenesis.
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http://dx.doi.org/10.1007/s10067-022-06315-8DOI Listing
August 2022

Hepatopancreatoduodenectomy for advanced biliary malignancies.

Chin Med J (Engl) 2022 Aug 2. Epub 2022 Aug 2.

Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.

Background: Hepatopancreatoduodenectomy (HPD) has been considered the only curative treatment for metastatic cholangiocarcinoma and some locally advanced gallbladder cancers (GBCs). However, HPD has not yet been included in treatment guidelines as a standard surgical procedure in consideration of its morbidity and mortality rates. The aim of this study was to evaluate the safety and effectiveness of HPD in treating biliary malignancies.

Methods: The medical records of 57 patients with advanced biliary cancer undergoing HPD from January 2009 to December 2019 were retrospectively retrieved. A case-control analysis was conducted at our department. Patients with advanced GBC who underwent HPD (HPD-GBC group) were compared with a control group (None-HPD-GBC group) Baseline characteristics, preoperative treatments, tumor pathologic features, operative results, and prognosis were assessed.

Results: Thirteen patients with cholangiocarcinoma and 44 patients with GBC underwent HPD at our department. Significant postoperative complications (grade III or greater) and postoperative pancreatic fistula were observed in 24 (42.1%) and 15 (26.3%) patients, respectively. One postoperative death occurred in the present study. Overall survival (OS) was longer in patients with advanced cholangiocarcinoma than in those with GBC (median survival time [MST], 31 months vs. 11 months; P  < 0.001). In the subgroup analysis of patients with advanced GBC, multivariate analysis demonstrated that T4 stage tumors (P = 0.012), N2 tumors (P = 0.001), and positive margin status (P = 0.004) were independently associated with poorer OS. Patients with either one or more prognostic factors exhibited a shorter MST than patients without those prognostic factors (P < 0.001).

Conclusion: HPD could be performed with a relatively low mortality rate and an acceptable morbidity rate in an experienced high- volume center. For patients with advanced GBC without an N2 or T4 tumor, HPD can be a preferable treatment option.
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http://dx.doi.org/10.1097/CM9.0000000000002067DOI Listing
August 2022

Graphene oxide links alterations of anti-viral signaling pathways with lipid metabolism suppressing TLR3 in vascular smooth muscle cells.

Mol Omics 2022 Aug 1. Epub 2022 Aug 1.

Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China.

Vascular smooth muscle cells (VSMCs), the main cells constructing blood vessels, are important in the regulation of the pathophysiology of vascular systems; however, relatively few studies have investigated the influence of nanomaterials (NMs) on VSMCs. In this study, we found that the interaction between graphene oxide and human VSMCs led to the cytotoxicity and morphological changes of cells. Because transcriptomic data suggested that graphene oxide decreased anti-viral signaling pathways decreasing Toll-like receptor 3 (TLR3), we further verified that graphene oxide decreased interferon induced protein with tetratricopeptide repeats 1 (IFIT1) and the radical -adenosyl methionine domain containing 2 (RSAD2), and TLR3-downstream genes involved in anti-viral responses. Due to the involvement of RSAD2 in lipid dysfunction, we also verified that graphene oxide disrupted lipid homeostasis and increased adipose triglyceride lipase (ATGL). Adding TLR3 agonist polyinosinic:polycytidylic acid (Poly IC) partially increased TLR3-downstream protein interleukin-8 (IL-8) and some lipid classes, particularly lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), in graphene oxide-exposed VSMCs. In mice receiving repeated intravenous injection of graphene oxide, significantly decreased TLR3, IFIT1 and RSAD2 but increased ATGL proteins were observed in aortas. We conclude that graphene oxide altered anti-viral signaling pathways and lipid metabolism decreasing TLR3 in VSMCs.
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http://dx.doi.org/10.1039/d2mo00086eDOI Listing
August 2022

Integration of Transcriptomic and Proteomic Profiles Reveals Multiple Levels of Genetic Regulation of Taproot Growth in Sugar Beet ( L.).

Front Plant Sci 2022 13;13:882753. Epub 2022 Jul 13.

Sugar Beet Physiological Research Institute, Inner Mongolia Agricultural University, Hohhot, China.

Sugar beet taproot growth and development is a complex biological process involving morphogenesis and dry matter accumulation. However, the molecular regulatory mechanisms underlying taproot growth and development remain elusive. We performed a correlation analysis of the proteome and transcriptome in two cultivars (SD13829 and BS02) at the start and the highest points of the taproot growth rate. The corresponding correlation coefficients were 0.6189, 0.7714, 0.6803, and 0.7056 in four comparison groups. A total of 621 genes were regulated at both transcriptional and translational levels, including 190, 71, 140, and 220 in the BS59-VS-BS82, BS59-VS-SD59, BS82-VS-SD82, and SD59-VS-SD82 groups, respectively. Ten, 32, and 68 correlated-DEGs-DEPs (cor-DEGs-DEPs) were significantly enrdiched in the proteome and transcriptome of the BS59-VS-BS82, SD59-VS-SD82, and BS82-VS-SD82 groups, respectively, which included ribonuclease 1-like protein, DEAD-box ATP-dependent RNA helicase, TolB protein, heat shock protein 83, 20 kDa chaperonin, polygalacturonase, endochitinase, brassinolide and gibberellin receptors (BRI1 and GID1), and xyloglucan endotransglucosylase/hydrolase (XTH). In addition, XTH could enhance the growth and development of Arabidopsis primary roots by improving cell growth in the root tip elongation zone. These findings suggested that taproot growth and expansion might be regulated at transcriptional and posttranscriptional levels and also may be attributed to cell wall metabolism to improve cell wall loosening and elongation.
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http://dx.doi.org/10.3389/fpls.2022.882753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326478PMC
July 2022

Noninvasive fetal genotyping of single nucleotide variants and linkage analysis for prenatal diagnosis of monogenic disorders.

Hum Genomics 2022 Jul 27;16(1):28. Epub 2022 Jul 27.

Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, People's Republic of China.

Background: High-cost, time-consuming and complex processes of several current approaches limit the use of noninvasive prenatal diagnosis (NIPD) for monogenic disorders in clinical application. Thus, a more cost-effective and easily implementable approach is required.

Methods: We established a low-cost and convenient test to noninvasively deduce fetal genotypes of the mutation and single nucleotide polymorphisms (SNPs) loci by means of targeted amplification combined with deep sequencing of maternal genomic and plasma DNA. The sequential probability ratio test was performed to detect the allelic imbalance in maternal plasma. This method can be employed to directly examine familial pathogenic mutations in the fetal genome, as well as infer the inheritance of parental haplotypes through a group of selected SNPs linked to the pathogenic mutation.

Results: The fetal mutations in 17 families with different types of monogenic disorders including hemophilia A, von Willebrand disease type 3, Duchenne muscular dystrophy, hyper-IgM type 1, glutaric acidemia type I, Nagashima-type palmoplantar keratosis, and familial exudative vitreoretinopathy were identified in the study. The mutations included various forms: point mutations, gene inversion, deletions/insertions and duplication. The results of 12 families were verified by sequencing of amniotic fluid samples, the accuracy of the approach in fetal genotyping at the mutation and SNPs loci was 98.85% (172/174 loci), and the no-call rate was 28.98% (71/245 loci). The overall accuracy was 12/12 (100%). Moreover, the approach was successfully applied in plasma samples with a fetal fraction as low as 2.3%.

Conclusions: We have shown in this study that the approach is a cost-effective, less time consuming and accurate method for NIPD of monogenic disorders.
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http://dx.doi.org/10.1186/s40246-022-00400-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327225PMC
July 2022

Genomic Analysis of Mycobacterium abscessus Complex Isolates from Patients with Pulmonary Infection in China.

Microbiol Spectr 2022 Jul 12:e0011822. Epub 2022 Jul 12.

Department of Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Members of the Mycobacterium abscessus complex (MABC) are multidrug-resistant nontuberculous mycobacteria and increasingly cause opportunistic pulmonary infections. However, the genetic typing of MABC isolates remains largely unclear in China. Genomic analyses were conducted for 69 MABC clinical isolates obtained from patients with lower respiratory tract infections in Shanghai Pulmonary Hospital between 2014 and 2016. The draft genomes of the 69 clinical strains were assembled, with a total length of 4.5 to 5.6 Mb, a percent GC content (GC%) ranging from 63.9 to 68.1%, and 4,492 to 5,404 genes per genome. Susceptibility test shows that most isolates are resistant to many antimicrobials, including clarithromycin, but susceptible to tigecycline. Analyses revealed the presence of genes conferring resistance to antibiotics, including macrolides, aminoglycosides, rifampicin, and tetracyclines. Furthermore, 80 to 114 virulence genes were identified per genome, including those related to the invasion of macrophages, iron incorporation, and avoidance of immune clearance. Mobile genetic elements, including insertion sequences, transposons, and genomic islands, were discovered in the genomes. Phylogenetic analyses of all MABC isolates with another 41 complete MABC genomes identified three clades; 46 isolates were clustered in clade I, corresponding to M. abscessus subsp. , and 25 strains belonged to existing clonal complexes. Overall, this is the first comparative genomic analysis of MABC clinical isolates in China. These results show significant intraspecies variations in genetic determinants encoding antimicrobial resistance, virulence, and mobile elements and controversial subspecies classification using current marker gene combinations. This information will be useful in understanding the evolution, antimicrobial resistance, and pathogenesis of MABC strains and facilitating future vaccine development and drug design. Over the past decade, infections by Mycobacterium abscessus complex (MABC) isolates have been increasingly reported worldwide. MABC strains often show a high incidence in cystic fibrosis (CF) patients, whereas in Asia, these strains are frequently recovered from non-CF patients with significant genomic diversity. The present work involves analyses of the antimicrobial resistance, virulence, and phylogeny of 69 selected MABC isolates from non-CF pulmonary patients in Shanghai Pulmonary Hospital by whole-genome sequencing; it represents the first comprehensive investigation of MABC strains in China at the genomic level. These findings highlight the diversity of this group of nontuberculous mycobacteria and provide a mechanistic understanding of evolution and pathogenesis, which is valuable for the development of novel and effective antimicrobial therapies for deadly MABC infections in China.
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http://dx.doi.org/10.1128/spectrum.00118-22DOI Listing
July 2022

Congenital (hypo-)dysfibrinogenemia and bleeding: A systematic literature review.

Thromb Res 2022 Jul 14;217:36-47. Epub 2022 Jul 14.

Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Collaborative Innovation Center of Hematology, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address:

Ranging from bleeding to thrombosis, the clinical features of congenital fibrinogen qualitative disorders, including dysfibrinogenemia and hypodysfibrinogenemia, are highly heterogeneous. Although the associations between some specific fibrinogen mutations and the thrombotic phenotypes have been well elucidated, the underlying mechanism between fibrinogen variants and bleeding events remains underestimated. After systematically reviewing the literature of (hypo-)dysfibrinogenemia patients with bleeding phenotypes, we identified several well-characterized bleeding-related fibrinogen variants in those patients. Several possible pathomechanisms are proposed to explain the genotype-phenotype associations: 1, mutations in the NH-terminal portion of the Aα chain hamper fibrinogen fitting into the active site cleft of thrombin and drastically slow the conversion of fibrinogen into monomeric fibrin; 2, mutations adding new N-linked glycosylation sites introduce bulky and negatively charged carbohydrate side chains and undermine the alignment of fibrin monomers during polymerization; 3, mutations generating unpaired cysteine form extra disulfide bonds between the abnormal fibrinogen chains and produce highly branched and fragile fibrin networks; 4, truncation mutations in the fibrinogen αC regions impair the lateral fibril aggregation, as well as factor XIII crosslinking, endothelial cell and platelet binding. These established relationships between specific variants and the bleeding tendency will help manage (hypo-)dysfibrinogenemia patients to avoid adverse bleeding outcomes.
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http://dx.doi.org/10.1016/j.thromres.2022.07.005DOI Listing
July 2022

Intraosseous delivery of platelet-targeted FVIII lentiviral vector in humanized NBSGW mice.

Blood Adv 2022 Jul 18. Epub 2022 Jul 18.

University of Washington, United States.

We previously showed that intraosseous (IO) delivery of factor VIII (FVIII, gene F8) lentiviral vector (LV) driven by the megakaryocyte-specific promoter, Gp1bα, (G-F8-LV) partially corrected the bleeding phenotype in hemophilia A mice for up to 5 months. In this study, we further characterized and confirmed the successful transduction of self-regenerating hematopoietic stem and progenitor cells (HSPCs) in treated mice. Additionally, secondary transplant of HSPCs isolated from G-F8-LV treated mice corrected the bleeding phenotype of the recipient HemA mice, indicating the potential of long-term transgene expression following IO-LV therapy. To facilitate the translation of this technology to human applications, we evaluated the safety and efficacy of this gene transfer therapy into human HSPCs. In vitro transduction of human HSPCs by the platelet-targeted G-F8-LV confirmed megakaryocyte-specific gene expression after preferential differentiation of HSPCs to megakaryocyte lineages. Lentiviral integration analysis detected a polyclonal integration pattern in G-F8-LV transduced human cells, profiling the clinical safety for hemophilia treatment. Most importantly, IO delivery of G-F8-LV to humanized NBSGW mice produced persistent FVIII expression in human platelets after gene therapy, and the megakaryocytes differentiated from human CD34+ HSPCs isolated from LV-treated humanized mice showed up to 10.2% FVIII expression, indicating efficient transduction of self-regenerating human HSPCs. Collectively, these results indicate the long-term safety and efficacy of IO-LV gene therapy strategy for hemophilia A in a humanized model, adding further evidence to the feasibility of translating this method for clinical applications.
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http://dx.doi.org/10.1182/bloodadvances.2022008079DOI Listing
July 2022

Amplification Profiling Identifies a Subtype of Melanoma Associated With Poor Survival and an Immunosuppressive Tumor Microenvironment.

Front Immunol 2022 1;13:725679. Epub 2022 Jul 1.

Department of Medical Oncology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China.

Background: Although melanoma is generally regarded as an immunogenic cancer that will respond to immune checkpoint inhibitors (ICIs), melanomas with amplification respond poorly to these therapies. Further understanding how amplification impacts the effectiveness of ICI therapy is important for the design of future clinical trials.

Methods: We used data from tumor samples taken from Chinese patients with melanoma analyzed at the Geneplus Institute (=302), as well as data from the Cancer Genome Atlas (TCGA) database (=367) and the Memorial Sloan Kettering Cancer Center (MSKCC) database (=350) to estimate the prevalence of amplification in melanoma, interrogate the relationship between amplification and survival in patients with melanoma, and explore the molecular mechanisms of amplification. We also established a murine model of melanoma harboring amplification and utilized RNA-seq to verify the findings from human tissue samples.

Results: Data from all three sources revealed a low frequency of amplification co-occurring with , , , and mutations. Data from TCGA did not show a statistically significant correlation between amplification and prognosis, irrespective of ICI use. In contrast, the MSKCC cohort showed that amplification was an unfavorable prognostic factor for patients with melanoma, especially for patients who received ICIs and had a high tumor mutation burden (TMB). The TCGA data showed that amplification was associated with a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immune boosting cells (follicular helper T cells naïve B cells, CD8 T cells). Murine models supported the association between a suppressive immune microenvironment and amplification; tumors with amplification had reduced mRNA expression of CD8, Gzm, B2m and Tap1, significantly higher proportions of resting CD4 memory T cells and significantly lower proportions of plasma cells, CD8 T cells, and T follicular helper cells. Furthermore, a Gene Set Enrichment Analysis (GSEA) analysis of data from the TCGA database suggested that signaling pathways involved in oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and Myc targets were differentially enriched in melanoma tumors with amplification. Finally, we observed a notable reduction in levels of angiogenesis-related molecules (encoded by , , , , and ) in a high amplification group from the TCGA database.

Conclusions: Melanoma with amplification is an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Therefore, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, and targeting oxidative and lipid metabolism pathways, may be effective therapeutic strategies for melanoma patients harboring amplification.
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http://dx.doi.org/10.3389/fimmu.2022.725679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9285001PMC
July 2022

An Unprecedented Fireproof, Anion-Immobilized Composite Electrolyte Obtained via Solidifying Carbonate Electrolyte for Safe and High-Power Solid-State Lithium-Ion Batteries.

Small 2022 Aug 17;18(32):e2202060. Epub 2022 Jul 17.

Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electrophotonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China.

The update of electrolytes from a liquid state to a solid state is considered effective in improving the safety and energy density of lithium-ion batteries (LIBs). Although numerous efforts have been made, solid-state electrolytes' (SSEs) insufficient charge transfer capability remains a significant obstruction to practical applications. Herein, a fireproof and anion-immobilized composite electrolyte is designed by solidifying carbonate electrolyte, exhibiting superior Li-ion conductivity (11.5 mS cm at 30 °C) and Li-ion transference number (0.90), which endows LIBs excellent rate capability and cycling stability. Elaborate characteristics and theoretical calculations demonstrate the presence of robust anion-molecule coordination (composed of lithium bond and Coulomb force) enables a more efficient ion transport, where the mobility of Li ion is enhanced meanwhile the anions are immobilized. This work highlights how the strong interactions between electrolyte components can be used to simultaneously regulate the migration of Li ion and anion, and realize a one-step conversion of inflammable liquid-state electrolyte to nonflammable solid-state electrolyte.
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http://dx.doi.org/10.1002/smll.202202060DOI Listing
August 2022

Significant π bonding in coinage metal complexes OCTMCCO from infrared photodissociation spectroscopy and theoretical calculations.

J Chem Phys 2022 Jul;157(1):014302

Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200438, China.

A series of coinage metal complexes in the form of TMC(CO) (TM = Cu, Ag, Au; n = 0-3) were generated using a laser-ablation supersonic expansion ion source in the gas phase. Mass-selected infrared photodissociation spectroscopy in conjunction with quantum chemical calculations indicated that the TMC(CO) complexes contain a linear OCTMCCO core anion. Bonding analyses suggest that the linear OCTMCCO anions are better described as the bonding interactions between a singlet ground state TM metal cation and the OC/CCO ligands in the singlet ground state. In addition to the strong ligands to metal σ donation bonding components, the π-bonding components also contribute significantly to the metal-ligand bonds due to the synergetic effects of the CO and CCO ligands. The strengths of the bonding of the three metals show a V-shaped trend in which the second-row transition metal Ag exhibits the weakest interactions whereas the third-row transition metal Au shows the strongest interactions due to relativistic effects.
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http://dx.doi.org/10.1063/5.0099789DOI Listing
July 2022

Anomalous origin of the left coronary artery from the pulmonary artery as a rare cause of mitral valve prolapse: a case report.

BMC Cardiovasc Disord 2022 07 4;22(1):304. Epub 2022 Jul 4.

Department of Cardiology, The Affiliated Hospital of Southwest Medical University, NO. 25 Taiping Street, Luzhou, 646000, Sichuan, China.

Background: Mitral valve prolapse (MVP) is an etiologically heterogeneous disorder. Early diagnosis and prompt treatment of the underlying disease are of great significance. Herein, we present a rare case of MVP caused by anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA).

Case Presentation: A 22-year-old female presented with a 16-year history of anterior mitral leaflet prolapse. However, she had never experienced any discomfort before. At a routine follow-up, a transthoracic echocardiogram showed anterior mitral leaflet prolapse (A2) with moderate mitral regurgitation, and a retrograde blood flow from an extremely dilated left coronary artery (LCA). Further coronary angiography and coronary computed tomography angiography confirmed the diagnosis of ALCAPA. She subsequently underwent successful LCA reimplantation and concomitant mitral valve replacement. Intraoperatively, her mitral annulus was mildly dilated, anterior mitral valve leaflet appeared markedly thickened with rolled edges, and a chordae tendineae connecting the anterior leaflet (A2) was ruptured and markedly shortened.

Conclusions: ALCAPA is a rare and potentially life-threatening congenital coronary artery anomaly that may cause mitral valve prolapse. Echocardiogram is an important screening tool for this disorder.
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http://dx.doi.org/10.1186/s12872-022-02729-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254612PMC
July 2022

A case report: Anesthetic management for open-heart surgery in a child with congenital insensitivity to pain with anhidrosis.

Paediatr Anaesth 2022 Sep 7;32(9):1070-1072. Epub 2022 Jul 7.

The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease also known as hereditary sensory and autonomic neuropathy. CIPA is characterized by a lack of pain sensitivity and impaired development of sweat glands. Surgery is required for patients with self-mutilation and skeletal developmental disorders. Due to the disease's rarity and intricacy, anesthesia poses its challenges. Although there have been a few cases of CIPA patients receiving surgery and anesthesia, the number is very limited. Here, we report a case of a child with CIPA who underwent open-heart surgery and discuss the anesthetic considerations. We conclude that patients with CIPA undergoing open-heart surgery require some opioids, that muscle relaxants and volatile anesthetics should be used with extreme caution, and that airway management and temperature control require special attention.
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http://dx.doi.org/10.1111/pan.14515DOI Listing
September 2022

Metabonomic Analysis Provides New Insights into the Response of Zhikong Scallop () to Heat Stress by Improving Energy Metabolism and Antioxidant Capacity.

Antioxidants (Basel) 2022 May 30;11(6). Epub 2022 May 30.

MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.

Temperature is an important factor affecting the growth, development and survival of marine organisms. A short episode of high temperature has been proven to be a severe threat to sustainable shellfish culture. Zhikong scallop (), a shellfish with broad economic and biological value in North China, has frequently experienced heat stress in summer in recent years. To understand the effects of heat stress on shellfish, the metabolism of was analyzed after exposure to 27 °C for either 6 h or 30 d. After 6 h of heat stress exposure, a total of 326 and 264 significantly different metabolites (SDMs) were identified in gill and mantle tissues, respectively. After 30 d of heat stress exposure, a total of 381 and 341 SDMs were found in the gill and mantle tissues, respectively. These SDMs were mainly related to the metabolism of amino acids, carbohydrates, lipids and nucleotides. A decline in pyruvic acid, and an increase in citric acid and fumaric acid in the gills and mantle of indicated an alteration in energy metabolism, which may be attributed to increased ATP production in order to overcome the heat stress. Among the SDMs, 33 metabolites, including pyruvic acid, glycine and citric acid, were selected as potential biomarkers for heat stress response in . In addition, a decline in glutamine and β-Alanine levels indicated oxidative stress in exposed to heat, as well as an increase in the total antioxidant capacity (T-AOC). Our findings suggested have the potential to adapt to heat stress by regulating energy metabolism and antioxidant capacity.
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http://dx.doi.org/10.3390/antiox11061084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219709PMC
May 2022

Alkaline Phosphatase Electrochemical Micro-Sensor Based on 3D Graphene Networks for the Monitoring of Osteoblast Activity.

Biosensors (Basel) 2022 Jun 13;12(6). Epub 2022 Jun 13.

State Key Lab of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050, China.

Alkaline phosphatase (ALP) is a significant biomarker that indicates osteoblast activity and skeletal growth. Efficient ALP detection methods are essential in drug development and clinical diagnosis. In this work, we developed an in-situ synthesized three-dimensional graphene networks (3DGNs)-based electrochemical sensor to determine ALP activity. The sensor employs an ALP enzymatic conversion of non-electroactive substrate to electroactive product and presents the ALP activity as an electrochemical signal. With 3DGNs as the catalyst and signal amplifier, a sample consumption of 5 μL and an incubation time of 2 min are enough for the sensor to detect a wide ALP activity range from 10 to 10,000 U/L, with a limit of detection of 5.70 U/L. This facile fabricated sensor provides a quick response, cost-effective and non-destructive approach for monitoring living adherent osteoblast cell activity and holds promise for ALP quantification in other biological systems and clinical samples.
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http://dx.doi.org/10.3390/bios12060406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221009PMC
June 2022

CPT2 K79 Acetylation Regulates Platelet Lifespan.

Blood Adv 2022 Jun 21. Epub 2022 Jun 21.

Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Short lifespan of platelets is a major challenge to platelet transfusion services due to the lack of effective intervention. Here, we found that the accumulation of long-chain acylcarnitines (LCACs) is responsible for mitochondrial damage and platelet storage lesion. Further studies showed that the blockade of fatty acid oxidation and the activation of AMPK/ACC/CPT1 pathways that promote fatty acid metabolism are important reasons for the accumulation of LCACs. The excessive accumulation of LCACs can cause mitochondrial damage and short lifespan of stored platelets. The mechanism study elucidated that NAD+ exhaustion and the subsequent decrease in Sirt3 activity caused an increase in the level of CPT2 K79 acetylation, which is the primary cause of the blockade of fatty acid oxidation and the accumulation of LCACs. Blocking LCACs generation with the inhibitors of AMPK or CPT1, the agonists of Sirt3, and antioxidants tremendously retarded platelet storage lesion in vitro and prolong the survival of stored platelets in vivo post transfusion by single or combined use. In short, we discovered that CPT2 acetylation attenuates fatty acid oxidation and exacerbates platelet storage lesion and may serve as a new target for improving platelet storage quality.
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http://dx.doi.org/10.1182/bloodadvances.2021006687DOI Listing
June 2022

LncRNA DS Cell Adhesion Molecule Antisense RNA 1 Facilitates Oral Squamous Cell Carcinoma Progression through The microRNA-138-5p/ Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit Axis.

Cell J 2022 May 27;24(5):222-229. Epub 2022 Apr 27.

Department of Stomatology, Affiliated Hospital of Chengde Medical College, Chengde, Hebei Province, China. Email:

Objective: A lot of lncRNAs are implicated in oral squamous cell carcinoma (OSCC) progression. The study aimed at investigating lncRNA DS cell adhesion molecule antisense RNA 1 (DSCAM-AS1)'s functional role and molecular mechanism in OSCC.

Materials And Methods: In this experimental study, a total of 46 pairs of OSCC samples and para-cancerous tissues were collected during surgery. In OSCC tissues and cell lines, quantitative real time polymerase chain reaction (qRTPCR) was performed for detecting DSCAM-AS1 and microRNA-138-5p (miR-138-5p) expression levels. Western blot was conducted to examine the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) expression level. Then, DSCAM-AS1 was knocked down with siRNA in OSCC cells and MTT and EdU assays were conducted to evaluate OSCC cell proliferation. Transwell assay was utilized for detecting OSCC cell migration and invasion capacities. Besides, the relationships among DSCAM-AS1, miR-138-5p, and EZH2 were explored through RNA immunoprecipitation, dual-luciferase reporter assay, qRT-PCR, and Western blot.

Results: DSCAM-AS1 expression was remarkably increased in OSCC tissues and cell lines, and DSCAM-AS1 knockdown could significantly restrain OSCC cell proliferation, migration, and invasion. MiR-138-5p was identified as a target of DSCAM-AS1, and its inhibitor could reverse the suppressive effects of DSCAM-AS1 knockdown on OSCC progression. EZH2 was verified as a target of miR-138-5p, and EZH2 knockdown could counteract the promotional impact of miR-138-5p inhibitor on OSCC progression. Additionally, DSCAM-AS1, as a ceRNA, could regulate EZH2 expression via miR-138-5p.

Conclusion: DSCAM-AS1 can play a tumor-promoting role in OSCC via miR-138-5p/EZH2 axis.
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http://dx.doi.org/10.22074/cellj.2022.7763DOI Listing
May 2022

Platinum atomic clusters embedded in polyoxometalates-carbon black as an efficient and durable catalyst for hydrogen evolution reaction.

J Colloid Interface Sci 2022 Oct 7;624:704-712. Epub 2022 Jun 7.

School of Chemical and Environmental Engineering, China University of Mining & Technology (Beijing), Beijing 100083, China; School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004, China. Electronic address:

Platinum-based catalysts are regarded as the Holy Grail of hydrogen evolution reaction (HER). As a benchmark catalyst for HER, the commercial Pt/C catalyst has low Pt utilization efficiency and high cost, which hinders its commercialization. Atomic clusters-based catalysts show high efficiency of atom utilization and high performance toward electrocatalysis. Herein, an environmentally friendly preparation strategy is proposed to construct Pt atomic clusters on the polyoxometalates-carbon black (Pt-POMs-CB) support. Density functional theory (DFT) calculations reveal that the Pt clusters can be stably anchored on the surface with the driving force arising from the charge transfer from Pt atoms to O atoms of the POMs. Benefiting from metal-support interaction, Pt atomic clusters embedded in silicotungstic acid-carbon black (Pt-STA-CB) exhibit excellent HER activity with an overpotential of 33.8 mV at 10 mA cm, and high mass activity is 1.62 A mg at 33.8 mV, which is 5.4 times that of the commercial Pt/C. In addition, the catalyst displays high stability of 800 h at current density of 500 mA cm. It provides a platform for facile and low-cost preparation of stable Pt-based catalysts, which is crucial for their large-scale production and practical application in the industry.
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http://dx.doi.org/10.1016/j.jcis.2022.06.018DOI Listing
October 2022

Association of the quantity, duration, and type of alcohol consumption on the development of gouty tophi.

Arthritis Care Res (Hoboken) 2022 Jun 13. Epub 2022 Jun 13.

Gout Laboratory, Shandong Provincial Clinical Research Center for Immune Diseases and Gout, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.

Objective: To examine the association of alcohol consumption with the presence and development of ultrasound (US)-detected tophi and subcutaneous tophi (sub-tophi) in a Chinese gout population.

Methods: A total of 554 patients with gout who underwent US and physical examination on the most frequently involved joints in gout were included. Multivariable analysis was performed to assess the associations of the duration, quantity, and type of alcohol consumption with the presence, size, and number of US-detected tophi and sub-tophi.

Results: Compared with non-drinkers, excessive drinkers (>70 g/week), long-term drinkers (≥10 years) and spirits drinkers had a greater proportion, size, and number of US-detected tophi and sub-tophi (all P < 0.05). After adjusting for confounders, excessive drinking (> 70 g/week) (odds ratio [OR]: 1.79; OR: 2.00), long-term alcohol consumption (≥ 10 years) (OR: 1.96; OR: 2.17), and spirits consumption of (OR: 1.81; OR: 2.10) were significantly associated with the presence of US-detected tophi and sub-tophi (all P < 0.05), with the highest OR among the identified risk factors. Among patients who already have US-detected tophi or sub-tophi, moderate drinking (≤ 70 g/week) was associated with larger or multiple tophi (all P < 0.05).

Conclusion: A longer duration and higher quantity of alcohol consumption as well as spirits consumption are predictors for the development of US-detected tophi and sub-tophi in patients with gout. Among people who have US-detected tophi and sub-tophi, weekly alcohol consumption leads to the development of tophi regardless of amount consumed. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/acr.24968DOI Listing
June 2022

A novel coumarin-TPA based fluorescent probe for turn-on hypochlorite detection and lipid-droplet-polarity bioimaging in cancer cells.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Oct 8;279:121481. Epub 2022 Jun 8.

School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, PR China.

A novel fluorescent compound, named C-TPA, based on coumarin (acceptor) and triphenylamine (donor) was facilely designed and fabricated through a one-step Suzuki coupling reaction. As a donor group, triphenylamine can efficiently enhance the fluorescence intensity and photostability of coumarin, and thus improve the detection efficiency. C-TPA-S was obtained from C-TPA treated with Lawesson's reagent and C-TPA-S can be used for the turn-on detection of hypochlorite through oxidative desulfurization with a low detection limit of 0.12 μM. Moreover, the intramolecular charge transfer process between the donor and acceptor group endows C-TPA with solvatochromism property and makes C-TPA a good candidate for polarity detection. The C-TPA with bright green fluorescence was highly efficient for imaging the microenvironment of polarity both in living cells and tissues with high selectivity and photostability, which can be applied in the diagnosis for the cancer cells.
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http://dx.doi.org/10.1016/j.saa.2022.121481DOI Listing
October 2022

KIF17 Modulates Epileptic Seizures and Membrane Expression of the NMDA Receptor Subunit NR2B.

Neurosci Bull 2022 Aug 9;38(8):841-856. Epub 2022 Jun 9.

Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, 400016, China.

Epilepsy is a common and severe brain disease affecting >65 million people worldwide. Recent studies have shown that kinesin superfamily motor protein 17 (KIF17) is expressed in neurons and is involved in regulating the dendrite-targeted transport of N-methyl-D-aspartate receptor subtype 2B (NR2B). However, the effect of KIF17 on epileptic seizures remains to be explored. We found that KIF17 was mainly expressed in neurons and that its expression was increased in epileptic brain tissue. In the kainic acid (KA)-induced epilepsy mouse model, KIF17 overexpression increased the severity of epileptic activity, whereas KIF17 knockdown had the opposite effect. In electrophysiological tests, KIF17 regulated excitatory synaptic transmission, potentially due to KIF17-mediated NR2B membrane expression. In addition, this report provides the first demonstration that KIF17 is modified by SUMOylation (SUMO, small ubiquitin-like modifier), which plays a vital role in the stabilization and maintenance of KIF17 in epilepsy.
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http://dx.doi.org/10.1007/s12264-022-00888-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352834PMC
August 2022

T cell repertoire in peripheral blood as a potential biomarker for predicting response to concurrent cetuximab and nivolumab in head and neck squamous cell carcinoma.

J Immunother Cancer 2022 06;10(6)

Department of Head and Neck-Endocrine Oncology, H Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA

Background: T cell receptor (TCR) signaling profile is a fundamental property that underpins both adaptive and innate immunity in the host. Despite its potential clinical relevance, the TCR repertoire in peripheral blood has not been thoroughly explored for its value as an immunotherapy efficacy biomarker in head and neck squamous cell carcinoma (HNSCC). The purpose of the present study is to characterize and compare the TCR repertoire in peripheral blood mononuclear cells (PBMC) from patients with HNSCC treated with the combination of cetuximab and nivolumab.

Methods: We used the immunoSEQ assay to sequence the TCR beta (TCR-B) chain repertoire from serially obtained PBMC at baseline and during the treatments from a total of 41 patients who received the combination (NCT03370276). Key TCR repertoire metrics, including diversity and clonality, were calculated and compared between patients with different therapy responses and clinical characteristics (eg, human papillomavirus (HPV) status and smoking history). Patient survival outcomes were compared according to patient groups stratified by the TCR-B clonotyping. To confirm the observed patterns in TCR spectrum, samples from patients who achieved complete response (CR) and partial response (PR) were further profiled with the immunoSEQ deep resolution assay.

Results: Our data indicated that the patients who achieved CR and PR had an increased TCR sequence diversity in their baseline samples, this tendency being more pronounced in HPV-negative patients or those with a smoking history. Notably, the CR/PR group had the lowest proportion of patients with oligoclonal TCR clones (2 out of 8 patients), followed by the stable disease group (9 out of 20 patients) and lastly the progressive disease group (7 out of 10 patients). An overall trend toward favorable patient survival was also observed in the polyclonal group. Finally, we reported the shared TCR clones across patients within the same response group, as well as the shared clones by aligning immunoSEQ reads with TCR data retrieved from The Cancer Genome Atlas- head and neck squamous cell carcinoma (TCGA-HNSC) cohort.

Conclusions: Our data suggest that, despite the great clinical heterogeneity of HNSCC and the limited responders in the present cohort, the peripheral TCR repertoires from pretreatment PBMC may be developed as biomarkers for the benefit of immunotherapy in HNSCC.
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http://dx.doi.org/10.1136/jitc-2022-004512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185557PMC
June 2022

The ORF7a protein of SARS-CoV-2 initiates autophagy and limits autophagosome-lysosome fusion via degradation of SNAP29 to promote virus replication.

Autophagy 2022 Jun 19:1-19. Epub 2022 Jun 19.

Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely related to various cellular aspects associated with autophagy. However, how SARS-CoV-2 mediates the subversion of the macroautophagy/autophagy pathway remains largely unclear. In this study, we demonstrate that overexpression of the SARS-CoV-2 ORF7a protein activates LC3-II and leads to the accumulation of autophagosomes in multiple cell lines, while knockdown of the viral gene via shRNAs targeting sgRNA during SARS-CoV-2 infection decreased autophagy levels. Mechanistically, the ORF7a protein initiates autophagy via the AKT-MTOR-ULK1-mediated pathway, but ORF7a limits the progression of autophagic flux by activating CASP3 (caspase 3) to cleave the SNAP29 protein at aspartic acid residue 30 (D30), ultimately impairing complete autophagy. Importantly, SARS-CoV-2 infection-induced accumulated autophagosomes promote progeny virus production, whereby ORF7a downregulates SNAP29, ultimately resulting in failure of autophagosome fusion with lysosomes to promote viral replication. Taken together, our study reveals a mechanism by which SARS-CoV-2 utilizes the autophagic machinery to facilitate its own propagation via ORF7a.
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http://dx.doi.org/10.1080/15548627.2022.2084686DOI Listing
June 2022

SARS-CoV-2 N Protein Antagonizes Stress Granule Assembly and IFN Production by Interacting with G3BPs to Facilitate Viral Replication.

J Virol 2022 06 2;96(12):e0041222. Epub 2022 Jun 2.

Beijing Institute of Biotechnology, Beijing, China.

SARS-CoV-2 is the causative agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19) and poses a significant threat to global health. N protein (NP), which is a major pathogenic protein among betacoronaviruses, binds to the viral RNA genome to allow viral genome packaging and viral particle release. Recent studies showed that NP antagonizes interferon (IFN) induction and mediates phase separation. Using live SARS-CoV-2 viruses, this study provides solid evidence showing that SARS-CoV-2 NP associates with G3BP1 and G3BP2 and . NP could efficiently suppress G3BP-mediated SG formation and potentiate viral infection by overcoming G3BP1-mediated antiviral innate immunity. G3BP1 conditional knockout mice (, -Cre) exhibit significantly higher lung viral loads after SARS-CoV-2 infection than wild-type mice. Our findings contribute to the growing body of knowledge regarding the pathogenicity of NP and provide insight into new therapeutics targeting NP. In this study, by assay and live SARS-CoV-2 virus infection, we provide solid evidence that the SARS-CoV-2 NP associates with G3BP1 and G3BP2 and . NP could efficiently suppress G3BP-mediated SG formation and potentiate viral infection by overcoming antiviral innate immunity mediated by G3BP1 in A549 cell lines and G3BP1 conditional knockout mice (-cKO) mice, which provide in-depth evidence showing the mechanism underlying NP-related SARS-CoV-2 pathogenesis through G3BPs.
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http://dx.doi.org/10.1128/jvi.00412-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9215227PMC
June 2022
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