Publications by authors named "Xiaodong Zhao"

266 Publications

Factors Associated with Recurrence of Hepatocellular Carcinoma in 197 Patients Following Transarterial Chemoembolization: A Retrospective Study from a Single Center.

Med Sci Monit 2021 Sep 17;27:e929879. Epub 2021 Sep 17.

Department of Medical Imaging, Weihai Central Hospital, Weihai, Shandong, China (mainland).

BACKGROUND Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths. Transarterial chemoembolization (TACE) has been widely applied for treating patients with unresectable HCC. This study explored the factors influencing early recurrence (ER) after TACE in HCC patients. MATERIAL AND METHODS A total of 197 patients were divided into the ER group and the non-ER group. Univariate and multivariate Cox regression analyses were carried out to explore the influencing factors. Univariate Kaplan-Meier survival curves and restricted cubic splines were plotted for visualizing the relations between the influencing factors and ER. RESULTS According to the multivariate analysis, for every 1-cm increase in the maximum tumor diameter, the risk of ER increased by 0.235 times (95% CI: 1.144-1.333, P<0.001). Patients with adjacent lobe invasion had a 1.227-fold higher risk of ER than those without (95% CI: 1.461-3.394, P<0.001). For every unit increase in neutrophil-to-lymphocyte ratio (NLR), the risk increased by 0.107-fold (95% CI: 1.012-1.211, P=0.027). Compared to patients at the very early/early Barcelona clinic liver cancer (BCLC) stage, those at the advanced/end stage had a 2.045-fold increased risk of ER (95% CI: 1.259-7.366, P=0.014). CONCLUSIONS The maximum tumor diameter, adjacent lobe invasion, NLR, and advanced/end stage BCLC stage were all risk factors for ER after TACE in HCC patients.
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http://dx.doi.org/10.12659/MSM.929879DOI Listing
September 2021

Clinical Application of Metagenomic Next-Generation Sequencing for Suspected Infections in Patients With Primary Immunodeficiency Disease.

Front Immunol 2021 13;12:696403. Epub 2021 Aug 13.

Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.

Background: Infections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Timely and accurate microbiological diagnosis is particularly important in these patients. Metagenomic next-generation sequencing (mNGS) has been used for pathogen detection recently. However, few reports describe the use of mNGS for pathogen identification in patients with PID.

Objective: To evaluate the utility of mNGS for detecting pathogens in patients with PID, and to compare it with conventional microbiological tests (CMT).

Methods: This single center retrospective study investigated the diagnostic performance of mNGS for pathogens detection in PID patients and compared it with CMT. Sixteen PID patients with suspected infection were enrolled, and medical records were analyzed to extract detailed clinical characteristics such as gene variation, immune status, microbial distribution, time-consuming of mNGS and CMT, treatment, and outcomes.

Results: mNGS identified pathogenic microbe in 93.75% samples, compared to 31.25% for culture and 68.75% for conventional methods, and detected an extra 18 pathogenic microorganisms including rare opportunistic pathogens and . Pathogen identification by mNGS required 48 hours, compared with bacterial culture for 3-7 days and even longer for fungus and culture.

Conclusions: mNGS has marked advantages over conventional methods for pathogenic diagnosis, particularly opportunistic pathogens and mixed infections, in patients with PID. This method might enable clinicians to make more timely and targeted therapeutic decisions, thereby improving the prognosis of these patients.
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http://dx.doi.org/10.3389/fimmu.2021.696403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414648PMC
August 2021

Prevalence, Characterization, and Pathogenicity of Subspecies Serovar Derby from Yaks in the Aba Tibetan Autonomous Prefecture, China.

Animals (Basel) 2021 Aug 13;11(8). Epub 2021 Aug 13.

Key Laboratory of Bio-Resources and Eco-Environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu 610064, China.

subsp. serovar Derby ( Derby) is one of the numerous non-typhoidal serovars and has been recognized as a food-borne pathogen. In 2019, outbreaks of salmonellosis were reported in 13 yak farms in the Aba Tibetan Autonomous Prefecture, China. A total of 32 salmonella strains were isolated from 162 fecal samples of yaks with diarrhea as well as from drinking water samples. The isolates were subjected to serovar identification, animal experiments, and whole-genome sequencing (WGS) analyses. The serovar of all the isolates was Derby, and the sequence types (STs) were ST40. The analysis of the differences of single-nucleotide polymorphisms (SNPs) showed that the salmonella strains isolated from 13 farms were clonally related. Animal experiments showed that the lethal dose (LD) was 4.57 × 10 CFU (colony-forming units); the shedding time of Derby in mice was 24 days; the bacterial loads in spleen were higher than those in other organs (ileum, liver, and cecum). Pathological analyses by hematoxylin and eosin (H&E) staining revealed obvious damage in the spleen, liver, and intestine. These results indicate that the Derby from yaks can cause infection in mice.
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http://dx.doi.org/10.3390/ani11082397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388676PMC
August 2021

Trends in TREC values according to age and gender in Chinese children and their clinical applications.

Eur J Pediatr 2021 Aug 17. Epub 2021 Aug 17.

Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.

T cell receptor excision circles (TRECs) are small circularized DNA elements produced during rearrangement of T cell receptor (TCR) genes. Because TRECs are fairly stable, do not replicate during mitosis, and are not diluted during division of naïve T cells (Dion et al. [1]), they are suitable for assessing the number of newly formed T cells (Ping and Denise [2]). In this study, we detected TRECs in 521 healthy Chinese children aged 0-18 years in different clinical settings. The TRECs decrease with aging and show lower levels in preterm and low birth weight (BW) babies compared to those in full-term infants, while the preterm babies can also show comparable levels of TRECs when they have a gestation age (GA)-matched BW. We found a strong correlation between TRECs and peripheral CD4 naïve T cell numbers, which was age-related. We also analyzed the TRECs in different PIDs. Since T cell defects vary in PIDs, TREC levels change inconsistently. For example, in Wiskott-Aldrich syndrome (WAS), combining the level of TREC with lymphocyte subsets can help to distinguish subtypes of disease.Conclusion: We established the reference value range for TRECs by evaluating children below 18 years old in China, which could be used to screen for PIDs during early life. What is Known: • The TREC levels are decreased with age, and there is a positive correlation between TRECs and the numbers of naïve T cells. What is New: • This is the largest study to determine TREC reference levels in healthy Chinese pediatric, we provide solid data showing a correlation between CD4 naïve T cell counts and TREC levels according to age. We point out the GA matched BW is need to be considered during the SCID newborn screening. We are the first group showed that TREC levels can help clinician distinguish different WAS phenotype.
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http://dx.doi.org/10.1007/s00431-021-04223-8DOI Listing
August 2021

Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation.

J Allergy Clin Immunol 2021 Aug 9. Epub 2021 Aug 9.

Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom. Electronic address:

Background: B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA.

Objective: We investigated the role of B cells in XLN pathogenesis.

Methods: We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response.

Results: XLN patients had normal naive B cells and plasmablasts, but reduced IgA B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells.

Conclusions: Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching.
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http://dx.doi.org/10.1016/j.jaci.2021.07.033DOI Listing
August 2021

Actoeside mitigated the renal proximal tubule cells damage triggered by high glucose through miR-766/VCAM1/NF-κB signalling pathway.

Arch Physiol Biochem 2021 Aug 2:1-10. Epub 2021 Aug 2.

Department of Endocrinology, Zibo Central Hospital, Zibo City, PR China.

Context: Diabetic nephropathy (DN) triggered by diabetes mellitus is one of the primary causes of end-stage renal failure worldwide.

Objective: This study intends to explore the function and potential mechanism of actoeside on renal proximal tubule (HK-2) cells damage induced by high-glucose (HG).

Methods: The DN model was established in HK-2 cells with 30 mM HG treatment. The viability, apoptosis and inflammation of HK-2 cells were analysed severally via CCK-8, flow cytomery and ELISA. The key factors related to NF-κB were detected by western blotting.

Results: Actoeside attenuated the HG-induced HK-2 cells damage. The differentially expression of miR-766 and VCAM1 in DN patients was reversed by actoeside. Moreover, the increased phosphorylation levels of p65 NF-κB/IκBα induced by HG were attenuated by actoeside.

Conclusions: Actoeside promoted the growth and repressed the apoptosis and inflammation of HK-2 cells via miR-766/VCAM1/NF-κB signalling pathway, affording a promising idea for the treatment of DN.
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http://dx.doi.org/10.1080/13813455.2021.1920983DOI Listing
August 2021

Identification of Key Biomarkers and Immune Infiltration in Systemic Juvenile Idiopathic Arthritis by Integrated Bioinformatic Analysis.

Front Mol Biosci 2021 14;8:681526. Epub 2021 Jul 14.

Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.

Systemic juvenile idiopathic arthritis (sJIA) is a rare and serious type of JIA characterized by an unknown etiology and atypical manifestations in the early stage, and early diagnosis and effective treatment are needed. We aimed to identify diagnostic biomarkers, immune cells and pathways involved in sJIA pathogenesis as well as potential treatment targets. The GSE17590, GSE80060, and GSE112057 gene expression profiles from the Gene Expression Omnibus (GEO) database were screened to obtain differentially expressed genes (DEGs) between sJIA and healthy controls. Common DEGs were subjected to pathway enrichment analysis; a protein-protein interaction network was constructed, and hub genes were identified. In addition, functional annotation of hub genes was performed with GenCLiP2. Immune infiltration analysis was then conducted with xCell, and correlation analysis between immune cells and the enriched pathways identified from gene set variation analysis was performed. The Connectivity Map database was used to identify candidate molecules for treating sJIA patients. Finally, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out, and the GEO dataset GSE8361 was applied for validation of hub gene expression levels in blood samples from healthy individuals with sJIA. A total of 73 common DEGs were identified, and analysis indicated enrichment of neutrophil and platelet functions and the MAPK pathway in sJIA. Six hub genes were identified, of which three had high diagnostic sensitivity and specificity; ARG1 and PGLYRP1 were validated by qRT-PCR and microarray data of the GSE8361 dataset. We found that increased megakaryocytes and decreased Th1 cells correlated positively and negatively with the MAPK pathway, respectively. Furthermore, MEK inhibitors and some kinase inhibitors of the MAPK family were identified as candidate agents for sJIA treatment. Our results indicate two candidate markers for sJIA diagnosis and reveal the important roles of platelets and the MAPK pathway in the pathogenesis of sJIA, providing a new perspective for exploring potential molecular targets for sJIA treatment.
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http://dx.doi.org/10.3389/fmolb.2021.681526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316978PMC
July 2021

Mechanisms of bentonite colloid aggregation, retention, and release in saturated porous media: Role of counter ions and humic acid.

Sci Total Environ 2021 Nov 22;793:148545. Epub 2021 Jun 22.

School of Nuclear Science and Technology, Lanzhou University, Lanzhou 730000, China; Frontiers Science Center for Rare Isotopes, Lanzhou University, Lanzhou 730000, China.

In the subsurface environment, colloids play an important role in pollutant transport by acting as the carriers. Understanding colloid release, transport, and deposition in porous media is a prerequisite for evaluating the potential role of colloids in subsurface contaminant transport. In this work, the aggregation, retention, and release of bentonite colloid in saturated porous sand media were investigated by kinetic aggregation and column experiments, the correlation and mechanism of these processes were revealed by combining colloid filtration theory, interaction energy calculation and density functional theory. The results showed that the retention and release of colloids were closely related to the dispersion stability and filtration effect. Multivalent cations with higher mineral affinity reduced the colloid stability, and the dispersion stability and mobility of the colloid were greatly improved by humic acid due to the enhancement of electrostatic repulsion and steric hindrance effects. The primary minimum interaction was found to contribute more to irreversible colloid retention in a Ca system, while the secondary energy minimum was found to be responsible for colloid release with the occurrence of transient solution chemistry. The deposited colloid aggregates could be redistributed and released when the solution chemistry became favorable towards dispersion. These findings provide essential insight into the environmental colloid fate as well as a vital reference for the risk of colloid-driven transport of contaminants in the subsurface aquifer environment.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148545DOI Listing
November 2021

Altered Functions of Neutrophils in Two Chinese Patients With Severe Congenital Neutropenia Type 4 Caused by Mutations.

Front Immunol 2021 8;12:699743. Epub 2021 Jul 8.

National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.

Background: SCN4 is an autosomal recessive disease caused by mutations in the gene. The clinical, molecular, and immunological features; function of neutrophils; and prognosis of patients with SCN4 have not been fully elucidated.

Methods: Two Chinese pediatric patients with mutations were enrolled in this study. Clinical data, genetic and immunologic characteristics, and neutrophil function were evaluated in patients and controls before and after granulocyte colony-stimulating factor (G-CSF) treatment.

Results: Both patients had histories of pneumonia, inguinal hernia, cryptorchidism, and recurrent oral ulcers. Patient 1 also had asthma and otitis media, and patient 2 presented with prominent ectatic superficial veins and inflammatory bowel disease. DNA sequencing demonstrated that both patients harbored heterozygous gene mutations. Spontaneous and FAS-induced neutrophil apoptosis were significantly increased in patients, and improved only slightly after G-CSF treatment, while neutrophil respiratory burst and neutrophil extracellular traps production remained impaired in patients after G-CSF treatment.

Conclusion: G-CSF treatment is insufficient for patients with SCN4 patients, who remain at risk of infection. Where possible, regular G-CSF treatment, long-term prevention of infection, are the optimal methods for cure of SCN4 patients. It is important to monitor closely for signs of leukemia in SCN4 patients. Once leukemia occurs in SCN4 patients, hematopoietic stem cell transplantation is the most important choice of treatment.
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http://dx.doi.org/10.3389/fimmu.2021.699743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296982PMC
July 2021

A Visual Analytics Approach for Structural Differences Among Graphs via Deep Learning.

IEEE Comput Graph Appl 2021 Sep-Oct;41(5):18-31. Epub 2021 Sep 10.

Representing and analyzing structural differences among graphs help gain insight into the difference related patterns such as dynamic evolutions of graphs. Conventional solutions leverage representation learning techniques to encode structural information, but lack an intuitive way of studying structural semantics of graphs. In this article, we propose a representation-and-analysis scheme for structural differences among graphs. We propose a deep-learning-based embedding technique to encode multiple graphs while preserving semantics of structural differences. We design and implement a web-based visual analytics system to support comparative study of features learned from the embeddings. One distinctive feature of our approach is that it supports semantics-aware construction, quantification, and investigation of latent relations encoded in graphs. We validate the usability and effectiveness of our approach through case studies with three datasets.
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http://dx.doi.org/10.1109/MCG.2021.3097799DOI Listing
September 2021

A novel TLE6 mutation, c.541+1G>A, identified using whole-exome sequencing in a Chinese family with female infertility.

Mol Genet Genomic Med 2021 Aug 15;9(8):e1743. Epub 2021 Jul 15.

The Reproductive Medicine Hospital of the First Hospital of Lanzhou University, Lanzhou, Gansu, China.

Background: Oocytes have a lot of maternal RNAs and proteins, which are used by the early embryo before zygotic genome activation. Transducin-like enhancer of split 6 (TLE6) is a component of a subcortical maternal complex which plays a critical role in early embryonic development.

Methods: The patient had been diagnosed with primary infertility for 6 years and had undergone multiple failed in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Genomic DNA samples were extracted from her parents' peripheral blood as well as hers. Whole-exome sequencing and Sanger validation were performed to identify candidate variants.

Results: We identified a novel transducin-like enhancer of split 6 (TLE6) gene mutations in the female patient with recurrent IVF/ICSI failure. The patient carried a homozygous mutation (NM_001143986.1(TLE6): c.541+1G>A) and had viable but low-quality embryos. Her parents both had heterozygous mutations at this locus.

Conclusion: Our study expands the mutational and phenotypic spectrum of TLE6 and suggests the important role of TLE6 during embryonic development. Our findings have implications for the genetic diagnosis of female infertility with recurrent IVF/ICSI failure.
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http://dx.doi.org/10.1002/mgg3.1743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404233PMC
August 2021

A Novel Mutation in the NBD Domain of Causes Mild Autoinflammation With Recurrent Urticaria.

Front Immunol 2021 23;12:674808. Epub 2021 Jun 23.

Department of Immunology, Ministry of Education Key laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

Background: NOD-like receptor family CARD-containing 4 protein (NLRC4) is a cytosolic protein that forms an inflammasome in response to flagellin and type 3 secretion system (T3SS) proteins from invading Gram-negative bacteria. mutations have been recently identified in early-onset severe autoinflammatory disorders. In this study, we reported a novel mutation in in two Chinese patients, who manifested with recurrent urticaria and arthralgia.

Methods: We summarized the clinical data of the two patients. Gene mutations were identified by whole-exome sequencing (WES). Swiss-PdbViewer was used to predict the pathogenicity of the identified mutations. Cytokine levels and caspase-1 activation were detected in the patient PBMCs with lipopolysaccharide (LPS) stimulation. All previously published cases with mutations were reviewed.

Results: We identified a missense heterozygous mutation (c.514G>A, p.Gly172Ser), which was located in the highly conserved residue of nucleotide-binding domain (NBD) of NLRC4. The mutation did not alter the expression of NLRC4 protein, but induced considerably much higher production of IL-1β and IL-6 in patient PBMCs than in healthy controls after LPS stimulation. Four NLRC4 inflammasomopathy phenotypes have been described, with severe inflammatory diseases including macrophage activation syndrome, enterocolitis and NOMID in patients with mutations in the NBD and HD1 domains, whereas a mild clinical phenotype was associated with two mutations in the WHD domain of NLRC4.

Conclusion: We identified a novel mutation in the NBD domain, and the patients just presented with a mild inflammatory phenotype. Thus, our findings reinforce the diversity of mutations and expand the clinical spectrum of associated diseases.
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http://dx.doi.org/10.3389/fimmu.2021.674808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260849PMC
June 2021

Differentially Expressed MiRNAs of Goat Submandibular Glands Among Three Developmental Stages Are Involved in Immune Functions.

Front Genet 2021 15;12:678194. Epub 2021 Jun 15.

Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China.

Submandibular glands (SMGs) are one of the primary components of salivary glands in goats. The proteins and biologically active substances secreted by the SMGs change with growth and development. Our previous studies showed that most of the differentially expressed genes in the SMGs of goats at different developmental stages are involved in immune-related signaling pathways, but the miRNA expression patterns in the same tissues are unknown. The aim of this study was to reveal the expression profile of miRNAs at three different developmental stages, detect differentially expressed miRNAs (DE miRNAs) and predict disease-related DE miRNAs. SMG tissue samples were collected from groups of 1-month-old kids, 12-month-old maiden goats and 24-month-old adult goats (three samples from each group), and high-throughout transcriptome sequencing was conducted. A total of 178, 241 and 7 DE miRNAs were discovered between 1-month-old kids and 12-month-old maiden goats, between 1-month-old kids and 24-month-old adult goats, and between 12-month-old maiden goats and 24-month-old adult goats, respectively. Among these DE miRNAs, 88 DE miRNAs with medium or high expression levels (TPM ≥50) were classified into five expression pattern clusters. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that some of the predicted target genes of the DE miRNAs in the five clusters were enriched in disease-related GO terms and pathways. MiRNA target genes in significant pathways were significantly enriched in Hepatitis B (FDR = 9.03E-10) and Pathways in cancer (FDR = 4.2E-10). Further analysis was performed with a PPI network, and 10 miRNAs were predicted to play an important role in the occurrence and prevention of diseases during the growth and development of goats.
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http://dx.doi.org/10.3389/fgene.2021.678194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239366PMC
June 2021

In-Situ Synthesis of [email protected] Nanosheets for Polymers Degradation in a Natural Environment.

Polymers (Basel) 2021 Jun 30;13(13). Epub 2021 Jun 30.

College of Materials and Environmental Engineering, Hangzhou Dianzi University, Xiasha Higher Education Zone, Hangzhou 310018, China.

Plastic photodegradation naturally takes 300-500 years, and their chemical degradation typically needs additional energy or causes secondary pollution. The main components of global plastic are polymers. Hence, new technologies are urgently required for the effective decomposition of the polymers in natural environments, which lays the foundation for this study on future plastic degradation. This study synthesizes the in-situ growth of TiO at graphene oxide (GO) matrix to form the [email protected] photocatalyst, and studies its application in conjugated polymers' photodegradation. The photodegradation process could be probed by UV-vis absorption originating from the conjugated backbone of polymers. We have found that the complete decomposition of various polymers in a natural environment by employing the photocatalyst [email protected] within 12 days. It is obvious that the [email protected] shows a higher photocatalyst activity than the TiO, due to the higher crystallinity morphology and smaller size of TiO, and the faster transmission of photogenerated electrons from TiO to GO. The stronger fluorescence (FL) intensity of [email protected] compared to TiO at the terephthalic acid aqueous solution indicates that more hydroxyl radicals (•OH) are produced for [email protected] This further confirms that the GO could effectively decrease the generation of recombination centers, enhance the separation efficiency of photoinduced electrons and holes, and increase the photocatalytic activity of [email protected] This work establishes the underlying basic mechanism of polymers photodegradation, which might open new avenues for simultaneously addressing the white pollution crisis in a natural environment.
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http://dx.doi.org/10.3390/polym13132158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272197PMC
June 2021

WASp Is Crucial for the Unique Architecture of the Immunological Synapse in Germinal Center B-Cells.

Front Cell Dev Biol 2021 14;9:646077. Epub 2021 Jun 14.

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, MD, United States.

B-cells undergo somatic hypermutation and affinity maturation in germinal centers. Somatic hypermutated germinal center B-cells (GCBs) compete to engage with and capture antigens on follicular dendritic cells. Recent studies show that when encountering membrane antigens, GCBs generate actin-rich pod-like structures with B-cell receptor (BCR) microclusters to facilitate affinity discrimination. While deficiencies in actin regulators, including the Wiskott-Aldrich syndrome protein (WASp), cause B-cell affinity maturation defects, the mechanism by which actin regulates BCR signaling in GBCs is not fully understood. Using WASp knockout (WKO) mice that express Lifeact-GFP and live-cell total internal reflection fluorescence imaging, this study examined the role of WASp-mediated branched actin polymerization in the GCB immunological synapse. After rapid spreading on antigen-coated planar lipid bilayers, GCBs formed microclusters of phosphorylated BCRs and proximal signaling molecules at the center and the outer edge of the contact zone. The centralized signaling clusters localized at actin-rich GCB membrane protrusions. WKO reduced the centralized micro-signaling clusters by decreasing the number and stability of F-actin foci supporting GCB membrane protrusions. The actin structures that support the spreading membrane also appeared less frequently and regularly in WKO than in WT GCBs, which led to reductions in both the level and rate of GCB spreading and antigen gathering. Our results reveal essential roles for WASp in the generation and maintenance of unique structures for GCB immunological synapses.
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http://dx.doi.org/10.3389/fcell.2021.646077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236648PMC
June 2021

Depressive State in the Emergency Department During COVID-19: A National Cross-Sectional Survey in China.

Front Psychiatry 2021 14;12:566990. Epub 2021 Jun 14.

Department of Emergency Medicine, The First Affiliate Hospital of Xinjiang Medical University, Wulumuqi, China.

Chinese emergency department (ED) staff encountered significant mental stress while fighting the coronavirus disease 2019 (COVID-19) pandemic. We sought to investigate the prevalence and associated factors for depressive symptoms among ED staff (including physicians, nurses, allied health, and auxiliary ED staff). A cross-sectional national survey of ED staff who were on duty and participated in combating the COVID-19 pandemic was conducted March 1-15, 2020. A total of 6,588 emergency medical personnel from 1,060 hospitals responded to this survey. A majority of respondents scored above 10 points on the PHQ-9 standardized test, which is associated with depressive symptoms. Those aged 31-45, those working in the COVID-19 isolation unit, and those with relatives ≤ 16 or ≥70 years old at home all had statistically significant associations with scoring >10 points. Depressive symptoms among Chinese emergency medical staff were likely quite common during the response to the COVID-19 pandemic and reinforce the importance of targeted ED staff support during future outbreaks.
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http://dx.doi.org/10.3389/fpsyt.2021.566990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236535PMC
June 2021

Intratracheal inoculation of AHc vaccine induces protection against aerosolized botulinum neurotoxin A challenge in mice.

NPJ Vaccines 2021 Jun 22;6(1):87. Epub 2021 Jun 22.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is generally known to be the most poisonous of all biological toxins. In this study, we evaluate the protection conferred by intratracheal (i.t.) inoculation immunization with recombinant Hc subunit (AHc) vaccines against aerosolized BoNT/A intoxication. Three AHc vaccine formulations, i.e., conventional liquid, dry powder produced by spray freeze drying, and AHc dry powder reconstituted in water are prepared, and mice are immunized via i.t. inoculation or subcutaneous (s.c.) injection. Compared with s.c.-AHc-immunized mice, i.t.-AHc-immunized mice exhibit a slightly stronger protection against a challenge with 30,000× LD aerosolized BoNT/A. Of note, only i.t.-AHc induces a significantly higher level of toxin-neutralizing mucosal secretory IgA (SIgA) production in the bronchoalveolar lavage of mice. In conclusion, our study demonstrates that the immune protection conferred by the three formulations of AHc is comparable, while i.t. immunization of AHc is superior to s.c. immunization against aerosolized BoNT/A intoxication.
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http://dx.doi.org/10.1038/s41541-021-00349-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219734PMC
June 2021

High-speed computational ghost imaging based on an auto-encoder network under low sampling rate.

Appl Opt 2021 Jun;60(16):4591-4598

Computational ghost imaging is difficult to apply under low sampling rate. We propose high-speed computational ghost imaging based on an auto-encoder network to reconstruct images with high quality under low sampling rate. The auto-encoder convolutional neural network is designed, and the object images can be reconstructed accurately without labeled images. Experimental results show that our method can greatly improve the peak signal-to-noise ratio and structural similarity of the test samples, which are up to 18 and 0.7, respectively, under low sampling rate. Our method only needs 1/10 of traditional deep learning samples to achieve fast and high-quality image reconstruction, and the network also has a certain generalization to the gray-scale images.
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http://dx.doi.org/10.1364/AO.422641DOI Listing
June 2021

Large-area Piezoelectric Single Crystal Composites via 3D-printing Assisted Dice-and-insert Technology for Hydrophone Applications.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Jun 4;PP. Epub 2021 Jun 4.

Compared with Pb(Zr,Ti)O3 (PZT) ceramics, piezoelectric ceramic composites (PCCs), and piezoelectric polyvinylidene fluoride (PVDF) polymer, piezoelectric single crystal composites (PSCCs) are thought to be promising candidates for hydrophone applications because of their superior hydrostatic performance. However, due to the brittleness and small dimensions of single crystals, the preparation of large-area or conformal PSCCs is to be challenged. Herein, we prepared a large-area PSCC with dimensions of 50 mm × 50 mm × 5 mm using 3D-printing assisted dice-and-insert technology. The hydrostatic piezoelectric performances for PSCC were investigated using a quasi-static method. The hydrostatic figure-of-merit (HFOM) of PSCC is approximately 1469×10-15 m2/N, which is higher by 69.4% than that of PCC. Furthermore, PSCC shows advantages in the dielectric loss, frequency constant, electromechanical coupling coefficient and hydrostatic pressure stability. The results suggest that PSCCs have great potential in substantially improving the sensitivity of hydrophones. In addition, 3D-printing assisted dice-and-insert technology breaks through the restriction of as-grown piezoelectric crystal size so as to make it possible for the applications where large-scale piezoelectric composites are required.
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http://dx.doi.org/10.1109/TUFFC.2021.3085842DOI Listing
June 2021

UNC13D mutation in a patient with juvenile polymyositis with recurrent macrophage activation syndrome.

Rheumatology (Oxford) 2021 Apr 30. Epub 2021 Apr 30.

Division of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.

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http://dx.doi.org/10.1093/rheumatology/keab391DOI Listing
April 2021

Smokeless tobacco analysis: Simultaneous extraction and purification of alkaloids, volatile N-nitrosamines, and polycyclic hydrocarbons for GC-MS/MS.

J Sep Sci 2021 Jul 22;44(13):2642-2654. Epub 2021 May 22.

Technology Center, China Tobacco He'nan Industrial Co. Ltd., Research Institute of CNTC, Zhengzhou, P. R. China.

Several smokeless tobacco products are available in the market and comprise complex chemical matrices. Sample preparation for analysis of the multiple classes of harmful compounds in smokeless tobacco products is highly cumbersome. In this study, a simultaneous extraction scheme was developed for three toxic analyte classes in smokeless tobacco products using a two-phase solution consisting of 5% aqueous NaOH and dichloromethane in a 1:4 ratio. The dichloromethane extract was used to analyze four alkaloids directly at levels greater than parts per million; however, passing the layer through a silica cartridge for further purification and concentration was necessary for determining 18 polycyclic aromatic hydrocarbons and four volatile N-nitrosoamines at the ppt level. The multitargets were determined by using gas chromatography with tandem mass spectrometry. The limits of detection for the 18 polycyclic aromatic hydrocarbons, four volatile N-nitrosoamines, three minor alkaloids, and nicotine were 0.2-1.2, 0.2-0.4, 0.6-1.0, and 10.2 μg/g, respectively. Four different smokeless tobacco substrates were fortified with three levels of mixed standards, and the recoveries ranged between 83 and 110%. The method was highly efficient, reduced the sample amounts, solvents, and the time required by approximately 60%. The method was used to assay 18 smokeless tobacco products, and showed potentials in assaying drugs and other plant-based substrates.
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http://dx.doi.org/10.1002/jssc.202100186DOI Listing
July 2021

Treatment of polyacrylamide-polluted wastewater using a revolving algae biofilm reactor: Pollutant removal performance and microbial community characterization.

Bioresour Technol 2021 Jul 7;332:125132. Epub 2021 Apr 7.

School of Marine Science, Yantai University, Yantai 264000, China.

Industries such as oil mining face challenges in the treatment of polyacrylamide (PAM)-containing wastewater produced during petroleum extraction. The feasibility of using revolving algae biofilm (RAB) reactors to treat PAM-contaminated wastewater for simultaneous removal of carbon and nitrogen was evaluated. The presence or absence of external nitrogen sources had a significant impact on the treatment effect of the RAB system. With the additional N source, the PAM, COD, TOC, and TN removal rates were 64.1 ± 2.0, 58 ± 1.5, 34.5 ± 1.5, and 85 ± 6.0%, respectively. High-throughput sequencing showed that the biofilms on RAB reactors contained a variety of bacteria, cyanobacteria, and green algae, degrading PAM through various mechanisms. The results of infrared spectroscopy analysis indicate that the product of these processes was carboxylic acid. Based on these results, it was concluded that RAB systems can be effectively applied to the treatment of polymer-containing wastewater.
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http://dx.doi.org/10.1016/j.biortech.2021.125132DOI Listing
July 2021

MiR-1297 attenuates high glucose-induced injury in HK-2 cells via targeting COL1A2.

Nephrology (Carlton) 2021 Jul 14;26(7):623-631. Epub 2021 Apr 14.

Department of Endocrinology, Zibo Central Hospital, Zibo, China.

Background: In this study, we aimed to explore whether COL1A2 and miR-1297 participated in the progression of diabetic nephropathy (DN) in vitro and classified the underlying mechanisms.

Methods: d-Glucose (30 mM; high glucose, HG)-stimulated HK-2 cells were used to mimic DN condition. RNA and non-coding RNA profiles were from Gene Expression Omnibus (GEO) database. The interaction between miR-1297 and COL1A2 was measured by dual-luciferase reporter assay. Gene Set Enrichment Analysis (GSEA) method was conducted to analyse COL1A2-associated signalling pathways. The role of miR-1297/COL1A2 in biological behaviours of HG-induced HK-2 cells were analysed by cell counting kit-8 and apoptosis assays.

Results: Bioinformatics analysis revealed that COL1A2 was up-regulated in DN tissues. We predicted and verified miR-1297 as the regulatory miRNA of COL1A2, and the expression of miR-1297 was decreased in DN tissues and HG-stimulated HK-2 cells. Overexpression of miR-1297 could promote cell proliferation and inhibit apoptosis to protect HK-2 cells from HG-induced damage. And knockdown of COL1A2 enhanced the protective effects of miR-1297 on HG-stimulated HK-2 cells. GSEA results revealed that several inflammatory pathways were enriched in COL1A2 high-expression group. Meanwhile, transfection of miR-1297 reduced the phosphorylation of NFκB and expression of three important pro-inflammatory genes including cytokine CCL5, adhesion molecules ICAM1 and VCAM1 via targeting COL1A2. These results suggested that miR-1297 protected HG-treated HK-2 cells probably through suppressing inflammation via targeting COL1A2.

Conclusion: This study sheds a light on the role miR-1297/COL1A2 in DN progression and provides a novel promising therapy strategy for suppressing DN progression.
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http://dx.doi.org/10.1111/nep.13881DOI Listing
July 2021

Effects of Neutrophil-to-Lymphocyte Ratio Combined With Interleukin-6 in Predicting 28-Day Mortality in Patients With Sepsis.

Front Immunol 2021 16;12:639735. Epub 2021 Mar 16.

Department of Emergency, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China.

Background: The current study aimed to evaluate the relationship between the neutrophil-to-lymphocyte ratio (NLR) combined with interleukin (IL)-6 on admission day and the 28-day mortality of septic patients.

Material And Methods: We conducted an observational retrospective study. Patients with presumed sepsis were included. We observed the correlation of studied biomarkers (NLR, IL-6, PCT, and CRP) and the severity scores (APACHE II and SOFA scores) by plotting scatter plots. The relationships of the studied biomarkers and 28-day mortality were evaluated by using Cox regression model, receiver-operating characteristic (ROC) curve, and reclassification analysis.

Results: A total of 264 patients diagnosed with sepsis were enrolled. It was revealed that IL-6 had the strongest correlation with both APACHE II and SOFA scores, followed by the NLR and PCT, and there was no obvious correlation between CRP and the illness severity. NLR and IL-6 were independent predictors of the 28-day mortality in septic patients in the Cox regression model [NLR, odds ratio 1.281 (95% CI 1.159-1.414), < 0.001; IL-6, odds ratio 1.017 (95% CI 1.005-1.028), =0.004]. The area under the ROC curve (AUC) of NLR, IL-6 and NLR plus IL-6 (NLR_IL-6) was 0.776, 0.849, and 0.904, respectively.

Conclusion: Our study showed that the levels of NLR and IL-6 were significantly higher in the deceased patients with sepsis. NLR and IL-6 appeared to be independent predictors of 28-day mortality in septic patients. Moreover, NLR combined with IL-6 could dramatically enhance the prediction value of 28-day mortality.
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http://dx.doi.org/10.3389/fimmu.2021.639735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007868PMC
September 2021

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review.

Front Immunol 2021 11;12:654406. Epub 2021 Mar 11.

Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.

Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled. To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions. A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed. The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection. STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.
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http://dx.doi.org/10.3389/fimmu.2021.654406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991083PMC
March 2021

Predictive value of immune cell counts and neutrophil-to-lymphocyte ratio for 28-day mortality in patients with sepsis caused by intra-abdominal infection.

Burns Trauma 2021 Jan 22;9:tkaa040. Epub 2021 Mar 22.

Medical school of Chinese PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China.

Background: The current study aimed to evaluate the value of immune cell counts and neutrophil-to-lymphocyte ratio (NLR) when attempting to predict 28-day mortality.

Methods: We conducted an observational retrospective study that included consecutive septic patients. Severity scores on the first day and peripheral circulating immune cell counts (at day 1, day 3, day 5 and day 7 of admission) were collected during each patient's emergency intensive care unit stay. We assessed the associations of peripheral circulating immune cell counts and NLR with the severity of illness. The relationships between 28-day mortality and peripheral circulating immune cell counts and NLR with were evaluated using Cox proportional cause-specific hazards models.

Results: A total of 216 patients diagnosed with sepsis caused by IAI were enrolled. The lymphocyte counts (days 1, 3, 5 and 7) and monocyte counts (days 3, 5 and 7) were significantly lower in non-survivors (n = 72) than survivors (n = 144). The NLR values at each time point were significantly higher in non-survivors. The day 1 lymphocyte counts, as well as the monocyte counts, were significantly lower in the highest-scoring group, when stratified by the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores, than in the other groups ( < 0.05). The day 1 NLR was significantly higher in the highest-scoring group than in the other groups ( < 0.05). The day 5 and day 7 lymphocyte counts, day 3 and day 7 monocyte counts and day 7 NLR were significant predictors of 28-day mortality in the Cox proportional hazards models (day 5 lymphocyte count: hazard ratio, 0.123 (95% CI, 0.055-0.279), < 0.001; day 7 lymphocyte count: hazard ratio, 0.115 (95% CI, 0.052-0.254), < 0.001; day 3 monocyte count: hazard ratio, 0.067 (95% CI, 0.005-0.861), = 0.038; day 7 monocyte count: hazard ratio, 0.015 (95% CI, 0.001-0.158), < 0.001; day 7 NLR: hazard ratio, 0.773 (95% CI, 0.659-0.905), = 0.001).

Conclusions: The results showed that circulating lymphocytes and monocytes were dramatically decreased within 7 days in non-survivors following sepsis from an IAI. Lymphocyte counts, monocyte counts and NLR appeared to be associated with the severity of illness, and they may serve as independent predictors of 28-day mortality in septic patients with IAIs.
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http://dx.doi.org/10.1093/burnst/tkaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982795PMC
January 2021

Single-Cell RNA Sequencing and Quantitative Proteomics Analysis Elucidate Marker Genes and Molecular Mechanisms in Hypoplastic Left Heart Patients With Heart Failure.

Front Cell Dev Biol 2021 25;9:617853. Epub 2021 Feb 25.

Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangzhou, China.

Objective: To probe markers and molecular mechanisms of the hypoplastic left heart (HLH) by single-cell RNA sequencing (scRNA-seq) and quantitative proteomics analysis.

Methods: Following data preprocessing, scRNA-seq data of pluripotent stem cell (iPSC)-derived cardiomyocytes from one HLH patient and one control were analyzed by the Seurat package in R. Cell clusters were characterized, which was followed by a analysis. Markers in the analysis were utilized for functional enrichment analysis. Quantitative proteomics analysis was based on peripheral blood samples from HLH patients without heart failure (HLH-NHF), HLH patients with heart failure (HLH-HF), and healthy controls. Hub genes were identified by the intersection of markers and differentially expressed proteins (DE-proteins), which were validated in the GSE77798 dataset, RT-qPCR, and western blot.

Results: Cardiomyocytes derived from iPSCs were clustered into mesenchymal stem cells, myocardium, and fibroblast cells. analysis revealed their differentiation trajectory. Markers in the three clusters were significantly associated with distinct biological processes and pathways. Finally, three hub genes (MMP2, B2M, and COL5A1) were identified, which were highly expressed in the left (LV) and right (RV) ventricles of HLH patients compared with controls. Furthermore, higher expression levels were detected in HLH patients with or without HF than in controls.

Conclusion: Our findings elucidate marker genes and molecular mechanisms of HLH, deepening the understanding of the pathogenesis of HLH.
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http://dx.doi.org/10.3389/fcell.2021.617853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946977PMC
February 2021

Epithelial-mesenchymal transition-related circular RNAs in lung carcinoma.

Cancer Biol Med 2021 Mar 12. Epub 2021 Mar 12.

Department of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo 315211, China.

The epithelial-mesenchymal transition (EMT) is a highly complex phenotypic conversion during embryogenesis, and is important for metastasis, which contributes to tumor deterioration and poor prognoses of cancer patients. Lung carcinoma has a high tendency to develop the EMT. Circular RNAs (circRNAs) are involved in EMT-related cell invasion and metastasis in various types of cancers. Moreover, circRNAs have been found to be a link to EMT-related transcription factors and EMT-associated signaling pathways. This review mainly focuses on the influence of EMT-related circRNAs on lung carcinomas. More specifically, the roles of EMT-inducing and EMT-suppressive circRNAs in lung carcinomas are discussed. With circRNAs potentially becoming promising biomarkers and therapeutic targets for cancer managements, they will hopefully stimulate the interest of medical workers in the early diagnosis, personalized treatment, and positive prognoses in the era of precision oncology.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185863PMC
March 2021

A Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency.

Front Immunol 2020 15;11:517544. Epub 2021 Feb 15.

National Clinical Research Center for Child Health and Disorders, Chongqing, China.

Mutations in the gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKKβ deficiency and impairs immune function. Here, we found that cells from both the patient and Y397H mice lacked or showed decreased levels of IKKβ protein, along with impaired lymphocyte function. IKKα and IKKγ protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKKβ protein was accelerated. Binding of human NF-κB to DNA in patient PBMCs fell upon stimulation with TNF-α or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that deficiency induces abnormal IKKβ protein degradation, leading to impaired NF-κB signaling and immune function. We postulate that the Y395H variant in the IKKβ protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability.
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http://dx.doi.org/10.3389/fimmu.2020.517544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917045PMC
April 2021

CPSF6 links alternative polyadenylation to metabolism adaption in hepatocellular carcinoma progression.

J Exp Clin Cancer Res 2021 Mar 1;40(1):85. Epub 2021 Mar 1.

Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.

Background: Alternative polyadenylation (APA) is an important mechanism of gene expression regulation through generation of RNA isoforms with distinct 3' termini. Increasing evidence has revealed that APA is actively involved in development and disease, including hepatocellular carcinoma (HCC). However, how APA functions in tumor formation and progression remains elusive. In this study, we investigated the role of cleavage factor I (CFIm) subunit CPSF6 in human hepatocellular carcinoma (HCC).

Methods: Expression levels of CPSF6 in clinical tissues and cell lines were determined by qRT-PCR and western blot. Functional assays, including the cell number, MTT, colony formation and transwell, were used to determine the oncogenic role of CPSF6 in HCC. Animal experiments were used to determine the role of CPSF6 in HCC tumorigenicity in vivo. Deep sequencing-based 3 T-seq was used to profile the transcriptome-wide APA sites in both HCC cells and CPSF6 knockdown HCC cells. The function of CPSF6-affected target NQO1 with distinct 3'UTRs was characterized by metabolism assays.

Results: We observed CPSF6 was upregulated in HCC and the high expression of CPSF6 was associated with poor prognosis in patients. Overexpression of CPSF6 promoted proliferation, migration and invasion of HCC cells in vitro and in vivo. Transcriptome-wide APA profiling analysis indicated that high expression of CPSF6 promoted the favorable usage of the proximal poly(A) site in the 3'UTR of NQO1. We demonstrated CPSF6-induced tumorigenic activities were mediated by the NQO1 isoform with short 3'UTR. Furthermore, we found that CPSF6 induced metabolic alterations in liver cells through NQO1.

Conclusion: CPSF6 plays a critical role in HCC progression by upregulating NQO1 expression through APA. These findings provide evidence to demonstrate that APA of NQO1 contributes to HCC progression and may have implications for developing new therapeutic strategy against this disease.
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http://dx.doi.org/10.1186/s13046-021-01884-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923339PMC
March 2021
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