Publications by authors named "Chao Tang"

473 Publications

A pipeline inspection robot for navigating tubular environments in the sub-centimeter scale.

Sci Robot 2022 May 25;7(66):eabm8597. Epub 2022 May 25.

Department of Mechanical Engineering, Tsinghua University, Beijing 100084, China.

In complex systems like aircraft engines and oil refinery machines, pipeline inspection is an essential task for ensuring safety. Here, we proposed a type of smart material-driven pipeline inspection robot (weight, 2.2 grams; length, 47 millimeters; diameter, <10 millimeters) that could fit into pipes with sub-centimeter diameters and different curvatures. We adopted high-power density, long-life dielectric elastomer actuators as artificial muscles and smart composite microstructure-based, high-efficiency anchoring units as transmissions. Fast assembling of components using magnets with an adjustable number of units was used to fit varying pipeline geometries. We analyzed the dynamic characteristics of the robots by considering soft material's unique properties like viscoelasticity and dynamic vibrations and tuned the activation voltage's frequency and phase accordingly. Powered by tethered cables from outside the pipe, our peristaltic pipeline robot achieved rapid motions horizontally and vertically (horizontal: 1.19 body lengths per second, vertical: 1.08 body lengths per second) in a subcentimeter-sized pipe (diameter, 9.8 millimeters). Besides, it was capable of moving in pipes with varying geometries (diameter-changing pipe, L-shaped pipe, S-shaped pipe, or spiral-shaped pipe), filled media (air or oil), and materials (glass, metal, or carbon fiber). To demonstrate its capability for pipeline inspection, we installed a miniature camera on its front and controlled the robot manually from outside. The robot successfully finished an inspection task at different speeds.
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http://dx.doi.org/10.1126/scirobotics.abm8597DOI Listing
May 2022

Oncolytic viral vectors in the era of diversified cancer therapy: from preclinical to clinical.

Clin Transl Oncol 2022 May 25. Epub 2022 May 25.

National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China.

With the in-depth research and wide application of immunotherapy recently, new therapies based on oncolytic viruses are expected to create new prospects for cancer treatment via eliminating the suppression of the immune system by tumors. Currently, an increasing number of viruses are developed and engineered, and various virus vectors based on effectively stimulating human immune system to kill tumor cells have been approved for clinical treatment. Although the virus can retard the proliferation of tumor cells, the choice of oncolytic viruses in biological cancer therapy is equally critical given their therapeutic efficacy, safety and adverse effects. Moreover, previously known oncolytic viruses have not been systematically classified. Therefore, in this review, we summarized and distinguished the characteristics of several common types of oncolytic viruses: herpes simplex virus, adenovirus, measles virus, Newcastle disease virus, reovirus and respiratory syncytial virus. Subsequently, we outlined that these oncolytic viral vectors have been transformed from preclinical studies in combination with immunotherapy, radiotherapy, chemotherapy, and nanoparticles into clinical therapeutic strategies for various advanced solid malignancies or circulatory system cancers.
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http://dx.doi.org/10.1007/s12094-022-02830-xDOI Listing
May 2022

Prediction of Response to Radiotherapy by Characterizing the Transcriptomic Features in Clinical Tumor Samples across 15 Cancer Types.

Comput Intell Neurosci 2022 9;2022:5443709. Epub 2022 May 9.

Radiation and Cancer Biology Laboratory, Radiation Oncology Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Institute and Chongqing Cancer Hospital, Chongqing University Cancer Hospital and Chongqing Cancer, Chongqing 400030, China.

Purpose: Radiotherapy (RT) is one of the major cancer treatments. However, the responses to RT vary among individual patients, partly due to the differences of the status of gene expression and mutation in tumors of patients. Identification of patients who will benefit from RT will improve the efficacy of RT. However, only a few clinical biomarkers were currently used to predict RT response. Our aim is to obtain gene signatures that can be used to predict RT response by analyzing the transcriptome differences between RT responder and nonresponder groups.

Materials And Methods: We obtained transcriptome data of 1664 patients treated with RT from the TCGA database across 15 cancer types. First, the genes with a significant difference between RT responder (R group) and nonresponder groups (PD group) were identified, and the top 100 genes were used to build the gene signatures. Then, we developed the predictive model based on binary logistic regression to predict patient response to RT.

Results: We identified a series of differentially expressed genes between the two groups, which are involved in cell proliferation, migration, invasion, EMT, and DNA damage repair pathway. Among them, MDC1, UCP2, and RBM45 have been demonstrated to be involved in DNA damage repair and radiosensitivity. Our analysis revealed that the predictive model was highly specific for distinguishing the and PD patients in different cancer types with an area under the curve (AUC) ranging from 0.772 to 0.972. It also provided a more accurate prediction than that from a single-gene signature for the overall survival (OS) of patients.

Conclusion: The predictive model has a potential clinical application as a biomarker to help physicians create optimal treatment plans. Furthermore, some of the genes identified here may be directly involved in radioresistance, providing clues for further studies on the mechanism of radioresistance.
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http://dx.doi.org/10.1155/2022/5443709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110128PMC
May 2022

Cholesterol and Hedgehog Signaling: Mutual Regulation and Beyond.

Front Cell Dev Biol 2022 27;10:774291. Epub 2022 Apr 27.

National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

The Hedgehog (HH) signaling is one of the key agents that govern the precisely regulated developmental processes of multicellular organisms in vertebrates and invertebrates. The HH pathway in the receiving cell includes Patched1, a twelve-pass transmembrane receptor, and Smoothened, a seven-transmembrane G-protein coupled receptor (GPCR), and the downstream GLI family of three transcriptional factors (GLI1-GLI3). Mutations of gene and the main components in HH signaling are also associated with numerous types of diseases. Before secretion, the HH protein undergoes post-translational cholesterol modification to gain full activity, and cholesterol is believed to be essential for proper HH signaling transduction. In addition, results from recent studies show the reciprocal effect that HH signaling functions in cholesterol metabolism as well as in cholesterol homeostasis, which provides feedback to HH pathway. Here, we hope to provide new insights into HH signaling function by discussing the role of cholesterol in HH protein maturation, secretion and HH signaling transduction, and the potential role of HH in regulation of cholesterol as well.
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http://dx.doi.org/10.3389/fcell.2022.774291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091300PMC
April 2022

Association between vitamin D deficiency and diabetic foot ulcer wound in diabetic subjects: A meta-analysis.

Int Wound J 2022 May 14. Epub 2022 May 14.

Xiangya School of Nursing School of Central South University, Hunan, China.

A meta-analysis was performed to evaluate the association between vitamin D deficiency and diabetic foot ulcer wounds in diabetic subjects. A systematic literature search up to March 2022 incorporated 7586 subjects with diabetes mellitus at the beginning of the study; 1565 were using diabetic subjects with foot ulcer wounds, and 6021 were non-ulcerated diabetic subjects. Statistical tools like the dichotomous and contentious method were used within a random or fixed-influence model to establish the odds ratio (OR) and mean difference (MD) with 95% confidence intervals (CIs) to evaluate the influence of vitamin D deficiency in managing diabetic foot ulcer wound. Diabetic subjects with foot ulcer wounds had significantly lower vitamin D levels (MD, -6.48; 95% CI, -10.84 to -2.11, P < .004), higher prevalence of vitamin D deficiency (<50 nmoL/L) (OR, 1.82; 95% CI, 1.32-2.52, P < .001), and higher prevalence of severe vitamin D deficiency (OR, 2.53; 95% CI, 1.65-3.89, P < .001) compared with non-ulcerated diabetic subjects. Diabetic subjects with foot ulcer wounds had significantly lower vitamin D levels, higher prevalence of vitamin D deficiency, and higher prevalence of severe vitamin D deficiency compared with non-ulcerated diabetic subjects. Further studies are required to validate these findings.
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http://dx.doi.org/10.1111/iwj.13836DOI Listing
May 2022

Roles of the mA Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses.

Front Immunol 2022 26;13:798583. Epub 2022 Apr 26.

Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

Purpose: Glioblastoma multiforme (GBM) is a common and aggressive form of brain tumor. The N-methyladenosine (mA) mRNA modification plays multiple roles in many biological processes and disease states. However, the relationship between mA modifications and the tumor microenvironment in GBM remains unclear, especially at the single-cell level.

Experimental Design: Single-cell and bulk RNA-sequencing data were acquired from the GEO and TCGA databases, respectively. We used bioinformatics and statistical tools to analyze associations between mA regulators and multiple factors.

Results: and were extensively expressed in the GBM microenvironment. mA regulators promoted the stemness state in GBM cancer cells. Immune-related BP terms were enriched in modules of mA-related genes. Cell communication analysis identified genes in the GALECTIN signaling network in GBM samples, and expression of these genes (, , , and ) correlated with that of mA regulators. Validation experiments revealed that in MK signaling network promoted migration and immunosuppressive polarization of macrophage. Expression of mA regulators correlated with ICPs in GBM cancer cells, M2 macrophages and T/NK cells. Bulk RNA-seq analysis identified two expression patterns (low mA/high ICP and high mA/low ICP) with different predicted immune infiltration and responses to ICP inhibitors. A predictive nomogram model to distinguish these 2 clusters was constructed and validated with excellent performance.

Conclusion: At the single-cell level, mA modification facilitates the stemness state in GBM cancer cells and promotes an immunosuppressive microenvironment through ICPs and the GALECTIN signaling pathway network. And we also identified two mA-ICP expression patterns. These findings could lead to novel treatment strategies for GBM patients.
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http://dx.doi.org/10.3389/fimmu.2022.798583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9086907PMC
May 2022

Cellulose accumulation mediated by PbrCSLD5, a cellulose synthase-like protein, results in cessation of pollen tube growth in Pyrus bretschneideri.

Physiol Plant 2022 May 8:e13700. Epub 2022 May 8.

State Key Laboratory of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing, China.

Cellulose, a key component of the cell wall, plays an important role in maintaining the growth of pollen tubes. However, the molecular mechanism of cellulose participating in the cessation of pear pollen tube growth remains unclear. Here, we reported that at 15 h post-cultured (HPC), the slow-growth pear pollen tubes showed thickened cell walls and cellulose accumulation in the inner wall. Transcriptome data and quantitative real-time PCR analysis showed that PbrCSLD5, a cellulose synthesis-like gene, was highly expressed in the 15 HPC pear pollen tubes. Knockdown of PbrCSLD5 caused a decrease in cellulose content in pear pollen tubes. Moreover, PbrCSLD5 overexpression in Arabidopsis resulted in the accumulation of cellulose and disruption of normal pollen tube growth. Transcription factor PbrMADS52 was found to bind to the promoter of PbrCSLD5 and enhanced its expression. Our results suggested that the PbrMADS52-PbrCSLD5 signaling pathway led to increased cellulose content in the pear pollen tube cell wall, thereby inhibiting pollen tube growth. These results provided new insights into the regulation of pollen tube growth. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ppl.13700DOI Listing
May 2022

A multi-classifier system to identify and subtype congenital adrenal hyperplasia based on circulating steroid hormones.

J Clin Endocrinol Metab 2022 May 5. Epub 2022 May 5.

Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, 197 Ruijin 2nd Road, Shanghai, P.R.China.

Context: Measurement of plasma steroids is necessary for diagnosis of congenital adrenal hyperplasia (CAH). We sought to establish an efficient strategy for detection and subtyping of CAH with a machine-learning algorithm.

Methods: Clinical phenotype and genetic testing were used to provide CAH diagnosis and subtype. We profiled 13 major steroid hormones by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multi-classifier system was established to distinguish 11β-hydroxylase deficiency (11βOHD), 17α-hydroxylase/17,20-lyase deficiency (17OHD) and 21α-hydroxylase deficiency (21OHD) in a discovery cohort (N=226). It was then validated in an independent cohort (N=111) and finally applied in a perspective cohort of 256 patients. The diagnostic performance on the basis of area under receiver operating characteristic curves was evaluated.

Results: A cascade logistic regression model, we named the "Steroidogenesis Score", was able to discriminate the three most common CAH subtypes: 11βOHD, 17OHD, 21OHD. In the perspective application cohort, the Steroidogenesis Score had a high diagnostic accuracy for all three subtypes, 11βOHD (AUC, 0.994; 95% CI, 0.983-1.000), 17OHD (AUC, 0.993; 95% CI, 0.985-1.000) and 21OHD (AUC, 0.979; 95% CI, 0.964-0.994). For nonclassic 21OHD patients, the tool presented with significantly higher sensitivity compared with measurement of basal 17α-hydroxyprogesterone (17OHP) (0.973 vs 0.840, p=0.005) and was not inferior to measurement of basal versus stimulated 17OHP (0.973 vs 0.947, p=0.681).

Conclusions: The Steroidogenesis Score was biochemically interpretable and showed high accuracy in identifying CAH patients, especially for nonclassic 21OHD patients, thus offering a standardized approach to diagnose and subtype CAH.
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http://dx.doi.org/10.1210/clinem/dgac271DOI Listing
May 2022

Surgery has a positive effect on spinal osteosarcoma prognosis: a population-based database study.

World Neurosurg 2022 Apr 30. Epub 2022 Apr 30.

Orthopedic Department, People's Hospital of Putuo District, Tongji University School of Medicine, Shanghai, 200060, China. Electronic address:

Purpose: The treatment of osteosarcoma of the spine remains controversial. Our aim is to explore the treatment of patients with spinal osteosarcoma.

Methods: We analyzed the date collected 727 spinal osteosarcoma patients from the Surveillance Epidemiology and End Results (SEER) databases between 1973 and 2015. X-tile software was performed to find the optimal cut-off values of age and economic income. Kaplan-Meier estimator method was adopted to analyze the overall survival (OS) and cancer-specific survival (CSS). Univariate and Multivariate Cox analyses were used to identify the independent prognostic factors. Propensity score matching (PSM) was introduced to reduce the possibility of selection bias. Logistic regression model was used to clarify the relevant factors that affect the patient's decision to surgery.

Results: Among 727 eligible spinal osteosarcoma patients, 370 (50.9%) patients received surgical treatment, 357 (49.1%) cases without surgery. There were significant differences in the effects of age at diagnosis, SEER historic stage and tumor grade on the choice of surgical treatment (All P < 0.05). Surgery was an independent prognostic factor for OS and CSS of spinal osteosarcoma patients. We get the same result after 1:1 PSM application. Spinal osteosarcoma patients undergone surgery group showed favorable survival than the other group.

Conclusions: Surgery can provide survival benefits for patients with osteosarcoma of the spine. Spinal osteosarcoma patients with undergone surgery have favorable survival and surgery can become a suitable treatment for patients.
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http://dx.doi.org/10.1016/j.wneu.2022.04.111DOI Listing
April 2022

DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling.

Development 2022 May 25;149(10). Epub 2022 May 25.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China.

The earliest hematopoietic stem and progenitor cells (HSPCs) are generated from the ventral wall of the dorsal aorta, through endothelial-to-hematopoietic transition during vertebrate embryogenesis. Notch signaling is crucial for HSPC generation across vertebrates; however, the precise control of Notch during this process remains unclear. In the present study, we used multi-omics approaches together with functional assays to assess global DNA methylome dynamics during the endothelial cells to HSPCs transition in zebrafish, and determined that DNA methyltransferase 1 (Dnmt1) is essential for HSPC generation via repression of Notch signaling. Depletion of dnmt1 resulted in decreased DNA methylation levels and impaired HSPC production. Mechanistically, we found that loss of dnmt1 induced hypomethylation of Notch genes and consequently elevated Notch activity in hemogenic endothelial cells, thereby repressing the generation of HSPCs. This finding deepens our understanding of HSPC specification in vivo, which will provide helpful insights for designing new strategies for HSPC generation in vitro.
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http://dx.doi.org/10.1242/dev.200390DOI Listing
May 2022

Plantaricin A, Derived from Lactiplantibacillus plantarum, Reduces the Intrinsic Resistance of Gram-Negative Bacteria to Hydrophobic Antibiotics.

Appl Environ Microbiol 2022 May 2;88(10):e0037122. Epub 2022 May 2.

College of Food Science and Technology, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China.

The outer membrane of Gram-negative bacteria is one of the major factors contributing to the development of antibiotic resistance, resulting in a lack of effectiveness of several hydrophobic antibiotics. Plantaricin A (PlnA) intensifies the potency of antibiotics by increasing the permeability of the bacterial outer membrane. Moreover, it has been proven to bind to the lipopolysaccharide of Escherichia coli via electrostatic and hydrophobic interactions and to interfere with the integrity of the bacterial outer membrane. Based on this mechanism, we designed a series of PlnA1 analogs by changing the structure, hydrophobicity, and charge to enhance their membrane-permeabilizing ability. Subsequent analyses revealed that among the PlnA1 analogs, OP4 demonstrated the highest penetrating ability, weaker cytotoxicity, and a higher therapeutic index. In addition, it decelerated the development of antibiotic resistance when the E. coli cells were continuously exposed to sublethal concentrations of erythromycin and ciprofloxacin for 30 generations. Further studies in mice with sepsis showed that OP4 heightens the potency of erythromycin against E. coli and relieves inflammation. In summary, our results showed that the PlnA1 analogs investigated in the present study, especially OP4, reduce the intrinsic antibiotic resistance of Gram-negative pathogens and expand the antibiotic sensitivity spectrum of hydrophobic antibiotics in Gram-negative bacteria. Antibiotic resistance is a global health concern due to indiscriminate use of antibiotics, resistance transfer, and intrinsic resistance of certain Gram-negative bacteria. The asymmetric bacterial outer membrane prevents the entry of hydrophobic antibiotics and renders them ineffective. Consequently, these antibiotics could be employed to treat infections caused by Gram-negative bacteria, after increasing their outer membrane permeability. As PlnA reportedly penetrates outer membranes, we designed a series of PlnA1 analogs and proved that OP4, one of these antimicrobial peptides, effectively augmented the permeability of the bacterial outer membrane. Furthermore, OP4 effectively improved the potency of erythromycin and alleviated inflammatory responses caused by Escherichia coli infection. Likewise, OP4 curtailed antibiotic resistance development in E. coli, thereby prolonging exposure to sublethal antibiotic concentrations. Thus, the combined use of hydrophobic antibiotics and OP4 could be used to treat infections caused by Gram-negative bacteria by decreasing their intrinsic antibiotic resistance.
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http://dx.doi.org/10.1128/aem.00371-22DOI Listing
May 2022

Surfactin effectively improves bioavailability of curcumin by formation of nano-capsulation.

Colloids Surf B Biointerfaces 2022 Apr 26;215:112521. Epub 2022 Apr 26.

College of Food Science and Technology, Nanjing University of Finance and Economics, Nanjing 210023, Jiangsu Province, China. Electronic address:

To improve the bioavailability of curcumin, surfactin was used to prepare curcumin-loaded nanoemulsions (Cur-NEs). Moreover, the physicochemical properties, digestive characteristics, as well as inhibition activity to Caco-2 cells of Cur-NEs were measured. Furthermore, the morphological analysis revealed that Cur-NEs with 320 mg/L surfactin appeared spherical nanoparticale (23.23 ± 2.86 nm) and uniform distribution. The encapsulation efficiency of Cur-NEs with 320 mg/L surfactin was 97.25 ± 1.28%. Simulated gastrointestinal digestion results indicated that surfactin elevated the sustained-release characteristics and higher bioaccessibility (40.92 ± 2.84%) of curcumin. Besides, Cur-NEs with 320 mg/L surfactin exhibited excellent stability in different temperature, pH and light irradiation. In addition, the inhibition of Cur-NEs with 320 mg/L surfactin to Caco-2 cells was 71.29%. Biochemical analysis showed that Cur-NEs enhanced the activity of lactate dehydrogenase, superoxide dismutase, catalase and glutathione peroxidase, as well as the reactive oxygen species content. RT-PCR and ELISA results also revealed that Cur-NEs inhibited Caco-2 cells through the activated mitochondria-mediated pathway. This study provided a strategy to encapsulate curcumin in nanoparticles with surfactin for improving bioavailability.
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http://dx.doi.org/10.1016/j.colsurfb.2022.112521DOI Listing
April 2022

Molecular mechanism of microRNAs regulating apoptosis in osteosarcoma.

Mol Biol Rep 2022 Apr 26. Epub 2022 Apr 26.

Trauma Surgery Department, Hannover Medical School (MHH), OE 6230 Carl-Neuberg-Straße 1, 30625, Hanover, Germany.

Osteosarcoma is a primary malignant bone tumor with no effective treatment. Apoptosis, one of the programmed cell death, is any pathological form of cell death mediated by intracellular processes. Under the pathological state, the de-regulated regulation of apoptosis can disrupt the balance between cell proliferation and death, causing osteosarcoma proliferation and metastasis. As carcinogenic or tumor suppressor factors, microRNAs (miRNAs) regulate apoptosis of osteosarcoma cells by regulating apoptosis-related genes and apoptosis-related signaling pathways, such as mitochondrial apoptosis pathway, death receptor pathway, and endoplasmic reticulum pathway. Meanwhile as these abnormal miRNAs can be stored and transported by exosomes, detecting exosomes can be seen an effective method to diagnose osteosarcoma in the early stage. This review provides the current knowledge of miRNAs and their target genes related to the apoptosis of osteosarcoma, summarizes abnormal expression and regulation of miRNAs and signaling pathways in osteosarcoma and prospects the detection of exosome as a method for early diagnosis of osteosarcoma.
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http://dx.doi.org/10.1007/s11033-022-07344-xDOI Listing
April 2022

The Reaction Pathway of miR-30c-5p Activates Lipopolysaccharide Promoting the Course of Traumatic and Hemorrhagic Shock Acute Lung Injury.

Biomed Res Int 2022 13;2022:3330552. Epub 2022 Apr 13.

Department of Science and Education, The First Hospital of Changsha, Changsha, 410008 Hunan, China.

Acute lung injury (ALI) is an acute hypoxic respiratory failure caused by diffuse inflammatory injury in alveolar epithelial cells during severe infection, trauma, and shock. Among them, trauma/hemorrhagic shock (T/HS) is the main type of indirect lung injury. Despite a great number of clinical studies, indirect factor trauma/hemorrhagic shock to the function and the mechanism in acute lung injury is not clear yet. Therefore, it is still necessary to carry on relevant analysis in order to thoroughly explore its molecular and cellular mechanisms and the pathway of disease function. In our research, we aimed to identify potential pathogenic genes and do modular analysis by downloading disease-related gene expression profile data. And our dataset is from the NCBI-GEO database. Then, we used the Clusterprofiler R package, GO function, and KEGG pathway enrichment analysis to analyze the core module genes. In addition, we also identified key transcription factors and noncoding RNAs. Based on the high degree of interaction of potential pathogenic genes and their involved functions and pathways, we identified 17 dysfunction modules. Among them, up to 9 modules significantly regulate the response to bacterial-derived molecules, and the response to lipopolysaccharide and other related functional pathways that mediate disease development. In addition, miR-290, miR-30c-5p, miR-195-5p, and miR-1-3p-based ncRNA and Jun, Atf1, and Atf3-based transcription factors have a total of 80 transcription drivers for functional modules. In summary, this study confirmed that miR-30c-5p activates lipopolysaccharide response pathway to promote the pathogenesis of ALI induced by hemorrhagic shock. This result can be an important direction for further research on related deepening diseases such as acute respiratory distress syndrome (ARDS). It further provides a piece of scientific medical evidence for revealing the pathogenic principle and cure difficulty of acute lung injury and also provides important guidance for the design of therapeutic strategies and drug development.
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http://dx.doi.org/10.1155/2022/3330552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021990PMC
April 2022

Efficacy and safety of vernakalant for cardioversion of recent-onset atrial fibrillation: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2022 Mar 11;101(10):e29038. Epub 2022 Mar 11.

The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China.

Background: Atrial fibrillation (AF) is the most common tachyarrhythmia encountered in clinical practice and is associated with substantial morbidity and mortality. This study aimed to determine the efficacy and safety of vernakalant for cardioversion of recent-onset AF.

Methods: A comprehensive systematic literature search will be conducted in Cochrane Library, PubMed, Web of Science, EMBASE, for randomized controlled trials (RCTs) about the vernakalant with AF. Two reviewers will independently assess the quality of the selected studies according to the Cochrane Collaboration's tool for RCTs. The bias risk of the RCT will be assessed by the Cochrane risk of bias (ROB) tool. The quality of the evidence will be evaluated by Grading of Recommendations Assessment Development and Evaluation (GRADE) system. Results from these questions will be graphed and assessed using Review Manager 5.3.

Results: The results of this meta-analysis will be published in a peer-reviewed journal.

Conclusion: This review will evaluate the safety and efficacy of vernakalant for patients with AF, provide more recommendations for patients or researchers, and high-level evidence for clinical decision-making.
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http://dx.doi.org/10.1097/MD.0000000000029038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913090PMC
March 2022

Regulator of G protein signaling 2 is inhibited by hypoxia-inducible factor-1α/E1A binding protein P300 complex upon hypoxia in human preeclampsia.

Int J Biochem Cell Biol 2022 Apr 14:106211. Epub 2022 Apr 14.

National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China. Electronic address:

Background: Preeclampsia is a pregnancy-related complication that causes maternal and fetal mortality. Despite extensive studies showing the role of hypoxia in preeclampsia progression, the specific mechanism remains unclear. The purpose of this study was to explore the possible mechanism underlying hypoxia in preeclampsia.

Methods: Human trophoblast-like JEG-3 cell line was used to investigate the molecular mechanisms underlying hypoxia contribution to preeclampsia and the expression correlation of key molecules was examined in human placental tissues. Methods include JEG-3 cell culture and hypoxia induction, RNA isolation and quantitative real-time PCR, transient transfection and dual-luciferase assay, western blot, immunoprecipitation, immunofluorescence staining, cell proliferation assay, chromatin immunoprecipitation assay, obtainment of human placental tissue sample and immunohistochemistry staining.

Results: Hypoxia-Inducible Factor-1α is up-regulated in clinical preeclampsia samples, where Regulator of G Protein Signaling 2 is down-regulated. Mechanistically, Hypoxia-Inducible Factor-1α is induced in response to hypoxia, which up-regulates E1A binding protein P300 expression and thereby forms a Hypoxia-Inducible Factor-1α/E1A binding protein P300 protein-protein complex that binds to the promoter of gene Regulator of G Protein Signaling 2 and subsequently inhibits the transcription of Regulator of G Protein Signaling 2, possibly contributing to the preeclampsia development. In addition, the expression of E1A binding protein P300 is increased in preeclampsia samples, and the expression of Regulator of G Protein Signaling 2 in preeclamptic placentas inversely correlates with the levels of E1A binding protein P300.

Conclusion: Our findings may provide novel insights into understanding the molecular pathogenesis of preeclampsia and may be a prognostic biomarker and therapeutic target for preeclampsia.
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http://dx.doi.org/10.1016/j.biocel.2022.106211DOI Listing
April 2022

Tianma Gouteng Decoction Exerts Pregnancy-Protective Effects Against Preeclampsia Regulation of Oxidative Stress and NO Signaling.

Front Pharmacol 2022 21;13:849074. Epub 2022 Mar 21.

National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Preeclampsia (PE), a pregnancy-specific syndrome with the major molecular determinants of placenta-borne oxidative stress and consequently impaired nitric oxide (NO) generation, has been considered to be one of the leading causes of maternal morbidity as well as mortality and preterm delivery worldwide. Several medical conditions have been found to be associated with increased PE risk, however, the treatment of PE remains unclear. Here, we report that Tianma Gouteng Decoction (TGD), which is used clinically for hypertension treatment, regulates oxidative stress and NO production in human extravillous trophoblast-derived TEV-1 cells. In human preeclamptic placental explants, reactive oxygen species (ROS) levels were elevated and NO production was inhibited, while TGD treatment at different periods effectively down-regulated the HO-induced ROS levels and significantly up-regulated the HO-suppressed NO production in human TEV-1 cells. Mechanistically, TGD enhanced the activity of total nitric oxide synthase (TNOS), which catalyze L-arginine oxidation into NO, and simultaneously, TGD promoted the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), two isoforms of nitric oxide synthetases (NOS) in human placenta, resulting in the increased NO generation. More importantly, TGD administration not only increased the weight gain during pregnancy and revealed a hypotensive effect, but also improved the placental weight gain and attenuated fetal growth restriction in an NG-nitro-L-arginine methyl ester (L-NAME)-induced mouse PE-like model. Our results thereby provide new insights into the role of TGD as a potentially novel treatment for PE.
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http://dx.doi.org/10.3389/fphar.2022.849074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985411PMC
March 2022

Chemical Pretreatment Activated a Plastic State Amenable to Direct Lineage Reprogramming.

Front Cell Dev Biol 2022 25;10:865038. Epub 2022 Mar 25.

State Key Laboratory of Natural and Biomimetic Drugs, MOE Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.

Somatic cells can be chemically reprogrammed into a pluripotent stem cell (CiPSC) state, mediated by an extraembryonic endoderm- (XEN-) like state. We found that the chemical cocktail applied in CiPSC generation initially activated a plastic state in mouse fibroblasts before transitioning into XEN-like cells. The plastic state was characterized by broadly activated expression of development-associated transcription factors (TFs), such as , , , and , with a more accessible chromatin state indicating an enhanced capability of cell fate conversion. Intriguingly, introducing such a plastic state remarkably improved the efficiency of chemical reprogramming from fibroblasts to functional neuron-like cells with electrophysiological activity or beating skeletal muscles. Furthermore, the generation of chemically induced neuron-like cells or skeletal muscles from mouse fibroblasts was independent of the intermediate XEN-like state or the pluripotency state. In summary, our findings revealed a plastic chemically activated multi-lineage priming (CaMP) state at the onset of chemical reprogramming. This state enhanced the cells' potential to adapt to other cell fates. It provides a general approach to empowering chemical reprogramming methods to obtain functional cell types bypassing inducing pluripotent stem cells.
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http://dx.doi.org/10.3389/fcell.2022.865038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990889PMC
March 2022

The impact of cold spells on schizophrenia admissions and the synergistic effect with the air quality index.

Environ Res 2022 Apr 7;212(Pt B):113243. Epub 2022 Apr 7.

Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, China. Electronic address:

Objectives: Under current global climate conditions, there are insufficient studies on the health influences of cold spells, especially on mental health. This study aimed to examine the effect of cold spells on schizophrenia admissions and to analyze the potential interaction effect with the air quality index (AQI).

Methods: Daily data on schizophrenia admissions and climatic variables in Hefei were collected from 2013 to 2019. Based on 20 definitions, the impacts of cold spells were quantified separately to find the most appropriate definition for the region, and meta-regression was used to explore the different effect sizes of the different days in a cold spell event. In addition, the potential interaction effect was tested by introducing a categorical variable, CSH, reflecting the cold spell and AQI level.

Results: The cold spell defined by temperature below the 6th centile while lasting for at least three days produced the optimum model fit performance. In general, the risk of schizophrenia admissions increased on cold spell days. The largest single-day effect occurred on the 12th day with RR = 1.081 (95% CI: 1.044, 1.118). In a single cold spell event, the effect of the 3rd and subsequent days of a cold spell (RR = 1.082, 95% CI: 1.036, 1.130) was higher than that on the 2nd day (RR = 1.054, 95% CI: 1.024, 1.085). Similarly, the effect of the 2nd day was also higher than that of the 1st day (RR = 1.027, 95% CI: 1.012, 1.042). We found a synergistic effect between cold spells and high AQI in the male group, and the relative excess risk due to interaction (RERI) was 0.018 (95% CI: 0.005-0.030).

Conclusions: This study suggested that the impacts of cold spells should be considered based on the definition of the most appropriate for the region when formulating targeted measures of schizophrenia. The discovery of the synergistic effect was referred to help the selection of the timing of precautions for susceptible people.
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http://dx.doi.org/10.1016/j.envres.2022.113243DOI Listing
April 2022

Are dopamine agonists still the first-choice treatment for prolactinoma in the era of endoscopy? A systematic review and meta-analysis.

Chin Neurosurg J 2022 Apr 8;8(1). Epub 2022 Apr 8.

School of Medicine, Southeast University, Nanjing, China.

Background: For prolactinoma patients, dopamine agonists (DAs) are indicated as the first-line treatment and surgery is an adjunctive choice. However, with the development of surgical technique and equipment, the effect of surgery has improved. The aim of this study was to assess the efficacy and safety of surgery versus DAs in patients with different types of prolactinomas.

Methods: A systematic search of literature using Web of Science, PubMed, Cochrane Library, and Clinical Trial databases was conducted until July 12, 2019. Prolactinoma patients treated with DAs (bromocriptine or cabergoline) or surgery (microscopic or endoscopic surgery) were included. Outcomes included the biochemical cure rate, recurrence rate, prolactin level, improvement rates of symptoms, and incidence rates of complications. A random-effects model was used to pool the extracted data. Qualitative comparisons were conducted instead of quantitative comparison.

Results: DAs were better than surgery in terms of the biochemical cure rate (0.78 versus 0.66), but surgery had a much lower recurrence rate (0.19 versus 0.57). Full advantages were not demonstrated in improvement rates of symptoms and incidence rates of complications with both treatment options. In microprolactinoma patients, the biochemical cure rate of endoscopic surgery was equal to the average cure rate of DAs (0.86 versus 0.86) and it surpassed the biochemical cure rate of bromocriptine (0.86 versus 0.76). In macroprolactinoma patients, endoscopic surgery was slightly higher than bromocriptine (0.66 versus 0.64) in terms of the biochemical cure rate.

Conclusion: For patients with clear indications or contraindications for surgery, choosing surgery or DAs accordingly is unequivocal. However, for patients with clinical equipoise, such as surgery, especially endoscopic surgery, in microprolactinoma and macroprolactinoma patients, we suggest that neurosurgeons and endocrinologists conduct high-quality clinical trials to address the clinical equipoise quantitatively.
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http://dx.doi.org/10.1186/s41016-022-00277-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994364PMC
April 2022

LncRNA LINC01270 aggravates the progression of gastric cancer through modulation of miR-326/EFNA3 axis.

Bioengineered 2022 04;13(4):8994-9005

Department of Oncology, Chaohu Hospital of Anhui Medical University, Chaohu, China.

Gastric cancer (GC) is lethal malignancy, which is associated with high mortality. Long noncoding RNA LINC01270 has been identified to act as a potential oncogene in several cancers. However, its role and related regulatory mechanism in GC are yet to be illustrated. The levels of lncRNA LINC01270, miR-326, and EphrinA3 (EFNA3) were assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8) and colony formation assays were applied for analyzing cell proliferation. Transwell assay was used for measuring cellular migration and invasion. Western blot analysis was employed for evaluating the protein levels. Luciferase reporter and RNA pull-down assays were utilized to verify the binding ability between LINC01270 (or EFNA3) and miR-326. Our findings indicated that LINC01270 expression was significantly up-regulated in GC tissues and cell lines. Additionally, LINC01270 knockdown attenuated GC progression through inhibiting cell proliferation, migration, and invasion. Functional experiments identified that lncRNA LINC01270 could positively regulate EFNA3 expression by serving as a competing endogenous RNA (ceRNA) for miR-326. Through rescue assays, inhibition of GC progression caused by LINC01270 suppression was found to be reversed by the application of miR-326 inhibitor or EFNA3 overexpression. Overall, our work demonstrated that lncRNA LINC01270 can accelerate cell proliferation, migration, and invasion via modulating miR-326/EFNA3 axis. These findings might implicate the potential role of lncRNA LINC01270 in GC treatment.
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http://dx.doi.org/10.1080/21655979.2022.2054204DOI Listing
April 2022

Probing terahertz dynamics of multidomain protein in cell-like confinement.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Jul 18;275:121173. Epub 2022 Mar 18.

Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201203, China; Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China; College of Pharmacy, Binzhou Medical University, Yantai 264003, China. Electronic address:

The development of meaningful descriptions of multidomain proteins exhibiting complex inter-domain dynamics modes is a key challenge for understanding their roles in molecular recognition and signalling processes. Here we developed a generally applicable approach for probing the low frequency collective hydration dynamics of multidomain proteins that uses terahertz spectroscopy of a protein molecule confined in a phospholipid reverse micelles environment (named Droplet THz). With the combination of normal mode analysis, we demonstrated the binding of calcium ions modulates the local inter-domain motion of the human coagulant factor VIII protein in a concentration-dependent manner. These findings highlight the Droplet THz as a valuable tool for dissecting the ultrafast dynamics of domain motion in the multidomain proteins and suggest a modulating mechanism of calcium ions on the structural flexibility and function of human coagulant proteins.
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http://dx.doi.org/10.1016/j.saa.2022.121173DOI Listing
July 2022

SCAPE: a mixture model revealing single-cell polyadenylation diversity and cellular dynamics during cell differentiation and reprogramming.

Nucleic Acids Res 2022 Mar 14. Epub 2022 Mar 14.

Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

Alternative polyadenylation increases transcript diversities at the 3' end, regulating biological processes including cell differentiation, embryonic development and cancer progression. Here, we present a Bayesian method SCAPE, which enables de novo identification and quantification of polyadenylation (pA) sites at single-cell level by utilizing insert size information. We demonstrated its accuracy and robustness and identified 31 558 sites from 36 mouse organs, 43.8% (13 807) of which were novel. We illustrated that APA isoforms were associated with miRNAs binding and regulated in tissue-, cell type-and tumor-specific manners where no difference was found at gene expression level, providing an extra layer of information for cell clustering. Furthermore, we found genome-wide dynamic changes of APA usage during erythropoiesis and induced pluripotent stem cell (iPSC) differentiation, suggesting APA contributes to the functional flexibility and diversity of single cells. We expect SCAPE to aid the analyses of cellular dynamics and diversities in health and disease.
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http://dx.doi.org/10.1093/nar/gkac167DOI Listing
March 2022

Supramolecular structure features and immunomodulatory effects of exopolysaccharide from Paecilomyces cicadae TJJ1213 in RAW264.7 cells through NF-κB/MAPK signaling pathways.

Int J Biol Macromol 2022 May 10;207:464-474. Epub 2022 Mar 10.

College of Food Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China. Electronic address:

This study investigated the supramolecular structure features and immunomodulatory effects of two exopolysaccharide fractions (EPS1 and EPS2) from Paecilomyces cicada TJJ1213 in vitro. AFM images revealed that EPS1 and EPS2 displayed different morphological features at different concentrations. Congo red and XRD assay further proved that EPS1 and EPS2 mainly exhibited amorphous structure with random coil conformation in solution. Furthermore, the immunomodulatory effect of EPSs was investigated on RAW264.7 cells. Results showed that EPS1 and EPS2 could enhance the phagocytic activity and induce the NO production and could also significantly up-regulate the mRNA expression of iNOS, TNF-α, IL-6, IL-1β, IFN-γ and IL-4. Western blot assay analysis demonstrated that EPSs increased protein expression of TLR4 and the nuclear translocation of NF-κB p50/p65. Additionally, the phosphorylation levels of MAPKs proteins (p38, ERK and JNK) were also remarkably increased. Thus, EPSs could active TLR4-NF-κB/MAPKs signaling pathways to exert the immunomodulatory effect on macrophages.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.03.029DOI Listing
May 2022

Platelet Transfusion in Patients With Sepsis and Thrombocytopenia: A Propensity Score-Matched Analysis Using a Large ICU Database.

Front Med (Lausanne) 2022 16;9:830177. Epub 2022 Feb 16.

Department of Emergency, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Purpose: Sepsis with thrombocytopenia is highly prevalent in critically ill intensive care unit (ICU) patients and is associated with adverse outcomes. Platelet transfusion is the primary treatment of choice. However, evidence for the beneficial effects of platelet transfusion in patients with sepsis and thrombocytopenia is scarce and low in quality. This study aimed to evaluate the association between platelet transfusion and mortality among ICU patients with sepsis and thrombocytopenia.

Patients And Methods: Using the Medical Information Mart for Intensive Care III database (v. 1.4), the outcomes of sepsis patients with platelet counts of ≤ 150,000/μL were compared between those who did and did not receive platelet transfusion. The primary outcomes were 28- and 90-day all-cause mortalities. The secondary outcomes were red blood cell (RBC) transfusion, ICU-free days, and hospital-free days. Propensity score matching was employed to assemble a cohort of patients with similar baseline characteristics.

Results: Among 7,765 eligible patients, 677 received platelet transfusion and were matched with 677 patients who did not receive platelet transfusion according to propensity scores. Platelet transfusion, as compared with no platelet transfusion, was associated with an increased risk of 28-day all-cause mortality [36.9 vs. 30.4%, odds ratio (OR), 1.21; 95% confidence interval (CI), 1.01-1.46; = 0.039], increased risk of 90-day all-cause mortality (50.8 vs. 44.6%, OR, 1.13; 95% CI, 1.00-1.31; = 0.048), fewer mean (standard deviation) 28-day ICU-free days (15.88 ± 8.97 vs. 18.64 ± 8.33 days, < 0.001), and fewer hospital-free days (10.29 ± 8.49 vs. 11.43 ± 8.85 days, = 0.017). The rate of RBC transfusion was not significantly different between the platelet transfusion and non-transfusion groups ( = 0.149). The results were maintained across several subgroup and sensitivity analyses.

Conclusion: In this study, platelet transfusion was associated with higher 28- and 90-day all-cause mortalities. These results suggest the potential hazards of platelet transfusion in ICU patients with sepsis and thrombocytopenia.
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http://dx.doi.org/10.3389/fmed.2022.830177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888830PMC
February 2022

Baicalin Targets HSP70/90 to Regulate PKR/PI3K/AKT/eNOS Signaling Pathways.

Molecules 2022 Feb 21;27(4). Epub 2022 Feb 21.

Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, National Centre for Mass Spectrometry in Beijing, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

Baicalin is a major active ingredient of traditional Chinese medicine , and has been shown to have antiviral, anti-inflammatory, and antitumor activities. However, the protein targets of baicalin have remained unclear. Herein, a chemical proteomics strategy was developed by combining baicalin-functionalized magnetic nanoparticles ([email protected]) and quantitative mass spectrometry to identify the target proteins of baicalin. Bioinformatics analysis with the use of Gene Ontology, STRING and Ingenuity Pathway Analysis, was performed to annotate the biological functions and the associated signaling pathways of the baicalin targeting proteins. Fourteen proteins in human embryonic kidney cells were identified to interact with baicalin with various binding affinities. Bioinformatics analysis revealed these proteins are mainly ATP-binding and/or ATPase activity proteins, such as CKB, HSP86, HSP70-1, HSP90, ATPSF1β and ACTG1, and highly associated with the regulation of the role of PKR in interferon induction and the antiviral response signaling pathway ( = 10), PI3K/AKT signaling pathway ( = 10) and eNOS signaling pathway ( = 10). The results show that baicalin exerts multiply pharmacological functions, such as antiviral, anti-inflammatory, antitumor, and antioxidant functions, through regulating the PKR and PI3K/AKT/eNOS signaling pathways by targeting ATP-binding and ATPase activity proteins. These findings provide a fundamental insight into further studies on the mechanism of action of baicalin.
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http://dx.doi.org/10.3390/molecules27041432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8874410PMC
February 2022

Identification of an IL-4-Related Gene Risk Signature for Malignancy, Prognosis and Immune Phenotype Prediction in Glioma.

Brain Sci 2022 Jan 29;12(2). Epub 2022 Jan 29.

Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.

Background: Emerging molecular and genetic biomarkers have been introduced to classify gliomas in the past decades. Here, we introduced a risk signature based on the cellular response to the IL-4 gene set through Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis.

Methods: In this study, we provide a bioinformatic profiling of our risk signature for the malignancy, prognosis and immune phenotype of glioma. A cohort of 325 patients with whole genome RNA-seq expression data from the Chinese Glioma Genome Atlas (CGGA) dataset was used as the training set, while another cohort of 667 patients from The Cancer Genome Atlas (TCGA) dataset was used as the validating set. The LASSO model identified a 10-gene signature which was considered as the optimal model.

Results: The signature was confirmed to be a good predictor of clinical and molecular features involved in the malignancy of gliomas. We also identified that our risk signature could serve as an independently prognostic biomarker in patients with gliomas ( < 0.0001). Correlation analysis showed that our risk signature was strongly correlated with the Tregs, M0 macrophages and NK cells infiltrated in the microenvironment of glioma, which might be a supplement to the existing incomplete innate immune mechanism of glioma phenotypes.

Conclusions: Our IL-4-related gene signature was associated with more aggressive and immunosuppressive phenotypes of gliomas. The risk score could predict prognosis independently in glioma, which might provide a new insight for understanding the IL-4 involved mechanism of gliomas.
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http://dx.doi.org/10.3390/brainsci12020181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870251PMC
January 2022

Synthetic robust perfect adaptation achieved by negative feedback coupling with linear weak positive feedback.

Nucleic Acids Res 2022 02;50(4):2377-2386

Center for Cell and Gene Circuit Design, CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.

Unlike their natural counterparts, synthetic genetic circuits are usually fragile in the face of environmental perturbations and genetic mutations. Several theoretical robust genetic circuits have been designed, but their performance under real-world conditions has not yet been carefully evaluated. Here, we designed and synthesized a new robust perfect adaptation circuit composed of two-node negative feedback coupling with linear positive feedback on the buffer node. As a key feature, the linear positive feedback was fine-tuned to evaluate its necessity. We found that the desired function was robustly achieved when genetic parameters were varied by systematically perturbing all interacting parts within the topology, and the necessity of the completeness of the topological structures was evaluated by destroying key circuit features. Furthermore, different environmental perturbances were imposed onto the circuit by changing growth rates, carbon metabolic strategies and even chassis cells, and the designed perfect adaptation function was still achieved under all conditions. The successful design of a robust perfect adaptation circuit indicated that the top-down design strategy is capable of predictably guiding bottom-up engineering for robust genetic circuits. This robust adaptation circuit could be integrated as a motif into more complex circuits to robustly implement more sophisticated and critical biological functions.
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http://dx.doi.org/10.1093/nar/gkac066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887471PMC
February 2022
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