Publications by authors named "Xun Sun"

523 Publications

Comparative radiological outcomes and complications of sacral-2-alar iliac screw versus iliac screw for sacropelvic fixation.

Eur Spine J 2021 May 13. Epub 2021 May 13.

Department of Spine Surgery, Tianjin Hospital, 406 Jiefang South Road, Hexi District, Tianjin, 300211, China.

Purpose: To compare the outcomes of sacropelvic fixation (SPF) using sacral-2-alar iliac (S2AI) screw with SPF using iliac screw (IS).

Methods: A comprehensive search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Scopus was performed for comparative studies between S2AI and IS for SPF. Two independent investigators selected qualified studies and extracted data indispensably. With 95% confidence intervals (CI), the odds ratio (OR) was applied to dichotomous outcomes and standardized mean difference (SMD) was applied to continuous outcomes for each item.

Results: We included data from thirteen studies involving 722 patients (S2AI, 357 patients; IS, 365 patients). In the pediatric population, the S2AI group had a smaller pelvic obliquity (PO) than the IS group at final follow-up (SMD, - 0.38; 95% CI, - 0.72 to - 0.04). Patients who underwent S2AI screws showed reduced rates of re-operation (S2AI, 13%; IS, 28%), implant failure (S2AI, 12%; IS, 26%) [screw loosening (S2AI, 8%; IS, 20%); screw breakage (S2AI, 2%; IS, 12%)], implant prominence (S2AI, 2%; IS, 14%), pseudarthrosis (S2AI, 3%; IS, 15%), wound infection (S2AI, 8%; IS, 22%) and less blood loss (S2AI, 2035.4 ml; IS, 2708.4 ml).

Conclusion: Radiological outcomes indicate an effective maintenance of the correction and arrest of progression of deformity by S2AI, which is equal or better than IS. SPF with S2AI screw has obviously lower incidence of postoperative complications and less blood loss. Given these advantages, the S2AI screw seems to be a beneficial alternative to IS.
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http://dx.doi.org/10.1007/s00586-021-06864-7DOI Listing
May 2021

Plasmon switching of gold nanoparticles through thermo-responsive terminal breathing of surface-grafted DNA in hydrated ionic liquids.

Analyst 2021 May 11. Epub 2021 May 11.

College of Food Science and Engineering, Ocean University of China, 5 Yushan Road, Qingdao 266003, China. and Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China.

Self-assembly performed in ionic liquids (ILs) as a unique solvent promises distinct functions and applications in sensors, therapeutics, and optoelectronic devices due to the rich interactions between nanoparticle building blocks and ILs. However, the general consideration that common nanoparticles are readily destabilized by counterions in an IL has largely prevented researchers from investigating controlled nanoparticle assembly in IL-based systems. This study explores the assembling behaviour of double-stranded (ds) DNA-functionalized gold nanoparticles (dsDNA-AuNPs) in hydrated ionic liquids. The DNA base pair stacking assembly of dsDNA-AuNPs occurs at a low IL concentration (<5%). However, a moderate ionic liquid concentration (5-40%) can de-hybridize dsDNA and leaves single-stranded (ss) DNA stabilizing the AuNPs. In concentrated ionic liquids (>40%), interestingly, the higher ionic strength leads to the assembly of DNA-AuNPs. The triphasic assembly trend is also generally observed regardless of the type of IL. By down-regulation of DNA's melting temperature with the IL, the assembly of DNA-AuNPs affords robust response to a lower temperature range, promising applications in plasmonic devices and range-tunable temperature sensors.
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http://dx.doi.org/10.1039/d1an00548kDOI Listing
May 2021

Time-resolved fluorescent lateral flow strip for easy and rapid quality control of edible oil.

Food Chem 2021 Apr 6;357:129739. Epub 2021 Apr 6.

School Food and Biological Engineering, Hefei University of Technology, China. Electronic address:

Gutter oil is strictly prohibited from being reprocessed back to the catering and food industry. Extensive attention has been paid to rapid screening of gutter oil to guarantee the safety of edible oil. Capsaicin, a special component of condiments, has been adopted as the marker of gutter oil. The time-resolved fluorescent microspheres are utilized for labeling of antibody to capsaicin, which are further applied for the construction of fluorescent lateral-flow-strip (LFS). By simple extraction of capsaicin with ethanol (or liquor) from the edible oil, the capsaicin can be rapid determined with the fluorescent LFS in less than 10 min. As low as 20 ng/mL capsaicin can be visually judged and 2.3 ng/mL is achieved as the detection limit by ImageJ analysis. The illegal gutter oil is also well screened with this time-resolved LFS. This method can be a useful candidate for routine quality monitoring of edible oil and a powerful tool for self-inspection at home.
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http://dx.doi.org/10.1016/j.foodchem.2021.129739DOI Listing
April 2021

Preventing tumor progression to the bone by induced tumor-suppressing MSCs.

Theranostics 2021 5;11(11):5143-5159. Epub 2021 Mar 5.

Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.

Advanced breast cancer metastasizes to many organs including bone, but few effective treatments are available. Here we report that induced tumor-suppressing (iTS) MSCs protected bone from metastases while un-induced MSCs did not. iTS MSCs were generated by overexpressing Lrp5, β-catenin, Snail, or Akt. Their tumor-suppressing capability was tested using a mouse model of mammary tumors and bone metastasis, human breast cancer tissues and cancer cell lines. In a mouse model, the induced MSC-derived conditioned medium (MSC CM) reduced mammary tumors and suppressed tumor-induced osteolysis. Tumor-promoting genes such as CXCL2 and LIF, as well as PDL1, a blocker of T-cell-based immune responses were downregulated. Proteomics analysis revealed that heat shock protein 90 (Hsp90ab1), calreticulin (Calr) and peptidylprolyl isomerase B (Ppib), which are highly expressed intracellular proteins in many cancers, were enriched in MSC CM as atypical tumor suppressors. Thus, overexpressing selected genes that were otherwise tumorigenic rendered MSCs the tumor-suppressing capability through the atypical suppressors, as well as p53 and Trail. Notably, the inhibitory effect of Lrp5- and Akt-overexpressing MSC CMs, Hsp90ab1 and Calr presented selective inhibition to tumor cells than non-tumor cells. The development of bone-resorbing osteoclasts was also suppressed by MSC CMs. Collectively, the results showed an anti-tumor effect of iTS MSCs and suggested novel therapeutic approaches to suppress the progression of tumors into the bone.
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http://dx.doi.org/10.7150/thno.58779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039940PMC
March 2021

Targeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis.

Nat Commun 2021 04 12;12(1):2174. Epub 2021 Apr 12.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.
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http://dx.doi.org/10.1038/s41467-021-22454-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042091PMC
April 2021

Disinfection characteristics of an advanced rotational hydrodynamic cavitation reactor in pilot scale.

Ultrason Sonochem 2021 May 3;73:105543. Epub 2021 Apr 3.

Key Laboratory of High Efficiency and Clean Mechanical Manufacture, Ministry of Education, School of Mechanical Engineering, Shandong University, Jinan 250061, China; National Demonstration Center for Experimental Mechanical Engineering Education, Shandong University, Jinan 250061, China. Electronic address:

Hydrodynamic cavitation is a promising technique for water disinfection. In the present paper, the disinfection characteristics of an advanced hydrodynamic cavitation reactor (ARHCR) in pilot scale were studied. The effects of various flow rates (1.4-2.6 m/h) and rotational speeds (2600-4200 rpm) on the removal of Escherichia coli (E. coli) were revealed and analyzed. The variation regularities of the log reduction and reaction rate constant at various cavitation numbers were established. A disinfection rate of 100% was achieved in only 4 min for 15 L of simulated effluent under 4200 rpm and 1.4 m/h, with energy efficiency at 0.0499 kWh/L. A comprehensive comparison with previously introduced HCRs demonstrates the superior performance of the presented ARHCR system. The morphological changes in E. coli were studied by scanning electron microscopy. The results indicate that the ARHCR can lead to serious cleavage and surface damages to E. coli, which cannot be obtained by conventional HCRs. Finally, a possible damage mechanism of the ARHCR, including both the hydrodynamical and sonochemical effects, was proposed. The findings of the present study can provide strong support to the fundamental understanding and applications of ARHCRs for water disinfection.
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http://dx.doi.org/10.1016/j.ultsonch.2021.105543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059091PMC
May 2021

Multivariate radiomics models based on F-FDG hybrid PET/MRI for distinguishing between Parkinson's disease and multiple system atrophy.

Eur J Nucl Med Mol Imaging 2021 Apr 7. Epub 2021 Apr 7.

Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, China.

Purpose: To construct multivariate radiomics models using hybrid F-FDG PET/MRI for distinguishing between Parkinson's disease (PD) and multiple system atrophy (MSA).

Methods: Ninety patients (60 with PD and 30 with MSA) were randomized to training and test sets in a 7:3 ratio. All patients underwent F-fluorodeoxyglucose (F-FDG) PET/MRI to simultaneously obtain metabolic images (F-FDG), structural MRI images (T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) and T2-weighted fluid-attenuated inversion recovery (T2/FLAIR)) and functional MRI images (susceptibility-weighted imaging (SWI) and apparent diffusion coefficient). Using PET and five MRI sequences, we extracted 1172 radiomics features from the putamina and caudate nuclei. The radiomics signatures were constructed with the least absolute shrinkage and selection operator algorithm in the training set, with progressive optimization through single-sequence and double-sequence radiomics models. Multivariable logistic regression analysis was used to develop a clinical-radiomics model, combining the optimal multi-sequence radiomics signature with clinical characteristics and SUV values. The diagnostic performance of the models was assessed by receiver operating characteristic and decision curve analysis (DCA).

Results: The radiomics signatures showed favourable diagnostic efficacy. The optimal model comprised structural (T1WI), functional (SWI) and metabolic (F-FDG) sequences (Radscore) with the area under curves (AUCs) of the training and test sets of 0.971 and 0.957, respectively. The integrated model, incorporating Radscore, three clinical symptoms (disease duration, dysarthria and autonomic failure) and SUV, demonstrated satisfactory calibration and discrimination in the training and test sets (0.993 and 0.994, respectively). DCA indicated the highest clinical benefit of the clinical-radiomics integrated model.

Conclusions: The radiomics signature with metabolic, structural and functional information provided by hybrid F-FDG PET/MRI may achieve promising diagnostic efficacy for distinguishing between PD and MSA. The clinical-radiomics integrated model performed best.
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http://dx.doi.org/10.1007/s00259-021-05325-zDOI Listing
April 2021

Inhibition of the Growth of Breast Cancer-Associated Brain Tumors by the Osteocyte-Derived Conditioned Medium.

Cancers (Basel) 2021 Mar 3;13(5). Epub 2021 Mar 3.

Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.

The brain is a common site of metastasis from advanced breast cancer but few effective treatments are available. We examined a therapeutic option with a conditioned medium (CM), focusing on the role of Lrp5 and β-catenin in Wnt signaling, and IL1ra in osteocytes. Osteocytes presented the innate anti-tumor effect and the overexpression of the above genes strengthened their action. In a mouse model, the injection of their CM inhibited mammary tumors and tumor-driven osteolysis. Importantly, Lrp5- and/or IL1ra-overexpressing osteocytes or the local administration of β-catenin-overexpressing CM markedly inhibited brain tumors. In the transport analysis, tumor-suppressing factors in CM were shown to diffuse through the skull. Mechanistically, the CM with overexpression of the above genes downregulated oncogenic genes such as MMP9, Runx2, TGFβ, and Snail in breast cancer cells. Also, the CM with β-catenin overexpression downregulated CXCL1 and CXCL5 and upregulated tumor suppressors such as LIMA1, DSP, p53, and TRAIL in breast cancer cells. Notably, whole-genome proteomics revealed that histone H4 was enriched in CM and acted as an atypical tumor suppressor. Lrp5-overexpressing MSCs were also shown to act as anti-tumor agents. Collectively, this study demonstrated the therapeutic role of engineered CM in brain tumors and the tumor-suppressing action of extracellular histone H4. The result sheds light on the potential CM-based therapy for breast cancer-associated brain metastases in a minimally invasive manner.
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http://dx.doi.org/10.3390/cancers13051061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959137PMC
March 2021

Engineering a sustained release vaccine with a pathogen-mimicking manner for robust and durable immune responses.

J Control Release 2021 May 29;333:162-175. Epub 2021 Mar 29.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address:

Sustained release vaccine carriers can facilitate an increased interaction time between the antigen and immune system to strengthen immune responses, but their promotion on adaptive immune responses, especially cellular immunity, are still unfavorable. Herein, we report a sustained antigen delivery vector, which carries abundant antigens, a nucleic acid adjuvant and pathogen-associated molecular patterns to simulate a natural pathogen to reinforce immune responses. Specifically, murine colorectal cancer cells MC38 lysate and Toll-like receptor 9 agonist CpG are loaded into yeast derived β-glucan particles (GPs). After vaccination, these particles can form a vaccine depot that continuously release the antigen similar to the traditional aluminum hydroxide gel, but recruit more immune cells and induce more cytokine secretion at the injection site. Stronger antibody responses, Th1 and Th17 biased cellular immunity and immune memory are achieved compared with aluminum hydroxide gel. More importantly, treatment with these particles significantly suppress tumor growth in a therapeutic tumor model. This work shed light on the efficacy of combining sustained antigen release with pathogen-mimicking manner in vaccine design.
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http://dx.doi.org/10.1016/j.jconrel.2021.03.037DOI Listing
May 2021

Vγ6 γδ T cells are critical for protection against infection by Escherichia coli in mice.

Eur J Immunol 2021 Apr 1. Epub 2021 Apr 1.

Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

γδ T cells producing IL-17A (γδTh17 cells) are known to be involved in peritonitis induced by Escherichia coli infection in mice. In vivo treatment with Vγ6-specific mAb (1C10-1F7) significantly hampered resolution of E. coli infection. Thus, Vγ6 γδTh17 cells mainly contributed to protection against E. coli infection.
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http://dx.doi.org/10.1002/eji.202049010DOI Listing
April 2021

Overexpression of MdATG8i improves water use efficiency in transgenic apple by modulating photosynthesis, osmotic balance, and autophagic activity under moderate water deficit.

Hortic Res 2021 Apr 1;8(1):81. Epub 2021 Apr 1.

State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, 712100, Yangling, Shaanxi, China.

Water deficit is one of the major limiting factors for apple (Malus domestica) production on the Loess Plateau, a major apple cultivation area in China. The identification of genes related to the regulation of water use efficiency (WUE) is a crucial aspect of crop breeding programs. As a conserved degradation and recycling mechanism in eukaryotes, autophagy has been reported to participate in various stress responses. However, the relationship between autophagy and WUE regulation has not been explored. We have shown that a crucial autophagy protein in apple, MdATG8i, plays a role in improving salt tolerance. Here, we explored its biological function in response to long-term moderate drought stress. The results showed that MdATG8i-overexpressing (MdATG8i-OE) apple plants exhibited higher WUE than wild-type (WT) plants under long-term moderate drought conditions. Plant WUE can be increased by improving photosynthetic efficiency. Osmoregulation plays a critical role in plant stress resistance and adaptation. Under long-term drought conditions, the photosynthetic capacity and accumulation of sugar and amino acids were higher in MdATG8i-OE plants than in WT plants. The increased photosynthetic capacity in the OE plants could be attributed to their ability to maintain optimal stomatal aperture, organized chloroplasts, and strong antioxidant activity. MdATG8i overexpression also promoted autophagic activity, which was likely related to the changes described above. In summary, our results demonstrate that MdATG8i-OE apple lines exhibited higher WUE than WT under long-term moderate drought conditions because they maintained robust photosynthesis, effective osmotic adjustment processes, and strong autophagic activity.
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http://dx.doi.org/10.1038/s41438-021-00521-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012348PMC
April 2021

MdHARBI1, a MdATG8i-interacting protein, plays a positive role in plant thermotolerance.

Plant Sci 2021 May 16;306:110850. Epub 2021 Feb 16.

State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address:

Autophagy is a major degradation pathway in plants for maintaining cellular homeostasis in response to various environmental stressors. ATG8 is one of a series of autophagy-related (ATG) proteins and plays a central role in both bulk and selective autophagy. Previously, we characterized MdATG8i in apple and demonstrated that it has a positive role in apple stress resistance. Although many ATG8-interacting proteins have been found in Arabidopsis, no protein has been reported to interact with MdATG8 in apple. Here, we identified MdHARBI1 as a MdATG8i-interacting protein in apple, however, the functions of HARBI1-like proteins have not been explored in plants. Expression analysis of MdHARBI1 and pro-MdHARBI1-GUS staining of transgenic Arabidopsis exposed to high temperature demonstrated that MdHARBI1 was significantly induced by heat stress. Moreover, heat-treated MdHARBI1-trangenic tomato plants maintained higher autophagic activity, accumulated fewer ROS, and displayed stronger chlorophyll fluorescence than wild-type plants. Because these phenotypes were consistent with those displayed by MdATG8i-overexpressing apple plants under high temperature, we concluded that the MdATG8i-interacting protein MdHARBI1 plays a critical role in the basal thermotolerance of plants, mainly by influencing autophagy pathways.
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http://dx.doi.org/10.1016/j.plantsci.2021.110850DOI Listing
May 2021

Identification and characterization of invertase family genes reveal their roles in vacuolar sucrose metabolism during Pyrus bretschneideri Rehd. fruit development.

Genomics 2021 Mar 8;113(3):1087-1097. Epub 2021 Mar 8.

Centre of Pear Engineering Technology Research, State Key Laboratory of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China. Electronic address:

23 invertase (PbrInvs) genes, including eight vacuolar invertases (PbrvacInvs), five cell wall invertases (PbrcwInvs) and 10 alkaline/neutral invertases (PbrA/N-Invs), were identified from P. bretschneideri Rehd. genome, with diverse chromosome locations, cis-acting elements, gene structures and motifs. Their expression profiles were tissue-specific, and postharvest light or temperature treatment would alter their expression profiles. During 'Dangshansuli' pear development, in association with visual/inner quality change was the alternations of invertase activity and the expression profiles of PbrInvs. In combination with results of subcellular sugar distribution as well as correlation analysis among sugar content, invertase activity and PbrInv mRNA abundance, PbrvacInv1 might be involved in sucrose decomposition during pear development. PbrvacInv1-GFP fusion protein mainly accumulated on the tonoplast (vacuolar membrane); meanwhile, transient overexpression of PbrvacInv1 in pear fruit would upregulate vacInv activity, causing higher fructose and lower sucrose when compared with that of the control. Furthermore, invertase inhibitor 5 (PbrInvInh5) could interact with PbrvacInv1.
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http://dx.doi.org/10.1016/j.ygeno.2021.01.028DOI Listing
March 2021

Nanoemulsions Target to Ectopic Lymphoids in Inflamed Joints to Restore Immune Tolerance in Rheumatoid Arthritis.

Nano Lett 2021 Mar 9;21(6):2551-2561. Epub 2021 Mar 9.

Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, P.R. China.

Inducing immune tolerance through repeated administration of self-antigens is a promising strategy for treating rheumatoid arthritis (RA), and current research indicates that coadministration of immunomodulators can further orchestrate the tolerogenic response. However, most of the clinical trials based on tolerance induction have negligible therapeutic effects. Peripheral lymphoid organs play critical roles in immunotherapy. Here, we design an engineered nanoemulsion for targeted codelivery of self-antigens and an immunomodulator to ectopic lymphoid structures (ELSs) in inflamed joints of RA. Namely, a citrullinated multiepitope self-antigen (CitP) and rapamycin are incorporated into the nanoemulsions (NEs@CitP/Rapa), which are fabricated by a facial method using commercialized pharmaceutical excipients. After intravenous administration, the nanoemulsion shows satisfactory accumulation in the inflamed paws and provides enhanced anti-inflammatory effect in various experimental murine models of RA. Our study provides a promising targeting strategy to induce immune tolerance for the treatment of RA.
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http://dx.doi.org/10.1021/acs.nanolett.0c05110DOI Listing
March 2021

The production, detection, and origin of irisin and its effect on bone cells.

Int J Biol Macromol 2021 May 27;178:316-324. Epub 2021 Feb 27.

Department of Spine Surgery, Tianjin Hospital, 406 Jiefang South Road, Hexi District, Tianjin 300211, China. Electronic address:

Irisin is a muscle factor discovered in 2012 that plays an important role in many tissues, including bone. Eight years since its discovery, there are still many controversies regarding its molecular biology, detection, and effects on bone. This article summarizes the points raised to date, and discusses the mechanisms by which irisin regulates bone cells. The information reviewed here provides a useful foundation for future research.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.02.181DOI Listing
May 2021

Thermodynamic Stability and Aggregation Kinetics of EF Helix and EF Loop Variants of Transthyretin.

Biochemistry 2021 Mar 1;60(10):756-764. Epub 2021 Mar 1.

Misfolding and aggregation of transthyretin (TTR) are linked to amyloid disease. Amyloidosis occurs when the TTR homotetramer dissociates into aggregation-prone monomers that self-assemble into amyloid. In familial transthyretin amyloidosis, hereditary amino acid substitutions destabilize TTR and promote aggregation. In this work, we used F nuclear magnetic resonance (NMR) to determine the effect of mutations in the EF helix (Y78F, K80D, K80E, and A81T) and EF loop (G83R and I84S) on the aggregation kinetics and stability of the TTR tetramer and monomer. The EF region acts as a scaffold that stabilizes interactions in both the strong and weak dimer interfaces of the tetramer and is the site of a cluster of pathogenic mutations. K80D and K80E are non-natural mutants that destabilize the EF helix and yield an equilibrium mixture of tetramer and monomer at neutral pH, providing a unique opportunity to determine the thermodynamic parameters for tetramer assembly under nondenaturing conditions. Of the pathogenic mutants studied, only A81T formed appreciable monomer at neutral pH. Real-time F NMR measurements showed that the pathogenic Y78F mutation accelerates aggregation by destabilizing both the tetrameric and monomeric species. The pathogenic mutations A81T, G83R, and I84S destabilize the monomer and increase its aggregation rate by disrupting a Schellman helix C-capping motif. These studies provide new insights into the mechanism by which relatively subtle mutations that affect tetramer or monomer stability promote entry of TTR into the dissociation-aggregation pathway.
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http://dx.doi.org/10.1021/acs.biochem.1c00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023301PMC
March 2021

Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer.

Cancer Cell Int 2021 Feb 25;21(1):135. Epub 2021 Feb 25.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China.

Background: The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.

Methods: A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.

Results: We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4 T cell, CD8 T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression.

Conclusions: SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.
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http://dx.doi.org/10.1186/s12935-021-01829-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905896PMC
February 2021

The effects of all-trans retinoic acid on immune cells and its formulation design for vaccines.

AAPS J 2021 02 24;23(2):32. Epub 2021 Feb 24.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, People's Republic of China.

As one of the most important metabolites of vitamin A, all-trans retinoic acid (RA) plays a crucial role in regulating immune responses. RA has been shown to promote the differentiation of naïve T and B cells and perform diverse functions in the presence of different cytokines. RA also induces gut tropic lymphocytes through upregulating the expression of chemokine (C-C motif) receptor 9 (CCR9) and α4β7 integrin. In addition, RA promotes the expression of the enzyme retinal dehydrogenase (RALDH) on dendritic cells, which in turn strengthens the ability to synthesize RA. Due to the insolubility of RA, proper formulation design can maximize its ability to improve immune responses for vaccines. Recent studies have developed some formulations co-loading RA and antigen, which can effectively imprint lymphocytes gut homing properties and induce intestine immune responses as well as systemic responses through parenteral administration, providing a promising direction for the protection against mucosal infections. Here, we review the mechanism and effects of RA on lymphocyte differentiation and gut homing, and recent progress of RA delivery systems to improve mucosal immune responses.
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http://dx.doi.org/10.1208/s12248-021-00565-1DOI Listing
February 2021

Determination of the mechanical properties of polymeric microneedles by micromanipulation.

J Mech Behav Biomed Mater 2021 05 10;117:104384. Epub 2021 Feb 10.

West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address:

Precise characterization of the mechanical properties of polymeric microneedles is crucial for their successful penetration into skin and delivery of the loaded active ingredients. However, most available strategies for this purpose are based on compression of the whole patch, which only provide the average rupture force of the needles and can not give information on the variations across individual microneedles in the patch. In this study, we determined the mechanical strength of individual microneedles of two types of hyaluronic acid microneedles with or without loaded model drugs using a micromanipulation technique. The applied force as a function of displacement of the microneedles was recorded, which was used to determine the rupture displacement, rupture force, and then to derive and calculate normal stress-deformation curve, rupture stress and Young's modulus of individual microneedles. The obtained data suggest that the molecular weight of the polymer and the loading of drug into the microneedles can significantly affect the rupture behavior and mechanical properties of the microneedles, which provides a foundation for preparing sufficiently strong microneedles for controlled drug delivery.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104384DOI Listing
May 2021

Probing Osteocyte Functions in Gelatin Hydrogels with Tunable Viscoelasticity.

Biomacromolecules 2021 Mar 5;22(3):1115-1126. Epub 2021 Feb 5.

Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana 47907, United States.

Bone is an attractive site for metastatic cancer cells and has been considered as "soil" for promoting tumor growth. However, accumulating evidence suggests that some bone cells (e.g., osteocytes) can actually suppress cancer cell migration and invasion direct cell-cell contact and/or through cytokine secretion. Toward designing a biomimetic niche for supporting 3D osteocyte culture, we present here a gelatin-based hydrogel system with independently tunable matrix stiffness and viscoelasticity. In particular, we synthesized a bifunctional macromer, gelatin-norbornene-boronic acid (i.e., GelNB-BA), for covalent cross-linking with multifunctional thiol linkers [e.g., four-arm poly(ethylene glycol)-thiol or PEG4SH] to form thiol-NB hydrogels. The immobilized BA moieties in the hydrogel readily formed reversible boronate ester bonds with 1,3-diols on physically entrapped poly(vinyl alcohol) (PVA). Adjusting the compositions of GelNB-BA, PEG4SH, and PVA afforded hydrogels with independently tunable elasticity and viscoelasticity. With this new dynamic hydrogel platform, we investigated matrix mechanics-induced growth and cytokine secretion of encapsulated MLO-A5 pre-osteocytes. We discovered that more compliant or viscoelastic gels promoted A5 cell growth. On the other hand, cells encapsulated in stiffer gels secreted higher amounts of pro-inflammatory cytokines and chemokines. Finally, conditioned media (CM) collected from the encapsulated MLO-A5 cells (i.e., A5-CM) strongly inhibited breast cancer cell proliferation, invasion, and expression of tumor-activating genes. This new biomimetic hydrogel platform not only serves as a versatile matrix for investigating mechano-sensing in osteocytes but also provides a means to produce powerful anti-tumor CM.
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http://dx.doi.org/10.1021/acs.biomac.0c01476DOI Listing
March 2021

High-Temperature Resistant Polyborosilazanes with Tailored Structures.

Polymers (Basel) 2021 Feb 1;13(3). Epub 2021 Feb 1.

Engineering Laboratory of Advanced Energy Materials, Ningbo Institute of Materials Technology & Engineering, Chinese Academy of Sciences, Ningbo 315201, China.

Boron-containing organosilicon polymers are widely used under harsh environments as preceramic polymers for advanced ceramics fabrication. However, harmful chemicals released during synthesis and the complex synthesis routes have limited their applications. To solve the problems, a two-component route was adopted to synthesize cross-linked boron-containing silicone polymer (CPBCS) via a solventless process. The boron content and CPBCSs' polymeric structures could be readily tuned through controlling the ratio of multifunctional boron hybrid silazane monomers (BSZ12) and poly[imino(methylsilylene)]. The CPBCSs showed high thermal stability and good mechanical properties. The CPBCS with Si-H/C=C ratio of 10:1 showed 75 wt% char yields at 1000 °C in argon, and the heat release capacity (HRC) and total heat release (THR) are determined to be 37.9 J/g K and 6.2 KJ/g, demonstrating high thermal stability and flame retardancy. The reduced modulus and hardness of CPBCS are 0.30 GPa and 2.32 GPa, respectively. The novel polysilazanes can be potentially used under harsh environments, such as high temperatures or fire hazards.
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http://dx.doi.org/10.3390/polym13030467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867192PMC
February 2021

MAX Phase Ceramics/Composites with Complex Shapes.

ACS Appl Mater Interfaces 2021 Feb 25;13(4):5645-5651. Epub 2021 Jan 25.

Engineering Laboratory of Advanced Energy Materials, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China.

Ceramics including oxides, carbides, nitrides, borides, carbonitrides, silicates, and MAX phases have wide applications in electrode materials, high-temperature structural materials, and anticorrosive materials for harsh environments. However, the difficulty in processing ceramics with complex shapes from green powders has been restricting applications in emerging areas. Herein, polymer-derived ceramics (PDCs) were used to assist the pressureless processing of MAX phase particles. The processing temperature could be lowered by 400 to 600 °C, which is favorable for both industrialization and engineering applications. The good processability of MAX-preceramic polymer mixtures and high accuracy of replica from preceramic polymer make it possible to fabricate artificial objects with complex shapes and fine texture. This method provides a method to fabricate MAX phase ceramics/composites, as well as some other ceramics.
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http://dx.doi.org/10.1021/acsami.0c22289DOI Listing
February 2021

Parkinson-like early autonomic dysfunction induced by vagal application of DOPAL in rats.

CNS Neurosci Ther 2021 May 21;27(5):540-551. Epub 2021 Jan 21.

Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.

Aim: To understand why autonomic failures, a common non-motor symptom of Parkinson's disease (PD), occur earlier than typical motor disorders.

Methods: Vagal application of DOPAL (3,4-dihydroxyphenylacetaldehyde) to simulate PD-like autonomic dysfunction and understand the connection between PD and cardiovascular dysfunction. Molecular and morphological approaches were employed to test the time-dependent alternation of α-synuclein aggregation and the ultrastructure changes in the heart and nodose (NG)/nucleus tractus solitarius (NTS).

Results: Blood pressure (BP) and baroreflex sensitivity of DOPAL-treated rats were significantly reduced accompanied with a time-dependent change in orthostatic BP, consistent with altered echocardiography and cardiomyocyte mitochondrial ultrastructure. Notably, time-dependent and collaborated changes in Mon-/Tri-α-synuclein were paralleled with morphological alternation in the NG and NTS.

Conclusion: These all demonstrate that early autonomic dysfunction mediated by vagal application of DOPAL highly suggests the plausible etiology of PD initiated from peripheral, rather than central site. It will provide a scientific basis for the prevention and early diagnosis of PD.
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http://dx.doi.org/10.1111/cns.13589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025611PMC
May 2021

Transcriptome analysis of pear leaves in response to calcium treatment during infection.

Phytopathology 2021 Jan 20. Epub 2021 Jan 20.

Nanjing, China;

Pear ( Rehd.), one of the most widely planted fruit trees in the world, is infected by pear ring rot disease, which is triggered by () fungus. Previous research has shown that exogenous calcium enhanced pear resistance to . To explore the molecular mechanism of calcium in pear pathogen resistance, we searched the differentially expressed genes (DEGs) between calcium and HO treatment with inoculation in pear by using RNA-seq data. On the basis of the standard of a proportion of calcium/HO fold change > 2, and the false discovery rate (FDR) < 0.05, 2812 and 572 genes with significant differential expression were identified between the HO and calcium treatments under inoculation at 2 days post inoculation (dpi) (D2) and 8 dpi (D8), respectively, indicating that significantly more genes in D2 responded to calcium treatment. Results of the gene annotation showed that DEGs were focused on plant-pathogen interactions, hormone signal transduction and phenylpropanoid biosynthesis in D2. Moreover, transient silencing of (Pear CalModulin-Like proteins 30), which had significantly higher expression in response to calcium than HO treatments, conferred compromised resistance to . Exogenous calcium treatment slightly alleviated the symptoms of TRV2- leaves compared with TRV2 leaves under inoculation, supporting its key role in pear resistance to . Overall, the information obtained in this study provides a possible mechanism of calcium in regulating pear resistance to .
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http://dx.doi.org/10.1094/PHYTO-10-20-0458-RDOI Listing
January 2021

Role of the Calcified Cartilage Layer of an Integrated Trilayered Silk Fibroin Scaffold Used to Regenerate Osteochondral Defects in Rabbit Knees.

ACS Biomater Sci Eng 2020 02 10;6(2):1208-1216. Epub 2020 Jan 10.

Department of Spine Surgery, Tianjin Hospital, Tianjin University, 406 Jiefang Nan Road, Hexi District, Tianjin 300211, People's Republic of China.

The repair of osteochondral defects remains challenging, given the complexity of native osteochondral tissue and the limited self-repair capacity of cartilage. Osteochondral tissue engineering is a promising strategy. Here, we fabricated a biomimetic osteochondral scaffold using silk fibroin and hydroxyapatite, including a calcified cartilage layer (CCL). We studied the role played by the CCL in terms of cell viability in vivo. We established osteochondral defects in rabbit knees to investigate the effects of CCL-containing scaffolds with or without adipose tissue-derived stem cells (ADSCs). We evaluated osteochondral tissue regeneration by calculating gross observational scores, via histological and immunohistochemical assessments, by performing quantitative biochemical and biomechanical analyses of new osteochondral tissue, and via microcomputed tomography of new bone at 4, 8, and 12 weeks after surgery. In terms of surface roughness and integrity, the CCL + ADSCs group was better than the CCL and the non-CCL + ADSCs groups at all time points tested; the glycosaminoglycan and collagen type II levels of the CCL + ADSCs group were highest, reflecting the important role played by the CCL in cartilage tissue repair. Subchondral bone smoothness was better in the CCL + ADSCs group than in the non-CCL + ADSCs and CCL groups. The CCL promoted smooth subchondral bone regeneration but did not obviously affect bone strength or quality. In conclusion, a biomimetic osteochondral scaffold with a CCL, combined with autologous ADSCs, satisfactorily regenerated a rabbit osteochondral defect. The CCL enhances cartilage and subchondral bone regeneration.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01661DOI Listing
February 2020

Mechanical Loading-Driven Tumor Suppression Is Mediated by Lrp5-Dependent and Independent Mechanisms.

Cancers (Basel) 2021 Jan 13;13(2). Epub 2021 Jan 13.

Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.

Bone is mechanosensitive and lipoprotein receptor-related protein 5 (Lrp5)-mediated Wnt signaling promotes loading-driven bone formation. While mechanical loading can suppress tumor growth, the question is whether Lrp5 mediates loading-driven tumor suppression. Herein, we examined the effect of Lrp5 using osteocyte-specific Lrp5 conditional knockout mice. All mice presented noticeable loading-driven tumor suppression in the loaded tibia and non-loaded mammary pad. The degree of suppression was more significant in wild-type than knockout mice. In all male and female mice, knee loading reduced cholesterol and elevated dopamine. It reduced tumor-promoting nexin, which was elevated by cholesterol and reduced by dopamine. By contrast, it elevated p53, TNF-related apoptosis-inducing ligand (TRAIL), and chemerin, and they were regulated reversely by dopamine and cholesterol. Notably, Lrp5 overexpression in osteocytes enhanced tumor suppression, and osteoclast development was inhibited by chemerin. Collectively, this study identified Lrp5-dependent and independent mechanisms for tumor suppression. Lrp5 in osteocytes contributed to the loaded bone, while the Lrp5-independent regulation of dopamine- and cholesterol-induced systemic suppression.
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http://dx.doi.org/10.3390/cancers13020267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828232PMC
January 2021

A phosphorylation-dependent switch in the disordered p53 transactivation domain regulates DNA binding.

Proc Natl Acad Sci U S A 2021 01 21;118(1). Epub 2020 Dec 21.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037

The tumor-suppressor p53 is a critical regulator of the cellular response to DNA damage and is tightly regulated by posttranslational modifications. Thr55 in the AD2 interaction motif of the N-terminal transactivation domain functions as a phosphorylation-dependent regulatory switch that modulates p53 activity. Thr55 is constitutively phosphorylated, becomes dephosphorylated upon DNA damage, and is subsequently rephosphorylated to facilitate dissociation of p53 from promoters and inactivate p53-mediated transcription. Using NMR and fluorescence spectroscopy, we show that Thr55 phosphorylation inhibits DNA-binding by enhancing competitive interactions between the disordered AD2 motif and the structured DNA-binding domain (DBD). Nonphosphorylated p53 exhibits positive cooperativity in binding DNA as a tetramer. Upon phosphorylation of Thr55, cooperativity is abolished and p53 binds initially to cognate DNA sites as a dimer. As the concentration of phosphorylated p53 is further increased, a second dimer binds and causes p53 to dissociate from the DNA, resulting in a bell-shaped binding curve. This autoinhibition is driven by favorable interactions between the DNA-binding surface of the DBD and the multiple phosphorylated AD2 motifs within the tetramer. These interactions are augmented by additional phosphorylation of Ser46 and are fine-tuned by the proline-rich domain (PRD). Removal of the PRD strengthens the AD2-DBD interaction and leads to autoinhibition of DNA binding even in the absence of Thr55 phosphorylation. This study reveals the molecular mechanism by which the phosphorylation status of Thr55 modulates DNA binding and controls both activation and termination of p53-mediated transcriptional programs at different stages of the cellular DNA damage response.
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http://dx.doi.org/10.1073/pnas.2021456118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817127PMC
January 2021

Preoperative Prognostic Nutritional Index Value is Related to Postoperative Delirium in Elderly Patients After Noncardiac Surgery: A Retrospective Cohort Study.

Risk Manag Healthc Policy 2021 6;14:1-8. Epub 2021 Jan 6.

Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City 221002, Jiangsu Province, People's Republic of China.

Purpose: Malnutrition has been considered as a risk factor for postoperative delirium (POD). The Prognostic Nutritional Index (PNI) is a validated tool for assessing nutritional status. This study aimed to investigate the association between preoperative PNI values and the occurrence of POD in elderly surgical patients.

Methods: The retrospective cohort study included 361 elderly individuals who underwent noncardiac surgery between 2018 and 2019. Perioperative data were collected from the patients' medical records. PNI was used to evaluate preoperative nutritional status. The primary outcome was the occurrence of POD. Univariate and multivariate logistic regression analyses were used to identify key factors associated with POD and assess the relationship between PNI values and the occurrence of POD. Receiver operating characteristic (ROC) curve analysis was used to assess the predictive value of PNI for POD.

Results: Seventy-two (19.9%) individuals developed postoperative delirium after surgery. Compared with patients of normal nutrition status (PNI ≥ 50), mild malnutrition (PNI 45-50) did not increase the risk of POD, while patients with moderate to severe malnutrition (PNI 40-45) (odds ratio [OR], 2.92; 95% confidence interval [CI], 1.31-6.50) and serious malnutrition (PNI < 40) (OR, 3.15; 95% CI, 1.12-8.83) were more likely to develop POD. The cut-off value of PNI was 46.05 by ROC curve analysis, the area under the curve (AUC) was 0.69 (95% CI 0.62-0.77).

Conclusion: Preoperative PNI value is related to postoperative delirium in elderly patients after noncardiac surgery.
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http://dx.doi.org/10.2147/RMHP.S280567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797345PMC
January 2021

Genome-wide identification and expression analysis of the pear autophagy-related gene PbrATG8 and functional verification of PbrATG8c in Pyrus bretschneideri Rehd.

Planta 2021 Jan 13;253(2):32. Epub 2021 Jan 13.

Center of Pear Engineering Technology Research, State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China.

Main Conclusion: Genome-wide identification, tissue-specific and stress expression analyses and functional characterization of PbrATG8s genes were conducted and the role of PbrATG8c in Botryosphaeria dothidea resistance was further investigated. Autophagy plays an important role in plant growth, development and stress tolerance. ATG8 has been reported to be an autophagy marker in many species. However, there is little information regarding ATG8 family members in pear (Pyrus bretschneideri Rehd). We performed a genome-wide analysis and identified nine PbrATG8 gene family members in pear. Phylogenetic analysis showed that PbrATG8 genes clustered into four major groups (Groups I-IV). Eight PbrATG8 genes were successfully mapped to 6 of the 17 chromosomes of the pear genome. The synteny results showed that two pairs are collinear. Gene expression data showed that all genes were differentially expressed in a range of pear tissues. Transcript analysis of PbrATG8 genes under dehydration, salt and pathogen infection stresses revealed that PbrATG8c responded to all test stresses. The PbrATG8c protein was localized in the nucleus and membrane. The silencing of PbrATG8c decreased the resistance to Botryosphaeria dothidea in pear. This study provides insights and rich resources for subsequent investigations of autophagy in pear.
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http://dx.doi.org/10.1007/s00425-020-03558-0DOI Listing
January 2021

Adaptive immune responses mediated age-related Plasmodium yoelii 17XL and 17XNL infections in 4 and 8-week-old BALB/c mice.

BMC Immunol 2021 Jan 11;22(1). Epub 2021 Jan 11.

Department of Immunology, College of Basic Medical Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China.

Backgroud: It is important to expound the opposite clinical outcomes between children and adulthood for eradicate malaria. There remains unknown about the correlation between adaptive immune response and age-related in malaria.

Methods: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA.

Results: The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4T-betIFN-γ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4GATA3IL-4 Th2 cells and CD4CXCR5 Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4 or activated CD4 T cells in the 8-week-old mice as compared to the 4-week-old group.

Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4 T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.
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http://dx.doi.org/10.1186/s12865-020-00391-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798208PMC
January 2021