Publications by authors named "Yun Ding"

209 Publications

A carrier-free nanoparticle with dual NIR/acid responsiveness by co-assembly of enediyne and IR820 for combined PTT/chemotherapy.

J Mater Chem B 2021 May 5. Epub 2021 May 5.

Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

Combined photothermal therapy/chemotherapy by co-delivery of a photosensitizer (PS) and a chemotherapeutic drug has demonstrated great potential for cancer treatment. The intrinsic drawbacks of traditional drug delivery systems (DDSs), such as tedious synthetic procedures, side effects originated from the carrier materials, low loading efficiency, and uncontrolled drug release, however, have impaired their further advancement. On the other hand, enediyne antibiotics are highly cytotoxic toward cancer cells through the generation of lethal carbon radicals via thermal-induced cyclization, endowing them with great potential to achieve enhanced synergistic anticancer performance by incorporation with the photothermal effect of PS. To this end, a carrier-free and NIR/acid dual-responsive DDS was constructed for combined photothermal therapy/chemotherapy. The facile co-assembly of maleimide-based enediyne and PS IR820 was achieved in aqueous solution to give nanoparticles (EICN) with a hydrodynamic diameter of 90 nm and high stability. In vitro study confirmed the acid/NIR dual-responsive degradation and drug release, free radical generation and DNA-cleaving ability of EICN, which was accomplished by the corporation of enediyne and IR820 moieties. Further tests on HeLa cells verified the excellent synergistic anticancer performance of EICN including the improved cellular uptake, NIR-enhanced drug release, DNA damage and histone deacetylase inhibitor capacity. Overall, this carrier-free DDS with dual acid/NIR-responsivity would potentially provide new insights for the development of combined photothermal/chemotherapy.
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http://dx.doi.org/10.1039/d1tb00279aDOI Listing
May 2021

Controlled synthesis of conjugated polymers in dendritic mesoporous silica nanoparticles.

Chem Commun (Camb) 2021 Apr;57(34):4146-4149

Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

A controlled polymerization strategy is developed by confining the step-growth polycondensation to take place exclusively in the nanochannels of dendritic mesoporous silica nanoparticles. A variety of conjugated polymers with rich structural patterns were obtained in high yields. The molecular weights were precisely controlled with narrow molecular weight distributions. The obtained conjugated polymers were freely processed in solution and casted in film, showing bright fluorescence emission. All the features of this controlled polymerization method endow the conjugated polymers great potential for future applications.
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http://dx.doi.org/10.1039/d1cc00338kDOI Listing
April 2021

circUBAP2 exacerbates malignant capabilities of NSCLC by targeting KLF4 through miR-3182 modulation.

Aging (Albany NY) 2021 Mar 19;13. Epub 2021 Mar 19.

Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, Fujian Province, China.

Chemo-resistance and refractoriness remain challenges for Non-small cell lung cancer (NSCLC) patients and the underlying molecular mechanisms haven't been fully explained. In this study, we investigated the influence of circUBAP2 on the NSCLC tumor cells. This study might provide novel therapeutic targets for NSCLC treatment. Clinical samples and NSCLC cell lines were used to investigate circUBAP2 expressions and their impact on tumor cell chemo-resistance. CCK8 and transwell assays were conducted to explore the differences of NSCLC tumor proliferation and migration capabilities affected by circUBAP2. Dual-luciferase reporter gene assay was performed to explore the detailed molecular mechanism of circUBAP2 regulation network. circUBAP2 exhibited significantly elevated average level in our clinical samples of NSCLC, compared with normal tissues. CircUBAP2 level was positively correlated with disease stage and metastatic status. circUBAP2 significantly enhanced the migration, proliferation and chemo-resistance of NSCLC cell lines. Further experiments indicated that circUBAP2 promoted malignant biological behavior of NSCLC tumor cells by targeting KLF4 through modulating miR-3182 expression. Our study demonstrated for the first time that circUBAP2 played an important role exacerbating malignant capabilities of NSCLC. circUBAP2-miR3182-KLF4 regulative network demonstrated in this study could be a novel therapeutic target for future NSCLC treatment.
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http://dx.doi.org/10.18632/aging.202745DOI Listing
March 2021

Additive Manufacturing of Wood Flour/PHA Composites Using Micro-Screw Extrusion: Effect of Device and Process Parameters on Performance.

Polymers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing 100029, China.

Based on additive manufacturing of wood flour and polyhydroxyalkanoates composites using micro-screw extrusion, device and process parameters were evaluated to achieve a reliable printing. The results show that the anisotropy of samples printed by micro-screw extrusion is less obvious than that of filament extrusion fused deposition modeling. The type of micro-screw, printing speed, layer thickness, and nozzle diameter have significant effects on the performance of printed samples. The linear relationship between the influencing parameters and the screw speed is established, therefore, the performance of printed products can be controlled by the extrusion flow rate related to screw speed.
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http://dx.doi.org/10.3390/polym13071107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037742PMC
March 2021

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases.

Int J Mol Sci 2021 Mar 10;22(6). Epub 2021 Mar 10.

Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA.

Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.
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http://dx.doi.org/10.3390/ijms22062805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001105PMC
March 2021

Evaluation of pembrolizumab for the treatment of advanced non-small cell lung cancer: a retrospective, single-centre, single-arm study.

J Thorac Dis 2021 Jan;13(1):282-290

Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China.

Background: Immune checkpoint inhibitors (ICIs) provided a paradigm shift for advanced non-small cell lung cancer (NSCLC) treatment and improved the clinical prognosis of such patients. Pembrolizumab is a humanized anti-programmed death cell protein 1 (PD-1) monoclonal antibody, approved for the treatment of patients with advanced or metastatic NSCLC. This article investigated and reported on the efficacy and safety of pembrolizumab in the treatment of advanced NSCLC in our center since 2019.

Methods: Patients with clinical stage III-IV NSCLC treated with pembrolizumab for ≥4 cycles were enrolled as participants in this study. Pembrolizumab was administered intravenously at a dose of 2 mg/kg every 3 weeks. A cycle was defined as 3 weeks of treatment. We assessed the efficacy and safety of pembrolizumab through the collection of researcher-assessed tumor response, survival, and safety data.

Results: A total of 24 patients were included in this study. The median follow-up time was 9 months (3-20 months) and the median period of pembrolizumab therapy was 7 cycles (4-21 cycles). The objective response rate (ORR) was 45.8% and disease control rate (DCR) was 70.8%. The median overall survival (OS) and progression-free survival (PFS) times were not reached. A total of 2 programmed death-ligand 1 (PD-L1)-negative participants were treated with pembrolizumab combined with chemotherapy and there was no significant progression during the follow-up period. During the follow-up period, 8 patients underwent surgery. The major pathological response (MPR) was 75% and pathological complete response (pCR) was 50%. A case that was preoperatively diagnosed with clinical stage IV achieved pCR after 6 cycles of pembrolizumab combined with chemotherapy. The incidence of adverse effects (AEs) was 83.3%, and 16.7% of these were serious AEs (grade ≥3), which was similar to the incidence reported in previous studies.

Conclusions: This real-world data supports the use of pembrolizumab for advanced NSCLC, including those cases that are PD-L1 negative. More importantly, pembrolizumab immunotherapy can also provide the potential of local treatment for patients with advanced NSCLC, which has wide application prospects in the field of surgery.
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http://dx.doi.org/10.21037/jtd-20-3413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867846PMC
January 2021

(()--(4-(((2-Amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) Ameliorated Aβ-Induced Alzheimer's Disease in SD Rats by Inhibiting Oxidative Stress and Apoptosis.

ACS Chem Neurosci 2021 02 31;12(4):640-650. Epub 2021 Jan 31.

Department of Physical and Chemical Inspection, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.

Our study investigated the protective effects of (()--(4-(((2-amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) , a novel glycogen synthase kinase-3β (GSK-3β) inhibitor, on the learning and memory function of rats with amyloid-β (Aβ)-induced Alzheimer's disease (AD) and explored the possible mechanisms. Sixty male Sprague-Dawley (SD) rats were randomly divided into five groups: the control, Aβ, donepezil, and low-dose and high-dose groups. The rats in the Aβ, donepezil, and two intervention groups received a single microinjection of 10 μg of Aβ into the hippocampus followed by intragastric administration of 0.5% sodium carboxymethyl cellulose (CMC-Na), 12 (mg/kg)/d donepezil hydrochloride and 6 or 18 (mg/kg)/d compound for 28 days, while the rats in the control group were treated with the vehicles. Learning and memory impairment were attenuated, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), acetylcholinesterase (AChE), and adenosine triphosphatase (ATPase) in the brain tissue were significantly increased ( < 0.05), and the concentrations of Aβ, phospho-tau (p-tau), and malondialdehyde (MDA) in the brain tissue were significantly decreased ( < 0.05) in the compound group compared to the Aβ group. In addition, compound regulated the imbalance in the concentrations of neurotransmitters and alleviated severe damage and apoptosis in the brains of the rats exposed to Aβ. The novel GSK-3β inhibitor could improve learning and memory dysfunction caused by Aβ through its antioxidant and antiapoptotic effects.
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http://dx.doi.org/10.1021/acschemneuro.0c00655DOI Listing
February 2021

Experimental and Computational Study on the Intramolecular Hydrogen Atom Transfer Reactions of Maleimide-Based Enediynes After Cycloaromatization.

J Org Chem 2021 01 29;86(2):1549-1559. Epub 2020 Dec 29.

Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

The follow-up reaction pathways of the diradical species formed from cycloaromatization of enediynes or enyne-allenes determine their ability of H-abstraction from DNA, significantly affecting their biological activity performance. To gain a deeper understanding of subsequent reaction pathways of the diradical intermediates formed from acyclic enediynes based on maleimide-assisted rearrangement and cycloaromatization (MARACA), a maleimide-based enediyne featuring methylene groups adjacent to the propargyl sites of the terminal alkynes was synthesized through the Sonogashira coupling reaction. Three thermal cyclization products after intramolecular hydrogen atom transfer (HAT) were obtained from the thermolysis experiment and their structures were confirmed by 1D and 2D nuclear magnetic resonance spectroscopic analysis. Density functional theory was employed to analyze the important elementary steps including rearrangement, cycloaromatization, and intramolecular HAT processes toward the formation of the cyclized products, where the low-energy barriers of HAT pathways relative to the formation of diradicals from cycloaromatization were successfully identified. Overall, the HAT processes to consume diradicals intramolecularly have become competitive with that of intermolecular H-abstraction, implying that the DNA-cleavage ability of enediynes can be further boosted once the HAT processes are halted. This study offers a promising direction for designing novel and potent acyclic enediynes for antitumor applications.
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http://dx.doi.org/10.1021/acs.joc.0c02401DOI Listing
January 2021

Synthesis of Conjugated Mesoporous Hyper-cross-linked Polymers for Efficient Capture of Dibenzothiophene and Iodine.

ACS Appl Mater Interfaces 2020 Dec 2;12(50):56454-56461. Epub 2020 Dec 2.

Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

Porous organic polymers have recently received great attention because of their promising applications in the removal of thiophene compounds in liquid fuels and for the nuclear waste (such as radioactive iodine isotopes) treatments. Herein, a series of conjugated mesoporous hyper-cross-linked polymers (CMHPs) were prepared through our newly developed silicon-promoted cationic polymerization in a straightforward manner. The CMHPs exhibited extended π-conjugation, intrinsic porosity, high surface area, and excellent physicochemical stability. They showed an outstanding dibenzothiophene uptake capacity of ∼1335 mg g, which far exceeded many reported porous organic polymers. Meanwhile, these CMHPs showed high adsorption capacity for iodine vapor. Altogether, the CMHPs prepared by the facile and metal-free cationic reactions have great potential in adsorption of harmful substances and environmental protection.
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http://dx.doi.org/10.1021/acsami.0c16816DOI Listing
December 2020

How retaining objects containing multiple features in visual working memory regulates the priority for access to visual awareness.

Conscious Cogn 2021 Jan 8;87:103057. Epub 2020 Dec 8.

Department of Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht, the Netherlands.

The content of visual working memory influences the access to visual awareness. Thus far, research has focused on retention of a single feature, whereas memoranda in real life typically contain multiple features. Here, we intermixed a delayed match-to-sample task to manipulate VWM content, and a breaking Continuous Flash Suppression (b-CFS) task to measure prioritization for visual awareness. Observers memorized either the color (Exp. 1), the shape (Exp. 2) or both the features (Exp. 3) of an item and indicated the location of a suppressed target. We observed that color-matching targets broke suppression faster than color-mismatching targets both when color was memory relevant or irrelevant. Shape only impacted priority for visual awareness through an interaction with color. We conclude that: (1) VWM can regulate the priority of visual information to access visual awareness along a single feature dimension; (2) different features of a memorandum vary in their potency to impact access to visual awareness, and the more dominant feature may even suppress the effect of the less dominant feature; (3) even stimuli that match an irrelevant feature dimension of the memorandum can be prioritized for visual awareness.
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http://dx.doi.org/10.1016/j.concog.2020.103057DOI Listing
January 2021

Condensation of DNA-Conjugated Imines with Homophthalic Anhydride for the Synthesis of Isoquinolones on DNA.

Bioconjug Chem 2020 12 12;31(12):2712-2718. Epub 2020 Nov 12.

Encoded Library Technologies/NCE Molecular Discovery, R&D Medicinal Science and Technology, GlaxoSmithKline, 200 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States.

Condensation of imines with anhydrides have been proven to be a valuable method for the synthesis of tetrahydroisoquinolones. Herein, we report the application of this chemistry with DNA-conjugated imines. Condensation of DNA-conjugated imine (which can be formed in situ from DNA-conjugated amines and aldehydes or DNA-conjugated aldehyde and primary amines) with homophthalic anhydride produces isoquinolones in moderate to excellent yields. The formed isoquinolone can be further derivatized with a variety of amines through amide bond formation. Development of this chemistry on-DNA enables the synthesis of an isoquinolone core-focused DNA-encoded library.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00508DOI Listing
December 2020

The priority for access to awareness of information matching VWM is mirror-invariant.

Cognition 2021 01 6;206:104463. Epub 2020 Oct 6.

Helmholtz Institute, Department of Experimental Psychology, Utrecht University, the Netherlands.

Previous studies suggest that 1) storing a visual representation of an item in visual working memory (VWM) prioritizes access to visual awareness for this item and that 2) VWM can contain representations of bound items instead of separate features. It is currently unclear whether VWM affects access to visual awareness at the individual feature level, the conjunction of multiple features level or the object level. To investigate this question, we conducted a series of experiments in which we combined a delayed match to sample task with a breaking Continuous Flash Suppression (b-CFS) task. On each trial, subjects memorized an object consisting of a disk with two halves with different colors for the later recall test and, between them, had to detect the location of a target initially presented under suppression. We varied the congruence in colors between the memory representation and to-be-detected target. Our results show that memory congruent objects (consisting of a conjunction of features) break CFS faster than memory incongruent objects. Interestingly, we also observe this congruence effect when we presented the memorized object in a horizontally-mirrored configuration of colors. However, we do not observe a faster effect when the target shares only a single feature of a memorized object (semi-congruent) or when the memory congruent target is rotated by 90°. Our results suggest that VWM prioritizes access to visual awareness for complex visual memoranda for which the spatial lay-out of the individual features does not need to exactly match the lay-out of the memoranda.
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http://dx.doi.org/10.1016/j.cognition.2020.104463DOI Listing
January 2021

The association between IL-1 family gene polymorphisms and colorectal cancer: A meta-analysis.

Gene 2021 Feb 28;769:145187. Epub 2020 Sep 28.

Library, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address:

Background: Colorectal cancer (CRC) is a major public health problem given its high incidence and mortality. This study focuses on examining the associations between IL-1α, IL-1β, and IL-1RN polymorphisms and colorectal cancer susceptibility.

Methods: A systematic literature search of PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure) and Wan Fang databases was conducted to identify relevant studies. Relevant data were extracted from the original included studies. The correlation was demonstrated based on the odds ratio (OR) and corresponding 95% confidence intervals (95% CIs). Publication bias was investigated by Egger's line regression test and Begg's funnel plot.

Results: Eighteen independent studies involving 6218 cases and 10160 controls were eligible for this pooled analysis. Overall, the result revealed that the IL-1α rs3783553 polymorphism was significantly associated with an increased risk of CRC (G vs. C, OR = 1.02, 95% CI = 0.90-1.15, I = 51%, P = 0.78; GG vs. CC, OR = 1.97, 95% CI = 1.04-3.74, I = 70%, P = 0.04; GC vs. CC, OR = 1.75, 95% CI = 1.12-2.75, I = 42%, P = 0.01; GG + GC vs. CC, OR = 1.85, 95% CI = 1.08-3.18, I = 63%, P = 0.03; and GG vs. GC + CC, OR = 1.28, 95% CI = 1.04-1.58, I = 39%, P = 0.02), and significance was also noted for IL-1RN VNTR under the dominant model (22 + 2L vs. LL, OR = 1.49, 95% CI = 1.01-2.19, I = 77%, P = 0.045) and allelic contrast model (2 vs. L, OR = 1.28, 95% CI = 1.00-1.64, I = 58.6%, P = 0.047). For IL-1β + 31C/T, significance was observed in the dominant model (CC + CT vs. TT, OR = 0.83, 95% CI = 0.69-0.99, I = 52%, P = 0.034) and the heterozygous model (CT vs. TT, OR = 0.80, 95% CI = 0.65-0.98, I = 60%, P = 0.04). For IL-1β + 511 C/T, a significant association was noted in four gene models (CT vs. TT, OR = 0.72, 95% CI = 0.63-0.83, I = 0%, P < 0.001; CC + CT vs. TT, OR = 0.74, 95% CI = 0.65-0.84, I = 0%, P < 0.001; CC vs. TT, OR = 0.77, 95% CI = 0.65-0.91, I = 30.9%, P = 0.003; C vs. T, OR = 0.87, 95% CI = 0.80-0.95, I = 38%, P = 0.001), but a significant relationship was not found in the recessive model (CC vs. CT + TT, OR = 1.09, 95% CI = 0.86-1.38, I = 57.1%, P = 0.25). In addition, borderline statistical significance was noted between IL-1β + 3954 Ins/Del and CRC in the homozygous model, but no significance was identified for IL-1β + 3737 G/A, Il-1β + 1464 G/C, and IL-1RN + 2018 T/C under all five genetic models. In the subgroup analysis of ethnic groups, significant associations with CRC were found for IL-1β + 31 (CC vs. TT: OR = 0.82, 95% CI = 0.67-0.99, I = 20.2%, P = 0.04; CT vs. TT: OR = 0.62, 95% CI = 0.47-0.82, I = 0%, P < 0.001; CC + CT vs. TT: OR = 0.69, 95% CI = 0.55-0.87, I = 29.7%, P = 0.001), IL-1β + 511 (CT vs. TT, OR = 0.65, 95% CI = 0.55-0.77, I = 0%, P < 0.001; CC + CT vs. TT, OR = 0.67, 95% CI = 0.58-0.78, I = 0%, P < 0.001; C vs. T, OR = 0.83, 95% CI = 0.75-0.92, I = 49.6%, P < 0.001) and IL-1RN + 2018 T/C in the allelic contrast model (T vs. C, OR = 0.66, 95% CI = 0.44-0.98, I = 0%, P = 0.04) among Asians but not in Caucasians. A significant association between IL-1β + 1464 G/C polymorphisms in Caucasians was observed under the recessive model (OR = 0.87, 95% CI = 0.77-0.98, I = 45%, P = 0.03).

Conclusion: The current meta-analysis demonstrated that IL-1α rs3783553, IL-1β + 31C/T, IL-1β + 511C/T, and IL-1RN VNTR are critical genes for CRC susceptibility.
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http://dx.doi.org/10.1016/j.gene.2020.145187DOI Listing
February 2021

Flavonoids ameliorate aluminum chloride-induced learning and memory impairments via suppression of apoptosis and oxidative stress in rats.

J Inorg Biochem 2020 11 13;212:111252. Epub 2020 Sep 13.

Department of Hygiene Detection, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address:

The study was to investigate the effects of flavonoids (rutin, puerarin, and silymarin) on learning and memory function in rats exposed to aluminum chloride (AlCl). Wistar rats were administered flavonoids at a dose of 100 mg/(kg·bw)/day or 200 mg/(kg·bw)/day after exposed to 281.40 mg/(kg·bw)/day AlCl·6HO. The results of Morris water maze suggested that rutin and puerarin increased the frequency of crossing the platform and swimming time spent in the target quadrant of AlCl-induced rats significantly. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay indicated that three flavonoids could alleviate apoptosis of hippocampal neurons induced by AlCl. Real time-PCR and western blot suggested that rutin, puerarin and 100 mg/(kg·bw)/day silymarin could decrease the AlCl-induced high expression of Bcl-2 associated X protein (Bax) mRNA and protein in hippocampus, but the expression of B cell lymphoma/leukemia-2 (Bcl-2) mRNA and protein was not significantly different among groups. Flavonoids could up regulate the low expression of autophagy related proteins (Beclin 1 (Bcl-2-interacting protein with a coiled-coil domain 1) and LC3 (microtubule-associated protein 1 light chain 3)) caused by AlCl exposure. Flavonoids could also adjust the change in adenosine triphosphatase, superoxide dismutase, glutathione peroxidase and malondialdehyde induced by intake of AlCl. The results of inductively coupled plasma atomic emission spectroscopy (ICP-AES) suggested that flavonoids could effectively reduce the high Al level in brain and serum of AlCl exposed rats. In conclusion, three flavonoids may improve learning and memory function by inhibiting excessive apoptosis and oxidative stress in AlCl exposed rats.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111252DOI Listing
November 2020

Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics.

Amino Acids 2020 Sep 18;52(9):1207-1226. Epub 2020 Sep 18.

Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, 92121, USA.

With the development of modern chemistry and biology, non-proteinogenic amino acids (NPAAs) have become a powerful tool for developing peptide-based drug candidates. Drug-like properties of peptidic medicines, due to the smaller size and simpler structure compared to large proteins, can be changed fundamentally by introducing NPAAs in its sequence. While peptides composed of natural amino acids can be used as drug candidates, the majority have shown to be less stable in biological conditions. The impact of NPAA incorporation can be extremely beneficial in improving the stability, potency, permeability, and bioavailability of peptide-based therapies. Conversely, undesired effects such as toxicity or immunogenicity should also be considered. The impact of NPAAs in the development of peptide-based therapeutics is reviewed in this article. Further, numerous examples of peptides containing NPAAs are presented to highlight the ongoing development in peptide-based therapeutics.
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http://dx.doi.org/10.1007/s00726-020-02890-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544725PMC
September 2020

Peptides to combat viral infectious diseases.

Peptides 2020 12 1;134:170402. Epub 2020 Sep 1.

Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, 92121, USA. Electronic address:

Viral infectious diseases have resulted in millions of deaths throughout history and have created a significant public healthcare burden. Tremendous efforts have been placed by the scientific communities, health officials and government organizations to detect, treat, and prevent viral infection. However, the complicated life cycle and rapid genetic mutations of viruses demand continuous development of novel medicines with high efficacy and safety profiles. Peptides provide a promising outlook as a tool to combat the spread and re-emergence of viral infection. This article provides an overview of five viral infectious diseases with high global prevalence: influenza, chronic hepatitis B, acquired immunodeficiency syndrome, severe acute respiratory syndrome, and coronavirus disease 2019. The current and potential peptide-based therapies, vaccines, and diagnostics for each disease are discussed.
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http://dx.doi.org/10.1016/j.peptides.2020.170402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462603PMC
December 2020

Progesterone Attenuates Allodynia of Inflamed Temporomandibular Joint through Modulating Voltage-Gated Sodium Channel 1.7 in Trigeminal Ganglion.

Pain Res Manag 2020 25;2020:6582586. Epub 2020 Jul 25.

Central Laboratory, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China.

Background: Women with temporomandibular disorders (TMDs) experience some amelioration of pain during pregnancy. Progesterone increases dramatically and steadily during pregnancy. Sodium channel 1.7 (Nav1.7) plays a prominent role in pain perceptions, as evidenced by deletion of Nav1.7 alone leading to a complete loss of pain. In a previous study, we showed that Nav1.7 in trigeminal ganglion (TG) is involved in allodynia of inflamed temporomandibular joint (TMJ). Whether progesterone modulates allodynia of inflamed TMJ through Nav1.7 in TG remains to be investigated.

Methods: The effects of progesterone on sodium currents of freshly isolated TG neurons were examined using whole-cell recording. Female rats were ovariectomized and treated with increasing doses of progesterone for 10 days. Complete Freund's adjuvant was administered intra-articularly to induce TMJ inflammation. TMJ nociceptive responses were evaluated by head withdrawal thresholds. Real-time PCR and Western blotting were used to examine Nav1.7 mRNA and protein expression in TG. Immunohistofluorescence was used to examine the colocalization of progesterone receptors (PR/) and Nav1.7 in TG.

Results: Whole-cell recording showed that progesterone could attenuate sodium currents. Moreover, progesterone dose-dependently downregulated Nav1.7 mRNA expression and reduced the sensitivity of TMJ nociception in ovariectomized rats. Furthermore, treatment with progesterone attenuated allodynia of inflamed TMJ in a dose-dependent manner and repressed inflammation-induced Nav1.7 mRNA and protein expression in ovariectomized rats. The progesterone receptor antagonist, RU-486, partially reversed the effect of progesterone on allodynia of inflamed TMJ and TMJ inflammation-induced Nav1.7 mRNA and protein expression.

Conclusion: Progesterone, by modulating trigeminal ganglionic Nav1.7, may represent a promising agent to prevent allodynia of inflamed TMJ.
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http://dx.doi.org/10.1155/2020/6582586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399782PMC
November 2020

E2F1-induced ferritin heavy chain 1 pseudogene 3 (FTH1P3) accelerates non-small cell lung cancer gefitinib resistance.

Biochem Biophys Res Commun 2020 10 3;530(4):624-631. Epub 2020 Aug 3.

Department of Thoracic Surgery, Shengli Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, China. Electronic address:

Long noncoding RNAs (lncRNAs) have been identified to be critical regulator for various human diseases and emerging evidence illustrate the essential function of lncRNAs in the non-small cell lung cancer (NSCLC). Here, our research team tried to identify the roles of lncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) in the NSCLC, as well as its molecular mechanism. LncRNA microarray analysis revealed that ferritin heavy chain 1 pseudogene 3 (FTH1P3) was up-regulated in the gefitinib-resistant cells (PC9/GR). Clinically, lncRNA FTH1P3 high-expression was closely correlated with NSCLC patients' unfavorable prognosis. Gain and loss of functional experiments revealed that FTH1P3 promoted the proliferation and invasion of NSCLC cells in vitro, and FTH1P3 knockdown repressed the tumor growth in vivo. Mechanistically, transcription factor E2F1 accelerated the transcription of FTH1P3. RNA immunoprecipitation and chromatin immunoprecipitation experiments showed that FTH1P3 can recruit lysine-specific demethylase 1 (LSD1) and epigenetically repress the TIMP3, thereby accelerating the tumorigenesis of NSCLC. In summary, these findings suggest that FTH1P3 plays a critical role in the gefitinib resistance and progression of NSCLC, providing a potential novel prognostic marker for NSCLC.
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http://dx.doi.org/10.1016/j.bbrc.2020.07.044DOI Listing
October 2020

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage.

Sci Rep 2020 07 28;10(1):12596. Epub 2020 Jul 28.

Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Beijing, China.

Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acute-on-chronic liver failure (ACLF). Meanwhile, the gp96 level positively correlated with hepatic necroinflammation. We employed two mouse liver damage and liver failure models induced by lipopolysaccharide (LPS) plus D-galactosamine (D-Galn), and concanavalin A (ConA) to identify the function of extracellular gp96. As a result, the inhibition of extracellular gp96 by a specific peptide efficiently mitigated both LPS/D-Galn- and ConA-induced liver injury and immune hyperactivation, whereas exogenous gp96 aggravated the symptoms of hepatic injury in mice but not in Kupffer cells-ablated mice. The exposure of Kupffer cells to gp96 induced the secretion of pro-inflammatory cytokines. Collectively, our data demonstrate that gp96 released from necrotic hepatocytes aggravates immune hyperactivation and promotes liver damage and possibly the development of liver failure mainly by activating Kupffer cells.
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http://dx.doi.org/10.1038/s41598-020-69517-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387550PMC
July 2020

Triggering the Antitumor Activity of Acyclic Enediyne through Maleimide-Assisted Rearrangement and Cycloaromatization.

J Org Chem 2020 08 22;85(15):9808-9819. Epub 2020 Jul 22.

Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

Acyclic enediynes are generally inactive under physiological conditions to be used as antitumor agents like their natural enediyne counterparts. A new mechanism named as maleimide-assisted rearrangement and cycloaromatization (MARACA) is uncovered to trigger the reactivity of acyclic enediynes. Through this mechanism, cascade 1,3-proton transfer processes are accelerated with the maleimide moiety at the ene position to enable the acyclic enediynes to undergo cycloaromatization and generate reactive radicals under physiological conditions. Computational studies suggest that the highest energy barrier for MARACA is 26.0 kcal/mol, much lower than that of Bergman cyclization pathway (39.6 kcal/mol). Experimental results show that maleimide-based enediynes exhibit low onset temperature, fast generation of radical species at 37 °C, and much faster reaction in aqueous solution than in nonpolar solvent, which is beneficial to achieve both high reactivity in physiological environment and high stability for storage and delivery in nonpolar media. The generated radical species are capable of causing high percentage of double-strand (ds) DNA cleavage, leading to significant cytotoxicity toward a panel of cancer cell lines with half inhibition concentration down to submicromolar level. Overall, the discovery of the MARACA mechanism provides a platform for designing novel acyclic enediynes with high potency for antitumor applications.
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http://dx.doi.org/10.1021/acs.joc.0c01124DOI Listing
August 2020

Diet drives convergent evolution of gut microbiomes in bamboo-eating species.

Sci China Life Sci 2021 Jan 29;64(1):88-95. Epub 2020 Jun 29.

CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.

Gut microbiota plays a critical role in host physiology and health. The coevolution between the host and its gut microbes facilitates animal adaptation to its specific ecological niche. Multiple factors such as host diet and phylogeny modulate the structure and function of gut microbiota. However, the relative contribution of each factor in shaping the structure of gut microbiota remains unclear. The giant (Ailuropoda melanoleuca) and red (Ailurus styani) pandas belong to different families of order Carnivora. They have evolved as obligate bamboo-feeders and can be used as a model system for studying the gut microbiome convergent evolution. Here, we compare the structure and function of gut microbiota of the two pandas with their carnivorous relatives using 16S rRNA and metagenome sequencing. We found that both panda species share more similarities in their gut microbiota structure with each other than each species shares with its carnivorous relatives. This indicates that the specialized herbivorous diet rather than host phylogeny is the dominant driver of gut microbiome convergence within Arctoidea. Metagenomic analysis revealed that the symbiotic gut microbiota of both pandas possesses a high level of starch and sucrose metabolism and vitamin B12 biosynthesis. These findings suggest a diet-driven convergence of gut microbiomes and provide new insight into host-microbiota coevolution of these endangered species.
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http://dx.doi.org/10.1007/s11427-020-1750-7DOI Listing
January 2021

Gadolinium complexes of macrocyclic diethylenetriamine-N-oxide pentaacetic acid-bisamide as highly stable MRI contrast agents with high relaxivity.

Dalton Trans 2020 Jul;49(26):8927-8932

Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China.

Gadolinium(iii) complexes are generally considered efficient magnetic resonance imaging (MRI) contrast agents (CAs) and widely used in clinical applications. High relaxivity and stability are two essential criteria for a Gd(iii)-complex to be used as a MRI-CA. One crucial strategy to achieve high relaxivity for small molecular Gd(iii)-based MRI contrast agents is to increase the hydration number q. Meanwhile, metal complexes with macrocyclic ligands have been proved to inherit high thermodynamic stability and kinetic inertness. Herein, a series of macrocyclic ligands based on diethylenetriamine-N-oxide pentaacetic acid-bisamide were synthesized. Among them, cyclo-DTPA-NO-C6O2 (3d) was the strongest ligand for Gd(iii) as confirmed by experimental results. The hydration number of the Gd-cyclo-DTPA-NO-C6O2 (4d) complex was characterized by luminescence measurements to be 3 and the coordination structure was confirmed with computational simulations. Consequently, the relaxivity of this complex (14.3 mM-1 s-1, 1.5 T, 25 °C) is about triple that of commercial MRI CAs. The conditional stability constant of the Gd(iii) complex, pGd, calculated from spectrophotometric titration studies, was comparable to that of one of the most stable commercial MRI-CAs, Gd-DTPA (Magnevist®). Meanwhile, the kinetic inertness of the complex was even higher than that of Gd-DTPA thanks to its macrocyclic coordination structure.
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http://dx.doi.org/10.1039/d0dt00248hDOI Listing
July 2020

Flash nanoprecipitation with Gd(III)-based metallosurfactants to fabricate polylactic acid nanoparticles as highly efficient contrast agents for magnetic resonance imaging.

Chem Asian J 2020 Aug 3;15(16):2475-2479. Epub 2020 Jul 3.

Shanghai Key Laboratory of Advanced Polymeric Materials School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China.

Polylactic acid (PLA) nanoparticles coated with Gd(III)-based metallosurfactants (MS) are prepared using a simple and rapid one-step method, flash nanoprecipitation (FNP), for magnetic resonance imaging (MRI) applications. By co-assembling the Gd(III)-based MS and an amphiphilic polymer, methoxy poly(ethylene glycol)-b-poly(ϵ-caprolactone) (mPEG-b-PCL), PLA cores were rapidly encapsulated to form biocompatible T contrast agents with tunable particle size and narrow size distribution. The hydrophobic property of Gd(III)-based MS were finely tuned to achieve their high loading efficiency. The size of the nanoparticles was easily controlled by tuning the stream velocity, Reynolds number and the amount of the amphiphilic block copolymer during the FNP process. Under the optimized condition, the relaxivity of the nanoparticles was achieved up to 35.39 mM  s (at 1.5 T), which is over 8 times of clinically used MRI contrast agents, demonstrating the potential application for MR imaging.
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http://dx.doi.org/10.1002/asia.202000624DOI Listing
August 2020

Saccades reset the priority of visual information to access awareness.

Vision Res 2020 08 18;173:1-6. Epub 2020 May 18.

Department of Experimental Psychology, Utrecht University, Utrecht, the Netherlands.

Subjectively, we experience a stable representation of the outside world across saccades. Although previous studies have reported that presaccadically acquired visual information influences postsaccadic perception, whether such information's priority to access visual awareness is either reset by each saccade or continuous across saccades remains unclear. To investigate this issue, we combined a breaking continuous flash suppression (b-CFS) with a saccade task. Before each saccade, a grating was presented in the peripheral visual field under suppression. After the saccade, the same grating was again presented under suppression at either the retinotopically matched, the spatiotopically matched, or a control location. By measuring the duration of the grating to break through CFS into awareness after a saccade, we could compare the breakthrough times across stimuli presented at the different locations. No difference in the reaction times between the spatiotopic and control location was observed, indicating that a saccade resets the buildup of an object's priority to access visual awareness. However, a longer breakthrough time was observed for the retinotopic as compared to the control location, suggesting that a form of retinotopic adaptation to the grating suppressed the priority to access visual awareness after a saccade.
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http://dx.doi.org/10.1016/j.visres.2020.04.010DOI Listing
August 2020

Application of Optical Laser 3D Surface imaging system (Sentinel) in breast cancer radiotherapy.

Sci Rep 2020 05 5;10(1):7550. Epub 2020 May 5.

Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, People's Republic of China.

It has been clearly confirmed that radiation therapy (RT) after breast conserving surgery (BCS) is an effective treatment modality comparable to mastectomy for early breast cancer. The purpose of this study was to further evaluate the accuracy of 3D surface imaging system (Sentinel) for breast cancer patients received BCS. The optical surface scans and CBCT scans were acquired before and immediately after couch movement correction. The deviation of the CBCT scans from the reference planning CT was considered an estimate for the residual errors for patient setup correction. The planning target volume (PTV) margins for treatment sessions was calculated according to the setup errors. We obtained a total of 245 sets of data collected from 49 breast cancer patients. Compared with Sentinel setup errors, the residual setup errors as determined by the CBCT scans after couch movement correction were reduced in the six directions. The PTV margins derived from the CBCT residual errors were all less than 5 mm in X, Y, and Z directions. Our results suggested that Optical surface imaging can be applied in positioning for breast cancer patient accurately without unnecessary imaging dose.
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http://dx.doi.org/10.1038/s41598-020-64496-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200723PMC
May 2020

Corrigendum to "The effect of maternal obesity on the expression and functionality of placental P-glycoprotein: Implications in the individualized transplacental digoxin treatment for fetal heart failure" [Placenta 36 (2015) 1138-1147].

Placenta 2020 02 28;91:66. Epub 2020 Jan 28.

Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address:

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http://dx.doi.org/10.1016/j.placenta.2020.01.011DOI Listing
February 2020

Hemp-based all-cellulose composites through ionic liquid promoted controllable dissolution and structural control.

Carbohydr Polym 2020 May 17;235:116027. Epub 2020 Feb 17.

College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, 100029 Beijing, China. Electronic address:

All-cellulose composites (ACC) were effectively prepared by a low energy consumption strategy. The ionic liquid of 1-butyl-3-methylimidazolium chloride (BMIMCl) was used to immerse hemp fabric before hot-pressing process at a relative low temperature. The tensile strength and modulus of prepared ACC reached 81.1 MPa and 1.50 GPa, respectively. The dissolution mechanism of ACC by BMIMCl was successfully observed by the cooperation of optical microscope and polarizing microscope. Scanning electron microscope (SEM), X-ray diffraction (XRD), thermal gravimetric analysis (TGA) and mechanical testing were carried out to investigate the effect of hot-pressing temperature on the properties of ACC samples. ACC sample exhibited the highest mechanical performance at hot-pressing temperature of 120 °C. This work provided a simple and promising pathway for industrial application of high performance and environmental-friendly all-cellulose composites.
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http://dx.doi.org/10.1016/j.carbpol.2020.116027DOI Listing
May 2020

Facilitating Myers-Saito cyclization through acid-triggered tautomerization for the development of maleimide-based antitumor agents.

J Mater Chem B 2020 03;8(9):1971-1979

Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

Enyne-allene compounds undergo Myers-Saito cyclization at physiological temperature to generate diradical intermediates that are capable of inducing DNA damage and cell death. The high reactivity of enyne-allene however limits their promising prospect as anticancer agents due to the spontaneous cyclization during storage and delivery. Regulating the cyclization process by taking advantage of the characteristics of a tumor cellular microenvironment, such as employing a low pH value to activate the cyclization process, is thus of essential importance. In this work, a novel enediyne (EDY) system with locked carbonyl groups was specifically designed and synthesized. Unlocking the protected carbonyl groups in the presence of acid would facilitate the rearrangement of propargyl moieties into an allene group, enabling the formation of an enyne-allene structure and occurrence of Myers-Saito cyclization. The pH-dependent diradical generation and DNA-cleavage ability of the designed EDY system were confirmed by electron paramagnetic resonance analysis and DNA gel electrophoresis. A promising cytotoxicity against HeLa cells with half inhibition concentrations (IC50) as low as 1.40 μM was obtained, which was comparable to those of many commercially applied anticancer drugs. Further in vitro experiments revealed that this EDY system induced intracellular DNA damage and subsequently resulted in S-phase arrest and cytotoxicity through programmed apoptosis.
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http://dx.doi.org/10.1039/c9tb02589hDOI Listing
March 2020

Microstructure and Fracture Behavior of Special Multilayered Steel.

Materials (Basel) 2020 Feb 9;13(3). Epub 2020 Feb 9.

State Key Laboratory of Advanced Processing and Recycling of Non-ferrous Metal, Department of Materials Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China.

In this research, multilayered steel (MLS), which is composed of middle-carbon martensite steel, high-carbon martensite steel, and a pure Ni thin layer was obtained by the accumulative roll-bonding method. The microstructure and mechanical properties of the MLS were investigated by scanning electron microscopy (SEM), Vickers microhardness, tensile, and bending tests. In-situ SEM tensile tests were used to observe the crack initiation and propagation processes during the tensile loading. The results show that the ultimate tensile strength and bending strength of the MLS can reach 946 MPa and 3153 MPa, and the maximum elongation can reach 18%, which is related to the better combined quality of the interface. The middle and larger martensite layer (ML) becomes the weakest link of tensile fracture and interfacial delamination of the MLS during the tensile processes, because there are lots of large hard blocks CrC phases distributed in the middle thicker ML layer. Besides, the MLS can withstand larger bending deformation. When the MLS was bent to 180 degrees, neither macro-cracks in the outer side of the bending parts nor interfacial delamination can be found.
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http://dx.doi.org/10.3390/ma13030789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040671PMC
February 2020

Mechanical and Thermal Properties of All-Wood Biocomposites through Controllable Dissolution of Cellulose with Ionic Liquid.

Polymers (Basel) 2020 Feb 6;12(2). Epub 2020 Feb 6.

School of Civil and Environmental Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia.

All-wood biocomposites were prepared with an efficient method. The ionic liquid of 1-butyl-3-methylimidazolium chloride (BMIMCl) was used to impregnate manchurian ash (MA) before hot-pressing, and the all-wood biocomposites were prepared by controllable dissolving and regenerating the cellulose in MA. The Fourier transform infrared analysis suggested that all the components of MA remained unchanged during the preparation. X-ray diffraction, thermogravimetric and scanning electron microscope analysis were carried out to study the process parameters of hot-pressing pressure and time on the crystallinity, thermal properties and microstructure of the all-wood biocomposites. The tensile strength of the prepared all-wood biocomposites reached its highest at 212.6 MPa and was increased by 239% compared with that of the original MA sample. The thermogravimetric analysis indicated that as the thermo-stability of the all-wood biocomposites increased, the mass of the residual carbon increased from 19.7% to 22.7% under a hot-pressing pressure of 10 MPa. This work provides a simple and promising pathway for the industrial application of high-performance and environmentally friendly all-wood biocomposites.
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http://dx.doi.org/10.3390/polym12020361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077382PMC
February 2020