Publications by authors named "Shuo Huang"

222 Publications

Tailoring morphologies of mesoporous polydopamine nanoparticles to deliver high-loading radioiodine for anaplastic thyroid carcinoma imaging and therapy.

Nanoscale 2021 Sep 17;13(35):15021-15030. Epub 2021 Sep 17.

Department of Nuclear Medicine, Xin Hua Hospital Affiliated To Shanghai Jiao Tong University School, 1665 Kongjiang Road, Shanghai 200092, China.

Anaplastic thyroid carcinoma (ATC), as one of the most aggressive human malignancies, cannot be cured by iodine (I) internal radiotherapy (RT) because the tumor cells cannot effectively take up I and are resistant to radiotherapy. In this study, a facile and simple method was proposed to synthesize mesoporous polydopamine nanoparticles (MPDA) and tailor their morphologies by component-adjusting Pluronic micelle-guided polymerization. Then, MPDA were used not only as nanocarriers to radiolabel I, but also as photothermal conversion agents for photothermal therapy (PTT) to promote RT. The iodine-labeling capacity and photothermal conversion efficiency of MPDA can be enhanced by optimizing their morphologies. It was found that MPDA NPs with a cerebroid pore channel structure (CPDA) showed the highest iodine-carrying capacity and a higher photothermal conversion efficiency as a result of their maximum specific surface area and unique morphology. In subsequent experiments and , our ATC animal models showed impressive therapeutic responses to CPDA-I NPs because of the synergistic effect of PTT and RT. Additionally, CPDA-I NPs can be utilized to obtain high-quality SPETC/CT images of tumors, which can guide clinical therapy for ATC. Considering their great biosafety, these radioiodine-labeled CPDA NPs may serve as a promising tool in combined therapy and diagnosis in ATC.
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http://dx.doi.org/10.1039/d1nr02892hDOI Listing
September 2021

Allosteric Switching of Calmodulin in a Mycobacterium smegmatis porin A (MspA) Nanopore-Trap.

Angew Chem Int Ed Engl 2021 Aug 27. Epub 2021 Aug 27.

Nanjing University, Chemistry, 163 Xianlin Ave, School of Chemistry and Chemical Engineering, Xixia District, 210023, Nanjing, CHINA.

Recent developments concerning large protein nanopores suggest a new approach to structure profiling of native folded proteins. In this work, the large vestibule of Mycobacterium smegmatis porin A (MspA) and calmodulin (CaM), a Ca2+-binding protein were used in the direct observation of the protein structure. Three conformers including the Ca2+-free, Ca2+-bound and target peptide-bound states of CaM were unambiguously distinguished. A disease related mutant, CaM D129G was also discriminated by MspA, revealing how a single amino acid replacement can interfere with the Ca2+ binding capacity of the whole protein. The binding capacity and aggregation effect of CaM induced by different ions (Mg2+/Sr2+/Ba2+/Ca2+/Pb2+/Tb3+) were also investigated and the stability of MspA in extreme conditions was evaluated. This work demonstrates the most systematic single molecule investigation of different allosteric conformers of CaM, acknowledging the high sensing resolution offered by the MspA nanopore trap.
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http://dx.doi.org/10.1002/anie.202110545DOI Listing
August 2021

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs.

Bone Res 2021 Aug 16;9(1):37. Epub 2021 Aug 16.

Department of Spine Surgery, Center of Orthopedics, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

A comprehensive understanding of the cellular heterogeneity and molecular mechanisms underlying the development, homeostasis, and disease of human intervertebral disks (IVDs) remains challenging. Here, the transcriptomic landscape of 108 108 IVD cells was mapped using single-cell RNA sequencing of three main compartments from young and adult healthy IVDs, including the nucleus pulposus (NP), annulus fibrosus, and cartilage endplate (CEP). The chondrocyte subclusters were classified based on their potential regulatory, homeostatic, and effector functions in extracellular matrix (ECM) homeostasis. Notably, in the NP, a PROCR resident progenitor population showed enriched colony-forming unit-fibroblast (CFU-F) activity and trilineage differentiation capacity. Finally, intercellular crosstalk based on signaling network analysis uncovered that the PDGF and TGF-β cascades are important cues in the NP microenvironment. In conclusion, a single-cell transcriptomic atlas that resolves spatially regulated cellular heterogeneity together with the critical signaling that underlies homeostasis will help to establish new therapeutic strategies for IVD degeneration in the clinic.
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http://dx.doi.org/10.1038/s41413-021-00163-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368097PMC
August 2021

Rapid and multiplex preparation of engineered porin A (MspA) nanopores for single molecule sensing and sequencing.

Chem Sci 2021 Jul 8;12(27):9339-9346. Epub 2021 Jun 8.

State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University 210023 Nanjing China

Acknowledging its unique conical lumen structure, porin A (MspA) was the first type of nanopore that has successfully sequenced DNA. Recent developments of nanopore single molecule chemistry have also suggested MspA to be an optimum single molecule reactor. However, further investigations with this approach require heavy mutagenesis which is labor intensive and requires high end instruments for purifications. We here demonstrate an efficient and economic protocol which performs rapid and multiplex preparation of a variety of MspA mutants. The prepared MspA mutants were demonstrated in operations such as nanopore insertion, sequencing, optical single channel recording (oSCR), nanopore single molecule chemistry and nanopore rectification. The performance is no different from that of pores however prepared by other means. The time of all human operations and the cost for a single batch of preparation have been minimized to 40 min and 0.4$, respectively. This method is extremely useful in the screening of new MspA mutants, which has an urgent requirement in further investigations of new MspA nanoreactors. Its low cost and simplicity also enable efficient preparations of MspA nanopores for both industrial manufacturing and academic research.
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http://dx.doi.org/10.1039/d1sc01399hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278974PMC
July 2021

Single Molecule Ratcheting Motion of Peptides in a Porin A (MspA) Nanopore.

Nano Lett 2021 08 28;21(15):6703-6710. Epub 2021 Jul 28.

State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

Diverse functions of proteins, including synthesis, catalysis, and signaling, result from their highly variable amino acid sequences. The technology allowing for direct analysis of protein sequences, however, is still unsatisfactory. Recent developments of nanopore sequencing of DNA or RNA have motivated attempts to realize nanopore sequencing of peptides in a similar manner. The core challenge has been to achieve a controlled ratcheting motion of the target peptide, which is currently restricted to a limited choice of compatible enzymes. By constructing peptide-oligonucleotide conjugates (POCs) and measurements with nanopore-induced phase-shift sequencing (NIPSS), direct observation of the ratcheting motion of peptides has been successfully achieved. The generated events show a clear sequence dependence on the peptide that is being tested. The method is compatible with peptides with either a conjugated N- or C-terminus. The demonstrated results suggest a proof of concept of nanopore sequencing of peptide and can be useful for peptide fingerprinting.
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http://dx.doi.org/10.1021/acs.nanolett.1c02371DOI Listing
August 2021

Nanopore Sequencing Accurately Identifies the Cisplatin Adduct on DNA.

ACS Sens 2021 08 28;6(8):3082-3092. Epub 2021 Jul 28.

State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, 210023 Nanjing, China.

Cisplatin, which selectively binds to N atoms of purines to inhibit normal replication and transcription, is a widely applied chemotherapeutic drug in the treatment of cancer. Though direct identification of cisplatin lesions on DNA is of great significance, existing sequencing methods have issues such as complications of preamplification or enrichment-induced false-positive reports. Direct identification of cisplatin lesions by nanopore sequencing (NPS) is in principle feasible. However, relevant investigations have never been reported. By constructing model sequences (83 nucleotides in length) containing a sole cisplatin lesion, identification of corresponding lesions by NPS is achieved with <10 ng of input sequencing library. Moreover, characteristic high-frequency noises caused by cisplatin lesions are consistently observed during NPS, clearly identifiable in corresponding high-pass filtered traces. This feature is, however, never observed in any other combinations of natural DNA bases and could be taken as a reference to identify cisplatin lesions on DNA. Further investigations demonstrate that cisplatin stalls the replication of phi29 DNA polymerase, which appears as a ∼5 pA level fluctuation in the single-molecule resolution. These results have confirmed the feasibility of NPS to identify cisplatin lesions at the genomic level and may provide new insights into understanding the molecular mechanism of platinum-based drugs.
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http://dx.doi.org/10.1021/acssensors.1c01212DOI Listing
August 2021

Corrigendum: A Novel Antioxidant Protects Against Contrast Medium-Induced Acute Kidney Injury in Rats.

Front Pharmacol 2021 9;12:724416. Epub 2021 Jul 9.

Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China.

[This corrects the article DOI: 10.3389/fphar.2020.599577.].
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http://dx.doi.org/10.3389/fphar.2021.724416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299940PMC
July 2021

Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway.

Nat Commun 2021 07 19;12(1):4391. Epub 2021 Jul 19.

Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.

Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2 cells promote acquired HO development. Lineage tracing studies reveal that Col2 cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1 LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2 lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis.
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http://dx.doi.org/10.1038/s41467-021-24643-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289847PMC
July 2021

Serratus anterior plane block reduces the prevalence of chronic postsurgical pain after modified radical mastectomy: A randomized controlled trial.

J Clin Anesth 2021 Jun 24;74:110410. Epub 2021 Jun 24.

Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China. Electronic address:

Study Objective: To determine whether ultrasound-guided serratus anterior plane block (SAPB) is associated with decreased prevalence of chronic postsurgical pain (CPSP) after modified radical mastectomy.

Design: Randomized, double-blind, placebo-controlled study.

Setting: University hospital.

Patients: We enrolled 198 patients aged 18-65 years with American Society of Anesthesiologists physical status I to II, undergoing unilateral modified radical mastectomy.

Interventions: Patients were randomly allocated to receive SAPB with 30 ml of 0.5% ropivacaine (SAPB group) or 0.9% normal saline (Control group).

Measurements: The primary outcome was the prevalence of CPSP three months after surgery. Secondary outcomes were area under the curve of the numeric rating scale pain scores over 24 h, postoperative 24-h morphine consumption, quality of recovery, length of post-anesthesia care unit stay, postoperative nausea and vomiting, dizziness, SAPB-related adverse events, the prevalence of CPSP at six months, and pain-related function at three and six months.

Main Results: Preoperative SAPB with 0.5% ropivacaine reduced the prevalence of CPSP at three postoperative months from 46/89 (51.7%) to 22/90 (25.6%), relative risk (95% confidence interval): 0.47 (0.31-0.72), P < 0.001. The prevalence of CPSP was reduced at six months from 37/89 (41.6%) to 17/90 (18.9%), relative risk (95% confidence interval): 0.72 (0.58-0.88), P = 0.001. Moreover, SAPB decreased the area under the curve of the numeric rating scale pain scores over 24 h, shortened the length of post-anesthesia care unit stay, reduced postoperative 24-h morphine consumption and the occurrence of postoperative nausea and vomiting, and improved quality of recovery and patient satisfaction, with P < 0.05 for all. No SAPB-related complications occurred.

Conclusions: Preoperative SAPB with ropivacaine improved acute postoperative analgesia and quality of recovery and decreased the prevalence of CPSP at three and six months after modified radical mastectomy.
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http://dx.doi.org/10.1016/j.jclinane.2021.110410DOI Listing
June 2021

How to do a modified vascular malformation suture for multiple intestinal lesions in blue rubber bleb nevus syndrome without bowel resection.

ANZ J Surg 2021 Jun 14. Epub 2021 Jun 14.

Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.

Intestinal resection surgery for multiple intestinal vascular malformations in the blue rubber bleb nevus syndrome is traumatic and time-consuming. This study and Video S1 introduce a novel vascular malformation suture method to manage this problem without bowel resection.
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http://dx.doi.org/10.1111/ans.17009DOI Listing
June 2021

Mapping Potential Engineering Sites of porin A (MspA) to Form a Nanoreactor.

ACS Sens 2021 06 9;6(6):2449-2456. Epub 2021 Jun 9.

State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

Protein nanopores can be engineered as nanoreactors to investigate single-molecule chemical reactions. Recent studies have demonstrated that porin A (MspA) nanopore is a superior engineering template acknowledging its geometrical advantages. However, reported engineering of MspA to form a nanoreactor has focused only on site 91 and mapping of other engineering sites have never been performed before. By taking tetrachloraurate(III) ([AuCl]) as a model reactant, potential engineering sites within the pore constriction of MspA have been thoroughly investigated. It is discovered that the produced event amplitude is inversely correlated to the cross-sectional diameter of the pore constriction size at the engineering site, providing evidence that site 91 is actually already the optimum place to introduce the chemical reactivity. Other unavailable engineering sites, which either significantly interfere with the pore assembly or produce reactive sites facing to the pore's exterior instead of to the pore lumen, were also spotted and discussed. All results demonstrated above have provided a complete map of engineering sites within the constriction area of MspA and may be beneficial as a reference in future engineering of corresponding nanoreactors.
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http://dx.doi.org/10.1021/acssensors.1c00792DOI Listing
June 2021

Structural-profiling of low molecular weight RNAs by nanopore trapping/translocation using Mycobacterium smegmatis porin A.

Nat Commun 2021 06 7;12(1):3368. Epub 2021 Jun 7.

State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.

Folding of RNA can produce elaborate tertiary structures, corresponding to their diverse roles in the regulation of biological activities. Direct observation of RNA structures at high resolution in their native form however remains a challenge. The large vestibule and the narrow constriction of a Mycobacterium smegmatis porin A (MspA) suggests a sensing mode called nanopore trapping/translocation, which clearly distinguishes between microRNA, small interfering RNA (siRNA), transfer RNA (tRNA) and 5 S ribosomal RNA (rRNA). To further profit from the acquired event characteristics, a custom machine learning algorithm is developed. Events from measurements with a mixture of RNA analytes can be automatically classified, reporting a general accuracy of ~93.4%. tRNAs, which possess a unique tertiary structure, report a highly distinguishable sensing feature, different from all other RNA types tested in this study. With this strategy, tRNAs from different sources are measured and a high structural conservation across different species is observed in single molecule.
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http://dx.doi.org/10.1038/s41467-021-23764-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185011PMC
June 2021

Intrauterine insemination (IUI) with or without letrozole for unexplained or mild male factor infertility: A randomized pilot study.

Eur J Obstet Gynecol Reprod Biol 2021 Jul 15;262:216-220. Epub 2021 May 15.

Department of Obstetrics and Gynaecology, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.

Objective: To study the feasibility of a randomized controlled trial (RCT) comparing intrauterine insemination (IUI) with and without letrozole in couples with unexplained or mild male factor infertility STUDY DESIGN: We performed a randomized pilot study including 100 couples with unexplained or mild male factor infertility in the Reproductive Medicine Centre of Peking University Third Hospital in China. The couples scheduled for IUI were randomized to IUI with or without ovarian stimulation (letrozole) for up to 3 cycles within a time horizon of 4 months. Women in the letrozole group received 5 mg oral letrozole daily starting from cycle day 3-5 for 5 days. Women in the natural cycle IUI group did not receive any ovarian stimulation before IUI. The primary outcome is ongoing pregnancy leading to live birth. The study was registered under trial number NCT03455426 RESULTS: Between March 2018 and January 2019, 158 couples were eligible to participate after initial screening and 100 (63.3 %) couples agreed to participate. Of the 100 recruited couples, 50 were randomly allocated to IUI with letrozole and 50 to natural cycle IUI. Live birth occurred in 12 women (24.0 %) in the letrozole group and 10 women (20.0 %) in the natural cycle group (RR 1.20 (95 % CI 0.57-2.52)). Clinical pregnancy rates were 28 % and 26 % in the letrozole group and natural cycle group respectively (RR 1.08 (95 % CI 0.56-2.05). There were no multiple pregnancies in both groups. Patients were willing to be randomized and useful information was gained to plan a definitive trial.

Conclusions: We showed that an RCT comparing IUI with letrozole versus natural cycle IUI in couples with unexplained or mild male factor infertility is feasible and acceptable.
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http://dx.doi.org/10.1016/j.ejogrb.2021.05.029DOI Listing
July 2021

Post-translational flavinylation is associated with diverse extracytosolic redox functionalities throughout bacterial life.

Elife 2021 May 25;10. Epub 2021 May 25.

Duchossois Family Institute, University of Chicago, Chicago, United States.

Disparate redox activities that take place beyond the bounds of the prokaryotic cell cytosol must connect to membrane or cytosolic electron pools. Proteins post-translationally flavinylated by the enzyme ApbE mediate electron transfer in several characterized extracytosolic redox systems but the breadth of functions of this modification remains unknown. Here, we present a comprehensive bioinformatic analysis of 31,910 prokaryotic genomes that provides evidence of extracytosolic ApbEs within ~50% of bacteria and the involvement of flavinylation in numerous uncharacterized biochemical processes. By mining flavinylation-associated gene clusters, we identify five protein classes responsible for transmembrane electron transfer and two domains of unknown function (DUF2271 and DUF3570) that are flavinylated by ApbE. We observe flavinylation/iron transporter gene colocalization patterns that implicate functions in iron reduction and assimilation. We find associations with characterized and uncharacterized respiratory oxidoreductases that highlight roles of flavinylation in respiratory electron transport chains. Finally, we identify interspecies gene cluster variability consistent with flavinylation/cytochrome functional redundancies and discover a class of 'multi-flavinylated proteins' that may resemble multi-heme cytochromes in facilitating longer distance electron transfer. These findings provide mechanistic insight into an important facet of bacterial physiology and establish flavinylation as a functionally diverse mediator of extracytosolic electron transfer.
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http://dx.doi.org/10.7554/eLife.66878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238504PMC
May 2021

Retinal glial remodeling by FGF21 preserves retinal function during photoreceptor degeneration.

iScience 2021 Apr 29;24(4):102376. Epub 2021 Mar 29.

Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

The group of retinal degenerations, retinitis pigmentosa (RP), comprises more than 150 genetic abnormalities affecting photoreceptors. Finding degenerative pathways common to all genetic abnormalities may allow general treatment such as neuroprotection. Neuroprotection may include enhancing the function of cells that directly support photoreceptors, retinal pigment epithelial cells, and Müller glia. Treatment with fibroblast growth factor 21 (FGF21), a neuroprotectant, from postnatal week 4-10, during rod and cone loss in P23H mice (an RP model) with retinal degeneration, preserved photoreceptor function and normalized Müller glial cell morphology. Single-cell transcriptomics of retinal cells showed that FGF21 receptor was specifically expressed in Müller glia/astrocytes. Of all retinal cells, FGF21 predominantly affected genes in Müller glia/astrocytes with increased expression of axon development and synapse formation pathway genes. Therefore, enhancing retinal glial axon and synapse formation with neurons may preserve retinal function in RP and may suggest a general therapeutic approach for retinal degenerative diseases.
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http://dx.doi.org/10.1016/j.isci.2021.102376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079476PMC
April 2021

Realization of nitrite accumulation in a sulfide-driven autotrophic denitrification process: Simultaneous nitrate and sulfur removal.

Chemosphere 2021 Sep 29;278:130413. Epub 2021 Mar 29.

School of Environmental Science and Engineering, Qingdao University, Qingdao, 266071, PR China.

The study was based on the removal of nitrate and sulfide, and aimed to nitrite accumulation. The process of autotrophic denitrification driven by sulfide as an electron donor was investigated in a sequencing batch reactor. The research showed that autotrophic denitrification successfully started on day 22, and the removal rates of NO-N and S-S were 95.8% and 100%, respectively, when the S/N molar ratio was 1.45. When the S/N ratio was reduced to 0.94, the phenomenon of NO-N accumulation was observed. NO-N continuously accumulated, and the maximum accumulation rate was 55.3% when the S/N ratio was 0.8. In the batch test, the study showed that NO-N accumulation was optimal when the S/N ratio was 0.8, and the NO-N concentration increased with increasing NO-N concentration at the same S/N ratio. Microbial communities also changed based on the high-throughput analysis, and Proteobacteria (59.5%-84%) was the main phylum. Arenimonas (11.4%-28.2%) and uncultured_f_ Chromatiaceae (5.7%-27.5%) were the dominant bacteria, which complete denitrification and desulfurization throughout the operating system. Therefore, this study provided a theoretical basis for the simultaneous removal of NO-N and S-S, as well as the accumulation of nitrite, and provided material support for anaerobic ammonia oxidation technology.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130413DOI Listing
September 2021

Biomechanical evaluation of a customized 3D-printed polyetheretherketone condylar prosthesis.

Exp Ther Med 2021 Apr 11;21(4):348. Epub 2021 Feb 11.

Department of Oral and Maxillofacial Surgery, School of Stomatology, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China.

The present study aimed to evaluate the biomechanical behavior of a custom 3D-printed polyetheretherketone (PEEK) condylar prosthesis using finite element analysis and mechanical testing. The Mimics software was used to create a 3D model of the mandible, which was then imported into Geomagic Studio software to perform osteotomy of the lesion area. A customized PEEK condyle prosthesis was then designed and the finite element model of the PEEK condyle prosthesis, mandible and fixation screw was established. The maximum stress of the prosthesis and screws, as well as stress and strain of the cortical and cancellous bones in the intercuspal position, incisal clench, left unilateral molar clench and right unilateral molar clench was analyzed. The biomechanical properties of the prosthesis were studied using two models with different lesion ranges. To simulate the actual clinical situation, a special fixture was designed. The compression performance was tested at 1 mm/min for the condyle prosthesis, prepared by fused deposition modeling (FDM). The results of a finite element analysis suggested that the maximum stress of the condyle was 10.733 MPa and the maximum stress of the screw was 9.7075 MPa; both were far less than the yield strength of the material. The maximum force that the two designed prostheses were able to withstand was 3,814.7±442.6 N (Model A) and 4,245.7±348.3 N (Model B). Overall, the customized PEEK condyle prostheses prepared by FDM exhibited a uniform stress distribution and good mechanical properties, providing a theoretical basis for PEEK as a reconstruction material for repairing the temporomandibular joint.
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http://dx.doi.org/10.3892/etm.2021.9779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903381PMC
April 2021

Refined mapping of stripe rust resistance gene YrP10090 within a desirable haplotype for wheat improvement on chromosome 6A.

Theor Appl Genet 2021 Jul 8;134(7):2005-2021. Epub 2021 Mar 8.

State Key Laboratory of Crop Stress Biology for Arid Areas, College of Agronomy, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China.

Key Message: A large genomic region spanning over 300 Mb on chromosome 6A under intense artificial selection harbors multiple loci associated with favorable traits including stripe rust resistance in wheat. The development of resistance cultivars can be an optimal strategy for controlling wheat stripe rust disease. Although loci for stripe rust resistance have been identified on chromosome 6A in previous studies, it is unclear whether these loci span a common genetic interval, and few studies have attempted to analyze the haplotype changes that have accompanied wheat improvement over the period of modern breeding. In this study, we used F families and F recombinant inbred lines (RILs) derived from a cross between a resistant CIMMYT wheat accession P10090 and the susceptible landrace Mingxian 169 to improve the resolution of the QTL on chromosome 6A. The co-located QTL, designated as YrP10090, was flanked by SNP markers AX-94460938 and AX-110585473 with a genetic interval of 3.5 cM, however, corresponding to a large physical distance of over 300 Mb in RefSeq v.1.0 (positions 107.1-446.5 Mb). More than 1,300 SNP markers in this genetic region were extracted for haplotype analysis in a panel of 1,461 worldwide common wheat accessions, and three major haplotypes (Hap1, Hap2, and Hap3) were identified. The favorable haplotype Hap1 associated with stripe rust resistance exhibited a large degree of linkage disequilibrium. Selective sweep analyses were performed between different haplotype groups, revealing specific genomic regions with strong artificial selection signals. These regions harbored multiple desirable traits associated with resilience to environmental stress, different yield components, and quality characteristics. P10090 and its derivatives that carry the desirable haplotype can provide a concrete foundation for bread wheat improvement including the genomic selection.
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http://dx.doi.org/10.1007/s00122-021-03801-6DOI Listing
July 2021

Clinical Potential of Extracellular Vesicles in Type 2 Diabetes.

Front Endocrinol (Lausanne) 2020 21;11:596811. Epub 2021 Jan 21.

Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, The First Hospital of Jilin University, Changchun, China.

Type 2 diabetes (T2D) is a major public health disease which is increased in incidence and prevalence throughout the whole world. Insulin resistance (IR) in peripheral tissues and insufficient pancreatic β-cell mass and function have been recognized as primary mechanisms in the pathogenesis of T2D, while recently, systemic chronic inflammation resulting from obesity and a sedentary lifestyle has also gained considerable attention in T2D progression. Nowadays, accumulating evidence has revealed extracellular vesicles (EVs) as critical mediators promoting the pathogenesis of T2D. They can also be used in the diagnosis and treatment of T2D and its complications. In this review, we briefly introduce the basic concepts of EVs and their potential roles in the pathogenesis of T2D. Then, we discuss their diagnostic and therapeutic potentials in T2D and its complications, hoping to open new prospects for the management of T2D.
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http://dx.doi.org/10.3389/fendo.2020.596811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859486PMC
June 2021

Emodin Inhibits the Proliferation of MCF-7 Human Breast Cancer Cells Through Activation of Aryl Hydrocarbon Receptor (AhR).

Front Pharmacol 2020 19;11:622046. Epub 2021 Jan 19.

Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China.

Natural products have proved to be a promising source for the development of potential anticancer drugs. Emodin, a natural compound from , is used to treat several types of cancers, including lung, liver, and pancreatic. However, there are few reports regarding its use in the treatment of breast cancer. Thus, the therapeutic effect and mechanism of emodin on MCF-7 human breast cancer cells were investigated in this study. Morphological observations and cell viability were evaluated to determine the anti-proliferation activity of emodin. Network pharmacology and molecular docking were performed to screen the potential targets. Western blot analysis was used to explore a potential antitumor mechanism. The results showed that emodin (50-100 μmol/L) could significantly inhibit the proliferation of MCF-7 cells in a time and dose-dependent manner. Furthermore, virtual screening studies indicated that emodin was a potent aryl hydrocarbon receptor (AhR) agonist in chemotherapy for breast cancer. Finally, when MCF-7 cells were treated with emodin (100 μmol/L) for 24 h, the AhR and cytochrome P450 1A1 (CYP1A1) protein expression levels were significantly upregulated compared with the control group. Our study indicated that emodin exhibited promising antitumor activity in MCF-7 cells, likely through activation of the AhR-CYP1A1 signaling pathway. These findings lay a foundation for the application of emodin in breast cancer treatment.
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http://dx.doi.org/10.3389/fphar.2020.622046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850984PMC
January 2021

TGF-β/Alk5 signaling prevents osteoarthritis initiation via regulating the senescence of articular cartilage stem cells.

J Cell Physiol 2021 Jul 16;236(7):5278-5292. Epub 2021 Jan 16.

Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.

Osteoarthritis (OA) is the most common joint disease. The surface of joint cartilage is a defensive and first affected structure of articular cartilage (AC) during the pathogenesis of OA. Alk5 signaling is critical for maintaining AC homeostasis, however, the role and underlying mechanism for the involvement of Alk5 signaling in the phenotypes of articular cartilage stem cells (ACSCs) at the surface of AC is still unclear. The role of Alk5 in OA development was explored using an ACSCs-specific Alk5-deficient (cKO) mouse model. Alterations in cartilage structure were evaluated histologically. Senescence was detected by SA-β-gal, while reactive oxygen species (ROS), MitoTracker, and LysoTracker staining were used to detect changes related to senescence. In addition, mice were injected intra-articularly with ganciclovir to limit the detrimental roles of senescent cells (SnCs). Alk5 cKO mice showed a decreased number of the slow-cell cycle cells and less lubricant secretion at the surface accompanied with drastically accelerated cartilage degeneration under ageing and surgically induced OA conditions. Further studies showed that Alk5 deficient ACSCs exhibited senescence-like manifestations including decreased proliferation and differentiation, more SA-β-gal-positive cells and ROS production, as well as significantly swollen mitochondria and lysosome breakdown. We further found that local limitation of the detrimental roles of SnCs can attenuate the development of posttraumatic OA. Taken together, our findings suggest that Alk5 signaling acts as an important regulator of the SnCs in the superficial layer during AC maintenance and OA initiation.
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http://dx.doi.org/10.1002/jcp.30231DOI Listing
July 2021

A Single-Molecule Observation of Dichloroaurate(I) Binding to an Engineered porin A (MspA) Nanopore.

Anal Chem 2021 01 31;93(3):1529-1536. Epub 2020 Dec 31.

State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, 210023 Nanjing, China.

Gold(I) compounds are known to bind sulfur-containing proteins, forming the basis in the design of gold(I)-based drugs. However, the intrinsic molecular mechanism of the chemical reaction is easily hidden when monitored in ensemble. We have previously demonstrated that porin A (MspA) can be engineered (MspA-M) to contain a specialized nanoreactor to probe chemical reactions involving tetrachloroaurate(III). Here, we provide further investigations of coordination interactions between dichloroaurate(I) and MspA-M. Gold compounds of different coordination geometry and valence states are as well probed and evaluated, demonstrating the generality of MspA-M. With single-molecule evidence, MspA-M demonstrates a preference for dichloroaurate(I) than tetrachloroaurate(III), an observation in a single molecule that has never been reported. By counting the maximum number of simultaneous ion bindings, the narrowly confined pore restriction also efficiently distinguishes dichloroaurate(I) and tetrachloroaurate(III) according to their differences in geometry or size. The above demonstration complemented a previous study by demonstrating other possible gold-based single-molecule chemical reactions observable by MspA. These observations bring insights in the understanding of gold-based coordination chemistry in a nanoscale.
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http://dx.doi.org/10.1021/acs.analchem.0c03840DOI Listing
January 2021

A Novel Antioxidant Protects Against Contrast Medium-Induced Acute Kidney Injury in Rats.

Front Pharmacol 2020 27;11:599577. Epub 2020 Nov 27.

Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China.

Many studies proposed that oxidative stress and apoptosis are key mechanisms in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). Xylose-pyrogallol conjugate (XP) is an original effective antioxidant that showed decent antioxidant and anti-apoptosis effect before. Thus the therapeutic effect and mechanism of XP in preventing CI-AKI in the short and long term were investigated in this research. Renal function and histological grade were evaluated to determine the severity of renal injury. Kidney samples were then collected for the measurement of oxidative stress markers and the detection of apoptosis. Transmission electron microscopy (TEM) and western blot of mitochondrial protein were utilized for the analysis of the mitochondrial conditions. The results demonstrated that the CI-AKI rats caused a significant decrease in renal function accompanied by a remarkable increase in Malondialdehyde (MDA), bax, caspase-3, cytochrome c (Cyt C) level, TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and damaged mitochondria, while a decline in antioxidase activities and mitochondrial superoxide dismutase 2 (SOD2) expression compared with the control rats. However, when XP (50 or 100 or 200 mg/kg/day) was given orally for consecutive 7 days before CI-AKI modeling, XP (200 mg/kg) showed a better capability to restore renal dysfunction, histopathological appearance, the level of apoptosis, mitochondrial damage, oxidative stress, and fibrosis generation without interference in computed tomographic imaging. Our study indicated that antioxidant XP played a nephroprotective role probably via antiapoptotic and antioxidant mechanisms. Besides, XP may regulate the mitochondria pathway via decreasing the ratio of bax/bcl-2, inhibiting caspase-3 expression, cytochrome c release, and superoxide dismutase 2 activity. Overall, XP as a high-efficient antioxidant may have the potentials to prevent CI-AKI.
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http://dx.doi.org/10.3389/fphar.2020.599577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729082PMC
November 2020

Co-Delivery of I and Prima-1 by Self-Assembled CD44-Targeted Nanoparticles for Anaplastic Thyroid Carcinoma Theranostics.

Adv Healthc Mater 2021 02 16;10(3):e2001029. Epub 2020 Dec 16.

Department of Nuclear Medicine, Xin Hua Hospital Affiliated To Shanghai Jiao Tong University School, 1665 Kongjiang Road, Shanghai, 200092, China.

New radionuclide-labeled targeting nanocarrier systems have generated new opportunities for tumor treatment and imaging. Nevertheless, such therapeutic strategy is clinically unfeasible on anaplastic thyroid carcinoma (ATC) patients, because of lacking suitable targets and resistance to radiation. In order to figure out a potential treatment, immuno-histochemical staining is performed in human ATC tissue species and high expression of cluster determinant 44 (CD44) is found. Therefore, a CD44-targeted delivery system is designed and constructed by self-assembly of tyrosine (Tyr)-hyaluronic acid (HA)-polyethyleneimine (PEI), which can radiolabel I and load a p53 mutant restoring regent, Prima-1. The I-labeled nanocomposites display an impressive tumor imaging as well as a long radiation treatment cycle. The I-labeled nanoparticles show remarkable anti ATC-tumor effects in vitro and in vivo, due to radiosensitization of Prima-1 by reactivation of the p53 mutants.
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http://dx.doi.org/10.1002/adhm.202001029DOI Listing
February 2021

Perceived Discrimination Trajectories and Depressive Symptoms Among Middle-Aged and Older Black Adults.

Innov Aging 2020 11;4(5):igaa041. Epub 2020 Sep 11.

Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background And Objectives: Perceived discrimination is a risk factor for poor mental health. However, most studies measure discrimination at one time point, which does not account for heterogeneity in the cumulative patterning of exposure to discrimination. To address this gap, we examine the association between discrimination trajectories and depressive symptoms among black middle-aged and older adults.

Research Design And Methods: Data were analyzed from a subsample of black Health and Retirement Study respondents (2006-2018, = 2926, older than 50 years). General discrimination and racial discrimination trajectories were constructed based on the Everyday Discrimination Scale using repeated measures latent profile analyses. We examined the extent to which the association between discrimination trajectories are differentially associated with depressive symptoms (8-item Center for Epidemiological Studies-Depression scale) using negative binomial regression models adjusted for potential confounders. Effect modification by age and gender was tested.

Results: Individuals in the persistently high (incident rate ratio [IRR]: 1.70; 95% confidence interval [CI]: 1.49-1.95) and moderate general discrimination trajectories (IRR: 1.19; 95% CI: 1.06-1.33) were more likely to have elevated depressive symptoms in comparison to those in the persistently low trajectory. This relationship was strongest among older adults aged older than 65 years. Respondents in the persistently high racial discrimination trajectory (IRR: 1.50; 95% CI: 1.29-1.73) had a higher risk of elevated depressive symptoms in comparison to respondents in the persistently low trajectory. Sensitivity analyses indicated that there was an independent association between persistently high racial discrimination trajectory class and elevated depressive symptoms, after adjusting for racial discrimination measured at a single time point.

Discussion And Implications: Characterizing longitudinal patterns of perceived discrimination may facilitate the stratification of mental health risk and vulnerability among black middle-aged and older adults. Trajectories of racial discrimination may inform risk of worse depressive symptoms more accurately than a single assessment of discrimination.
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http://dx.doi.org/10.1093/geroni/igaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724643PMC
September 2020

Remote ischemic conditioning: A potential therapeutic strategy of type 2 diabetes.

Med Hypotheses 2021 Jan 23;146:110409. Epub 2020 Nov 23.

Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China; China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, No. 1 Xinmin Street, Changchun 130021, China. Electronic address:

Type 2 diabetes (T2D) is one of the major public diseases which is characterized by peripheral insulin resistance (IR) and progressive pancreatic β-cell failure. While in the past few years, some new factors, such as inflammation, oxidative stress, immune responses and other potential pathways, have been identified to play critical roles in T2D, and thereby provide novel promising targets for the treatment of T2D. Remote ischemic conditioning (RIC) is a non-invasive and convenient operation performed by transient, repeated ischemia in distant place. Nowadays, RIC has been established as a potentially powerful therapeutic tool for many diseases, especially in I/R injuries. Through activating a series of neural, humoral and immune pathways, it can release multiple protective signals, which then regulating inflammation, oxidative stress, immune response and so on. Interestingly, several recent studies have discovered that the beneficial effects of RIC on I/R injuries might be abolished by T2D, wherein the higher basal levels of inflammation and oxidative stress, dysregulation of immune system and some potential pathways secondary to hyperglycemia may play critical roles. In contrast, a higher intensity of conditioning could restore the protective effects. Based on the overlapped mechanisms RIC and T2D performs, we provide a hypothesis that RIC may also play a protective role in T2D via targeting these signaling pathways.
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http://dx.doi.org/10.1016/j.mehy.2020.110409DOI Listing
January 2021

CBS and MAT2A improve methionine-mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation.

Cell Prolif 2021 Jan 12;54(1):e12950. Epub 2020 Nov 12.

State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China.

Objectives: Early pregnancy loss is a major clinical concern in animal and human reproduction, which is largely influenced by embryo implantation. The importance of methionine for embryo implantation is widely neglected.

Materials And Methods: We performed a series of experiments with primiparous rats fed diets containing different levels of methionine during early pregnancy to investigate the role of methionine in embryonic implantation and pregnancy outcomes, and used them to perform in vivo metabolic assessments and in vitro uterine explant culture. In addition, through transcriptome analysis and silencing the expression of cystathionine β-synthase (CBS, the key enzyme in transsulfuration pathway) and cell adhesion assay, we measured signalling within Ishikawa, pTr and JAR cells.

Results: We determined the relevance and underlying mechanism of methionine on embryo implantation. We showed that methionine deprivation sharply decreased embryo implantation sites, expression of CBS and transsulfuration pathway end products, which were reversed by maternal methionine supplementation during early pregnancy. Moreover, we found CBS improved methionine-mediated cell proliferation and DNA synthesis by CBS inhibition or interference. In addition, transcriptome analysis also revealed that CBS influenced the signalling pathway-associated cell proliferation and DNA synthesis, as well as a correlation between CBS and methionine adenosyltransferase 2A (MAT2A), implying that MAT2A was possibly involved in cell proliferation and DNA synthesis. Further analysis revealed that MAT2A influenced S-adenosylmethionine receptor SAMTOR expression, and SAMTOR activated mTORC1 and its downstream S6K1 and CAD, ultimately enhancing DNA synthesis in the embryo and uterus.

Conclusions: Taken together, these studies demonstrate that CBS and MAT2A improve methionine-mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation.
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http://dx.doi.org/10.1111/cpr.12950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791180PMC
January 2021

Access to 2-pyridinylamide and imidazopyridine from 2-fluoropyridine and amidine hydrochloride.

Org Biomol Chem 2020 Nov;18(45):9292-9299

School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020 China.

Under catalyst-free conditions, an efficient method to synthesize 2-pyridinylamides has been developed, and the protocol uses inexpensive and readily available 2-fluoropyridine and amidine derivatives as the starting materials. Simultaneously, the copper-catalysed approach to imidazopyridine derivatives has been established with high chemoselectivity and regiospecificity. The results suggest that the nitrogen-heterocycles containing iodide substituents can also be compatible for the reaction via the cascade Ullmann-type coupling, and the nucleophilic substitution reaction provides the target products in a one-pot manner.
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http://dx.doi.org/10.1039/d0ob01904fDOI Listing
November 2020

Orthodontic treatment induces Th17/Treg cells to regulate tooth movement in rats with periodontitis.

Iran J Basic Med Sci 2020 Oct;23(10):1315-1322

Department of Orthodontics, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China.

Objectives: Here we investigated the regulation of Th17 and Treg cells in orthodontic tooth movement during periodontal inflammation.

Materials And Methods: Fifty-six SD rats were divided into a control (24 rats) and a tooth movement group during the recovery stage of periodontitis (RM group, 32 rats). Periodontitis was established by silk ligation and local injection of LPS. Orthodontic tooth movement was achieved by nickel-titanium springs on the maxillary first molars. The proportions of Th17 cells and Treg cells were evaluated by flow cytometry. Gene expression of ROR-γt and Foxp3 was determined by real-time PCR. Expression of ROR-γt, Foxp3, RANK, RANKL, and OPG was detected by immunohistochemical staining. Osteoclasts were detected by TRAP staining. Relationships between Th17/Treg cells, osteoclasts, and related factors were estimated by correlation and regression analysis.

Results: During orthodontic tooth movement in the recovery stage of periodontitis, the proportion of Th17 cells, ROR-γt, RANK, osteoclasts, and the RANKL/OPG ratio increased and then decreased. The proportion of Treg cells and Foxp3 increased, then decreased, and increased again. Levels of RANKL and OPG increased, then decreased, then increased, and finally decreased. The Th17/Treg ratio initially decreased, then increased, and decreased again. Th17 cells were positively correlated with RANK and RANKL, the RANKL/OPG ratio, and counts of osteoclasts. Treg cells were negatively correlated with RANK expression and numbers of osteoclasts. The Th17/Treg ratio was positively correlated with RANK expression and numbers of osteoclasts.

Conclusion: Under periodontal inflammation conditions, the Th17/Treg ratio might regulate orthodontic tooth movement through changing osteoclasts metabolism.
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http://dx.doi.org/10.22038/ijbms.2020.44437.10419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585537PMC
October 2020
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