Publications by authors named "Wei Xiang"

581 Publications

The role of mutations in "see-saw effect" of Daptomycin-resistant methicillin-resistant isolates.

Antimicrob Agents Chemother 2021 Oct 18:AAC0129521. Epub 2021 Oct 18.

Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

The emergence of daptomycin-resistant (DAP-R) strains has become a global problem. Point mutations in are the main cause of daptomycin (DAP) treatment failure. However, the impact of these specific point-mutations in methicillin-resistant (MRSA) strains associated with DAP resistance and the "see-saw effect" of distinct beta-lactams remains unclear. In this study, we used three series of clinical MRSA strains with three distinct mutated alleles from clone complexes (CC) 5 and 59 to explore the "see-saw effect" and the combination effect of DAP plus beta-lactams. Through construction of deletion and complementation strains of SA268, we determined that -S295A, -S337L and one novel mutation of I348del within the bifunctional domain lead to DAP resistance. Compared with wild-type cloned from a DAP-susceptible (DAP-S) strain, these three mutations conferred the "see-saw effect" to distinct beta-lactams in the SA268Δ strains and mutated- (I348del and S337L) did not alter the cell surface positive charge ( > 0.05). The susceptibility to beta-lactams increased significantly in DAP-R CC59 strains and the "see-saw effect" was found to be associated with distinct mutated alleles and the category of beta-lactams. The synergistic activity of DAP plus oxacillin was detected in all DAP-R MRSA strains. Continued progress in understanding the mechanism of restoring susceptibility to beta-lactam antibiotics mediated by the mutation and its impact on beta-lactam combination therapy will provide fundamental insights into treatment of MRSA infections.
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http://dx.doi.org/10.1128/AAC.01295-21DOI Listing
October 2021

Genetic inhibition of Nuclear Factor of Activated T-cell c2 (NFATc2) prevents atrial fibrillation in CREM transgenic mice.

Cardiovasc Res 2021 Oct 14. Epub 2021 Oct 14.

Cardiovascular Research Institute.

Aims: Abnormal intracellular calcium handling contributes to the progressive nature of atrial fibrillation (AF), the most common sustained cardiac arrhythmia. Evidence in mouse models suggests that activation of the nuclear factor of activated T-cell (NFAT) signaling pathway contributes to atrial remodeling. Our aim was to determine the role of NFATc2 in AF in humans and mouse models.

Methods And Results: Expression levels of NFATc1-c4 isoforms were assessed by quantitative reverse transcription-polymerase chain reaction in right atrial appendages from patients with chronic AF. NFATc1 and NFATc2 mRNA levels were elevated in chronic AF (cAF) patients compared with those in sinus rhythm (SR). Western blotting revealed increased cytosolic and nuclear levels of NFATc2 in AF patients. Similar findings were obtained in CREM-IbΔC-X transgenic (CREM) mice, a model of progressive AF. Telemetry ECG recordings revealed age-dependent spontaneous AF in CREM mice, which was prevented by NFATc2 knockout in CREM: NFATc2-/- mice. Programmed electrical stimulation revealed that CREM: NFATc2-/- mice lacked an AF substrate. Morphometric analysis and histology revealed increased atrial weight and atrial fibrosis in CREM mice compared with WT controls, which was reversed in CREM: NFATc2-/- mice. Confocal microscopy showed an increased Ca2+ spark frequency despite a reduced sarcoplasmic reticulum (SR) Ca2+ load in CREM mice compared with controls, whereas these abnormalities were normalized in CREM: NFATc2-/- mice. Western blotting revealed that genetic inhibition of Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of S2814 on RyR2 in CREM: RyR2-S2814A mice suppressed NFATc2 activation observed in CREM mice, suggesting that NFATc2 is activated by excessive SR Ca2+ leak via RyR2. Finally, chromatin immunoprecipitation sequencing from AF patients identified Ras And EF-Hand Domain-Containing Protein (RASEF) as a direct target of NFATc2 mediated transcription.

Conclusion: Our findings reveal activation of the NFAT signaling pathway in patients of Chinese and European descent. NFATc2 knockout prevents the progression of AF in the CREM mouse model.

Translational Perspective: Atrial fibrillation (AF) is a progressive disease characterized by electrical and structural remodeling which promotes atrial arrhythmias. This study provides evidence for increased 'nuclear factor of activated T-cell' (NFAT) signaling in patients with chronic AF. Studies in the CREM transgenic model of progressive AF revealed that the NFATc2 isoform mediates atrial remodeling associated with AF substrate development. Chromatin immunoprecipitation sequencing of atrial biopsies from AF patients identified 'Ras And EF-Hand Domain-Containing Protein' (RASEF) as a downstream target of NFATc2-mediated transcription, suggesting that targeting these factors might be beneficial for curtailing AF progression.
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http://dx.doi.org/10.1093/cvr/cvab325DOI Listing
October 2021

Incidence of postoperative pulmonary complications in patients undergoing minimally invasive versus median sternotomy valve surgery: propensity score matching.

J Cardiothorac Surg 2021 Oct 9;16(1):287. Epub 2021 Oct 9.

Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan, 4300, People's Republic of China.

Objective: Postoperative pulmonary complications (PPCs) are common incidents associated with an increased hospital stay, readmissions into the intensive care unit (ICU), increased costs, and mortality after cardiac surgery. Our study aims to analyze whether minimally invasive valve surgery (MIVS) can reduce the incidence of postoperative pulmonary complications compared to the full median sternotomy (FS) approach.

Methods: We reviewed the records of 1076 patients who underwent isolated mitral or aortic valve surgery (80 MIVS and 996 FS) in our institution between January 2015 and December 2019. Propensity score-matching analysis was used to compare outcomes between the groups and to reduce selection bias.

Results: Propensity score matching revealed no significant difference in hospital mortality between the groups. The incidence of PPCs was significantly less in the MIVS group than in the FS group (19% vs. 69%, respectively; P < 0.0001). The most common PPCs were atelectasis (P = 0.034), pleural effusions (P = 0.042), and pulmonary infection (P = 0.001). Prolonged mechanical ventilation time (> 24 h) (P = 0.016), blood transfusion amount (P = 0.006), length of hospital stay (P < 0.0001), and ICU stay (P < 0.0001) were significantly less in the MIVS group. Cardiopulmonary bypass (CBP), aortic cross-clamping, and operative time intervals were significantly longer in the MIVS group than in the matched FS group (P < 0.001). A multivariable analysis revealed a decreased risk of PPCs in patients undergoing MIVS (odds ratio, 0.25; 95% confidence interval, 0.006-0.180; P < 0.0001).

Conclusion: MIVS for isolated valve surgery reduces the risk of PPCs compared with the FS approach.
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http://dx.doi.org/10.1186/s13019-021-01669-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501915PMC
October 2021

Synergistic Effect of Microstructure Engineering and Local Crystal Structure Tuning to Improve the Cycling Stability of Ni-Rich Cathodes.

ACS Appl Mater Interfaces 2021 Oct 6;13(41):48720-48729. Epub 2021 Oct 6.

School of Chemical Engineering, Sichuan University, Chengdu 610065, PR China.

Ultrahigh Ni-rich layered oxides have been regarded as one of the most promising cathode candidates. However, cycling instability induced by interfacial reactions and irreversible H2-H3 lattice distortion is yet to be demonstrated by an effective strategy that could construct a stable grain interface and microstructure. Here, Ni-rich cathode LiNiCoMnO is modified by B and Ti to realize the synchronous regulation of a microstructure and the oxygen framework robustness. Compared with the large equiaxed crystalline grains for the pristine cathode, highly elongated grains with a strong radially oriented crystallographic texture in which the (003) facet is maximized are produced for Ti and B-modified LiNiCoMnO. With the suppressed H2-H3 phase transition and cation mixing provided by radially oriented grains and turned local crystal oxygen framework robustness during cycling, the co-modified cathode exhibits enhanced Li diffusion kinetics and a capacity retention of 78.3% after 100 cycles, which outperformed the 38.5% for the pristine cathode. The improved cycling performance suggests the significance of the turned microstructure and local crystal structure in suppressing internal strain and crystal structure degradation. The synchronous realization of microstructure engineering and local crystal structure turning by optimal element combination would provide a heuristic solution for the construction of high perform Ni-rich cathodes.
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http://dx.doi.org/10.1021/acsami.1c14239DOI Listing
October 2021

Exploration of MRI T2 Mapping Image Application in Articular Disc Displacement of the Temporomandibular Joint in Adolescents.

Int J Gen Med 2021 24;14:6077-6084. Epub 2021 Sep 24.

Department of Radiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, People's Republic of China.

Purpose: To explore the application of magnetic resonance imaging (MRI) T2 mapping technique in clinical practice through morphological and quantitative analysis of T2 mapping sequences in adolescents with temporomandibular disorders (TMDs) and control groups comprising healthy participants.

Patients And Methods: A total of 45 and 63 patients, who had articular disc displacement with and without reduction, respectively, were assigned to the experimental groups, and 57 participants with normal articular discs of the temporomandibular joint were considered as the control group. All participants in the three groups underwent MRI. T2 mapping was performed in the oblique sagittal plane. The regions of interest (ROIs) for the T2 relaxation time maps of the disc were selected manually. The performance of morphological and structural changes and quantitative parameters in MRI T2 mapping image artifacts were statistically compared.

Results: In the control group, the mean T2 value was 39.284 ±5.634 ms, in the group of disc displacement with reduction, the mean T2 value was 33.634 ±4.235 ms, and in the group of disc displacement without reduction, the mean T2 value was 30.982 ±3.205 ms. The T2 mapping values of the experimental groups, together with different morphological structures, were significantly lower than were those of the control group.

Conclusion: MRI T2 mapping enables a more accurate evaluation of TMD severity. Sequentially, it helps provide a more reliable medical imaging basis for classifying diagnosis and evaluation in clinical practice.
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http://dx.doi.org/10.2147/IJGM.S330116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478363PMC
September 2021

Identifying the effect of fluorination on cation and anion redox activity in Mn based cation-disordered cathode.

J Colloid Interface Sci 2021 Sep 21;607(Pt 2):1333-1342. Epub 2021 Sep 21.

College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu 610059, PR China; Yibin Tianyuan Group Co., Ltd., Yibin 644000, PR China. Electronic address:

Li-rich disordered rock-salt cathode (DRX) materials with advantage of low cost, long cycle life, nature abundant resource and high power and energy density attracted a great deal of scholarly attention. However, the poor cycle stability and the unclear realization of cation and anion redox activity in low-cost element system have severely hindered the construction of high-performance DRX. Herein, a promising class of Ti-Mn based cathode materials LiMnNbTiO and LiMnTiOF were designed and successfully synthesized to construct high energy density DRX and investigate the effect of fluorination on cation and anion redox activity. The results show that both fluoridized and unfluoridized DRX possess a similar structure (Fm-3 m), but distinctly different charge/discharge profiles. The fluoridized cathode shows high initial charge/discharge capacity of 317.3/283.9 mAh g, specific energy density of 1370.4/735.5 Wh kg and stable capacity retention with a discharge capacity of 202.6 mAh g after 20 cycles at 20 mA g. Combining relevant spectroscopic results and HRTEM images, we revealed that the excellent cyclability of LiMnTiOF is rooted in the weakened adverse effects of moderated oxygen redox and the reduced Jahn-Teller distortion effect resulting from Mn, endowing the fluoridized DRX with better structural stability and larger Mn/Mn reservoir. The strategy of constructing low cost oxyfluoride and the understanding of the mechanism of fluorination induced cation and anion redox activity would provide reference for the development of high-performance DRX materials.
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http://dx.doi.org/10.1016/j.jcis.2021.09.101DOI Listing
September 2021

Short-term observation of direct oral anticoagulant use in an atrial fibrillation patient with high bleeding risk and kidney transplant: a case report.

J Geriatr Cardiol 2021 Aug;18(8):692-696

Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.

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http://dx.doi.org/10.11909/j.issn.1671-5411.2021.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390934PMC
August 2021

LncRNA Neat1/miR-298-5p/Srpk1 Contributes to Sevoflurane-Induced Neurotoxicity.

Neurochem Res 2021 Dec 15;46(12):3356-3364. Epub 2021 Sep 15.

Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University, No. 415, Fengyang Road, Huangpu District, 200003, Shanghai, China.

Sevoflurane is a widely used volatile anesthetic, that can cause long-term neurotoxicity and learning and memory impairment. Long non-coding RNAs (lncRNAs) have been demonstrated to function as key mediators in neurotoxicity. This study aimed to investigate the effects of lncRNA Neat1 on sevoflurane-induced neurotoxicity. The expression of Neat1, miR-298-5p, and Srpk1 was measured by RT-qPCR. Cell viability, cell apoptosis, inflammation markers, and reactive oxygen species (ROS) generation were examined by CCK-8, TUNEL, ELISA, and the ROS kit. The interaction between miR-298-5p and Neat1 or Srpk1 was confirmed by luciferase reporter assay. In our study, it was found that sevoflurane aggravated neurotoxicity through inhibiting cell viability and enhancing cell apoptosis, neuroinflammation, and ROS generation. Neat1 was up-regulated in sevoflurane-treated HT22 cells, and Neat1 knockdown improved sevoflurane-mediated neurotoxicity. Through the exploration of the ceRNA mechanism, we found that Neat1 bound with miR-298-5p, and Srpk1 was a direct target gene of miR-298-5p. Finally, rescue assays proved that up-regulation of Srpk1 reversed the effects of Neat1 knockdown on neurotoxicity. In conclusion, our study revealed that lncRNA Neat1 facilitated sevoflurane-stimulated neurotoxicity by sponging miR-298-5p to up-regulate Srpk1. These findings might provide novel insights into the treatment of sevoflurane-induced neurotoxicity.
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http://dx.doi.org/10.1007/s11064-021-03436-5DOI Listing
December 2021

MiR-9-1 Suppresses Cell Proliferation and Promotes Apoptosis by Targeting UHRF1 in Lung Cancer.

Technol Cancer Res Treat 2021 Jan-Dec;20:15330338211041191

Shanghai Tenth People's Hospital, 278245Tongji University School of Medicine, Shanghai, China.

Lung cancer is listed as the most common reason for cancer-related death all over the world despite diagnostic improvements and the development of chemotherapy and targeted therapies. MicroRNAs control both physiological and pathological processes including development and cancer. A microRNA-9 to 1 (miR-9 to 1) overexpression model in lung cancer cell lines was established and miR-9 to 1 was found to significantly suppress the proliferation rate in lung cancer cell lines, colony formation in vitro, and tumorigenicity in nude mice of A549 cells. Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) was then identified to direct target of miR-9 to 1. The inhibition of UHRF1 by miR-9 to 1 causes G1 arrest and p15, p16, and p21 were re-expressed in miR-9 to 1 group in mRNA level and protein level. Silence of UHRF1 expression in A549 cells resulted in the similar re-expression of p15, p16, p21 which is similar with miR-9 to 1 infection. Therefore, we concluded that UHRF1 is a new target for miR-9 to 1 to suppress cell proliferation by re-expression of tumor suppressors p15, p16, and p21 mediated by UHRF1.
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http://dx.doi.org/10.1177/15330338211041191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445543PMC
September 2021

An end-to-end network for segmenting the vasculature of three retinal capillary plexuses from OCT angiographic volumes.

Biomed Opt Express 2021 Aug 16;12(8):4889-4900. Epub 2021 Jul 16.

Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA.

The segmentation of retinal capillary angiograms from volumetric optical coherence tomographic angiography (OCTA) usually relies on retinal layer segmentation, which is time-consuming and error-prone. In this study, we developed a deep-learning-based method to segment vessels in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP) directly from volumetric OCTA data. The method contains a three-dimensional convolutional neural network (CNN) for extracting distinct retinal layers, a custom projection module to generate three vascular plexuses from OCTA data, and three parallel CNNs to segment vasculature. Experimental results on OCTA data from rat eyes demonstrated the feasibility of the proposed method. This end-to-end network has the potential to simplify OCTA data processing on retinal vasculature segmentation. The main contribution of this study is that we propose a custom projection module to connect retinal layer segmentation and vasculature segmentation modules and automatically convert data from three to two dimensions, thus establishing an end-to-end method to segment three retinal capillary plexuses from volumetric OCTA without any human intervention.
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http://dx.doi.org/10.1364/BOE.431888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407822PMC
August 2021

Facile In Situ Chemical Cross-Linking Gel Polymer Electrolyte, which Confines the Shuttle Effect with High Ionic Conductivity and Li-Ion Transference Number for Quasi-Solid-State Lithium-Sulfur Battery.

ACS Appl Mater Interfaces 2021 Sep 10;13(37):44497-44508. Epub 2021 Sep 10.

School of Chemical Engineering, Sichuan University, No. 24 South Section 1, Yihuan Road, Chengdu 610065, P. R. China.

As a secondary Li-ion battery with high energy density, lithium-sulfur (Li-S) batteries possess high potential development prospects. One of the important ingredients to improve the safety and energy density in Li-S batteries is the solid-state electrolyte. However, the poor ionic conductivity largely limits its application for the commercial market. At present, the gel electrolyte prepared by combining the electrolyte or ionic liquid with the all-solid electrolyte is an effective method to solve the low ion conductivity of the solid electrolyte. We present a cross-linked gel polymer electrolyte with fluoroethylene carbonate (FEC) as a solid electrolyte interface (SEI) film formed for Li-S quasi-solid-state batteries, which can be simply synthesized without initiators. This gel polymer electrolyte with FEC as an additive ([email protected]) possesses high ionic conductivity (0.830 × 10 S/cm at 25 °C and 1.577 × 10 S/cm at 85 °C) and extremely high Li-ion transference number ( = 0.674). In addition, the strong ability toward anchoring polysulfides resulting in the high electrochemical performance of Li-S batteries was confirmed in [email protected] by the diffusion experiment, X-ray photoelectron spectroscopy analysis (XPS), and scanning electron microscopy (SEM) mapping of the S element. Such a high ion conductivity (IC) gel polymer electrolyte enables a competitive specific capacity of 940 mAh/g at 0.2C and supreme cycling performance for 180 cycles at 0.5C, which is far beyond that of conventional poly(ethylene oxide)-based quasi-solid-state Li-S batteries.
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http://dx.doi.org/10.1021/acsami.1c16148DOI Listing
September 2021

Osteoblasts Regulate the Expression of ADAMTS and MMPs in Chondrocytes through ERK Signaling Pathway.

Z Orthop Unfall 2021 Sep 9. Epub 2021 Sep 9.

Department of Orthopaedics, The First Affiliated Hospital of the Medical Colleges, Shihezi University, China.

Objective: Degradative enzymes such as matrix metalloproteinase (MMP) and disintegrin metalloproteinase with platelet thrombin-sensitive protein-like motifs (ADAMTS) play a key role in the development of osteoarthritis (OA). We aimed to investigate the effects of OA subchondral osteoblasts on the expression of ADAMTS4, ADAMTS5, MMP-3, MMP-9, and MMP-13 in chondrocytes and the regulation of mitogen-activated protein kinase (MAPK) signaling pathway.

Methods: A rat knee OA model was constructed by cutting the anterior cruciate ligament of the knee joints, and normal rat articular cartilage chondrocytes (N-ACC), OA rat articular cartilage chondrocytes (O-ACC), normal subchondral bone osteoblasts (N-SBO), and OA subchondral bone osteoblasts (O-SBO) were isolated and extracted. The expressions of O-ACC and O-SBO COL1 and COL2 were detected respectively. Chondrocytes were identified by immunofluorescence of COL2 and toluidine blue staining, and osteoblasts were identified by COL1 immunofluorescence, alkaline phosphatase (ALP), and Alizarin Red staining. Gene expression of COL1, COL2, and aggrecan in normal chondrocytes and OA chondrocytes, and gene expression of osteoblast ALP and osteocalcin (OCN) were detected by RT-PCR to identify the two chondrocytes and the two osteoblast phenotypes. The constructing N-ACC group, O-ACC group, N-ACC + N-SBO group, N-ACC + O-SBO group, O-ACC + N-SBO group, O-ACC + O-SBO group, I + N-ACC + O-SBO group, and I + O-ACC + O-SBO group cell cultures, and the expression of ERK, ADAMTS4, ADAMTS5, MMP-3, MMP-9, and MMP-13 genes in chondrocytes cultured for 0, 24, 48, and 72 h were detected by RT-PCR. The protein expressions of pERK, ADAMTS4, ADAMTS5, MMP-3, MMP-9, and MMP-13 were detected by Western blot.

Results: · The X-ray showed that the knee joint space of the affected limb became narrow.. · The results of RT-PCR of COL2 and aggrecan gene in OA and normal chondrocytes suggest that the relative expression of COL2 in OA articular chondrocytes (0.24 ± 0.07) is significantly lower than that in normal cartilage (0.61 ± 0.07) (p < 0.05). The relative expression of AGG (0.37 ± 0.16) in OA chondrocytes was significantly lower than that of normal chondrocytes AGG (1.30 ± 0.25) (p < 0.05). The expression of COL1 was very low, and was not statistically significant.. · The results of RT-PCR of the osteoblast ALP and OCN gene indicated that gene expression of ALP (12.30 ± 1.17) and OCN (20.47 ± 4.19)was upregulated when compared with the relative expression of ALP (4.66 ± 0.71) (p < 0.05) and OCN (12.17 ± 2.76) (p < 0.05) in normal osteoblasts, indicating that osteoblasts of OA have greater osteogenic potential than normal osteoblasts.. · The expressions of ADAMTS4, ADAMTS5, MMP-3, MMP-9, and MMP-13 genes and proteins in OA chondrocytes or normal chondrocytes were basically unchanged when they were cocultured with normal osteoblasts. Indirect coculture of OA osteoblasts and chondrocytes could promote the expression of ADAMTS4, ADAMTS5, MMP-3, MMP-9, and MMP-13 genes and proteins in chondrocytes. Overexpression of ADAMTS and MMP in coculture systems can be reversed by MAPK-ERK inhibitors..

Conclusions: · OA subchondral bone osteoblasts can promote the overexpression of ADAMTS and MMPs in chondrocytes.. · The ERK signaling pathway may be involved in the regulation of the effect of subchondral bone osteoblasts on chondrocytes..
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http://dx.doi.org/10.1055/a-1527-7900DOI Listing
September 2021

Comparative Evaluation of the Incidence of Postoperative Pulmonary Complications After Minimally Invasive Valve Surgery vs. Full Sternotomy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Propensity Score-Matched Studies.

Front Cardiovasc Med 2021 23;8:724178. Epub 2021 Aug 23.

Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Postoperative pulmonary complications remain a leading cause of increased morbidity, mortality, longer hospital stays, and increased costs after cardiac surgery; therefore, our study aims to analyze whether minimally invasive valve surgery (MIVS) for both aortic and mitral valves can improve pulmonary function and reduce the incidence of postoperative pulmonary complications when compared with the full median sternotomy (FS) approach. A comprehensive systematic literature research was performed for studies comparing MIVS and FS up to February 2021. Randomized controlled trials (RCTs) and propensity score-matching (PSM) studies comparing early respiratory function and pulmonary complications after MIVS and FS were extracted and analyzed. Secondary outcomes included intra- and postoperative outcomes. A total of 10,194 patients from 30 studies (6 RCTs and 24 PSM studies) were analyzed. Early mortality differed significantly between the groups (MIVS 1.2 vs. FS 1.9%; = 0.005). Compared with FS, MIVS significantly lowered the incidence of postoperative pulmonary complications (odds ratio 0.79, 95% confidence interval [0.67, 0.93]; = 0.004) and improved early postoperative respiratory function status (mean difference -24.83 [-29.90, -19.76]; < 0.00001). Blood transfusion amount was significantly lower after MIVS ( < 0.02), whereas cardiopulmonary bypass time and aortic cross-clamp time were significantly longer after MIVS ( < 0.00001). Our study showed that minimally invasive valve surgery decreases the incidence of postoperative pulmonary complications and improves postoperative respiratory function status.
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http://dx.doi.org/10.3389/fcvm.2021.724178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419439PMC
August 2021

Downregulation of Filamin a Expression in the Aorta Is Correlated With Aortic Dissection.

Front Cardiovasc Med 2021 13;8:690846. Epub 2021 Aug 13.

Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Filamins (FLNs) are actin cross-linking proteins, and as scaffolding proteins, FLNs are closely associated with the stabilization of the cytoskeleton. Nevertheless, the biological importance of FLNs in aortic dissection (AD) has not been well-elucidated. In this study, we first reanalyzed datasets downloaded from the Gene Expression Omnibus (GEO) database, and we found that in addition to the extracellular matrix, the actin cytoskeleton is a key structure associated with AD. Given that FLNs are involved in remodeling the cytoskeleton to affect cellular functions, we measured their expression levels in the aortas of patients with Stanford type A AD (TAAD). Our results showed that the mRNA and protein levels of FLNA were consistently decreased in dissected aortas of both humans and mice, while the FLNB protein level was upregulated despite decreased FLNB mRNA levels, and comparable expression levels of FLNC were observed between groups. Furthermore, the immunohistochemistry results demonstrated that FLNA was highly expressed in smooth muscle cells (SMCs) of aorta in non-AD samples, and downregulated in the medial layer of the dissected aortas of humans and mice. Moreover, we revealed that FOS and JUN, forming a dimeric transcription factor called AP-1 (activating protein-1), were positively correlated with the expression of FLNA in aorta. Either overexpression of FOS or JUN alone, or overexpression of FOS and JUN together, facilitated the expression of FLNA in primary cultured human aortic SMCs. In the present study, we not only detected the expression pattern of FLNs in aortas of humans and mice with or without AD, but we also found that the expression of FLNA in the AD samples was significantly reduced and that AP-1 might regulate the expression of FLNA. Our findings will contribute to the elucidation of the pathological mechanisms of AD and provide potential therapeutic targets for AD.
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http://dx.doi.org/10.3389/fcvm.2021.690846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414519PMC
August 2021

Outcomes of intramural hematoma involving the ascending aorta and extending into the descending thoracic aorta.

J Vasc Surg 2021 Sep 2. Epub 2021 Sep 2.

Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. Electronic address:

Objective: The optimal treatment of intramural hematoma (IMH) involving the ascending aorta remains controversial. This study aimed to analyze the results of the management of patients with acute IMH involving the ascending aorta and extending into the descending thoracic aorta, to compare outcomes of descending thoracic endovascular aortic repair (TEVAR) with that of medical therapy (MT), and to assess the risk factors associated with adverse aortic events.

Methods: We retrospectively analyzed all patients diagnosed with acute IMH involving the ascending aorta and extending into the descending thoracic aorta from January 2012 to December 2019. The primary end points during follow-up were aortic disease-related death and adverse aorta-related events that required surgical or endovascular treatment, such as aortic rupture, the progression of aortic disease, or endoleak.

Results: We identified a total of 135 patients with acute IMH involving the ascending aorta and extending into the descending thoracic aorta, of whom 104 underwent descending TEVAR (group 1) and 31 were managed with MT (group 2). Freedom from adverse aorta-related events at 1, 3, and 5 years was significantly higher for patients who underwent descending TEVAR compared with those managed with MT (89.2%, 88.2%, and 84.0% vs 74.2%, 74.2%, and 74.2%, respectively; P = .026). The 1-, 3-, and 5-year survival rates for patients in the descending TEVAR group was 100%, 100%, and 100%, respectively, which was significantly higher than the survival of the MT group: 93.5%, 93.5%, and 81.9%, respectively (P = .002). On a univariate analysis among patients receiving MT, those who suffered adverse aorta-related events showed a higher prevalence of renal insufficiency (55.6% vs 9.1%; P = .003). In MT patients, multivariate analysis showed that renal insufficiency was the only independent risk factor associated with adverse aorta-related events (hazard ratio, 8.691; 95% confidence interval, 2.056-36.737; P = .003).

Conclusions: Based on our study, compared with MT, descending TEVAR might be the more favorable treatment for patients with IMH involving the ascending aorta and extending into the descending thoracic aorta. Patients with renal insufficiency are more likely to experience adverse aorta-related events, which implies the need for subsequent intervention or an increased risk of mortality. The risk factor would be helpful for clinical decision-making.
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http://dx.doi.org/10.1016/j.jvs.2021.07.231DOI Listing
September 2021

The regulatory role of antisense lncRNAs in cancer.

Cancer Cell Int 2021 Aug 30;21(1):459. Epub 2021 Aug 30.

Department of Urology, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Changsha, 410013, Hunan, China.

Antisense long non-coding RNAs (antisense lncRNAs), transcribed from the opposite strand of genes with either protein coding or non-coding function, were reported recently to play a crucial role in the process of tumor onset and development. Functionally, antisense lncRNAs either promote or suppress cancer cell proliferation, migration, invasion, and chemoradiosensitivity. Mechanistically, they exert their regulatory functions through epigenetic, transcriptional, post-transcriptional, and translational modulations. Simultaneously, because of nucleotide sequence complementarity, antisense lncRNAs have a special role on its corresponding sense gene. We highlight the functions and molecular mechanisms of antisense lncRNAs in cancer tumorigenesis and progression. We also discuss the potential of antisense lncRNAs to become cancer diagnostic biomarkers and targets for tumor treatment.
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http://dx.doi.org/10.1186/s12935-021-02168-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404292PMC
August 2021

Aortic root aortopathy in bicuspid aortic valve associated with high genetic risk.

BMC Cardiovasc Disord 2021 08 30;21(1):413. Epub 2021 Aug 30.

Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan, 430030, People's Republic of China.

Background: The bicuspid aortic valve (BAV) is prone to ascending aortic dilatation (AAD) involving both the tubular segment and the aortic root. The genetic factor was proposed as one of the most important mechanisms for AAD. We hypothesized that the rare genetic variants mainly contribute to the pathogenesis of aortic roots in affected individuals.

Methods: The diameter of aortic root or ascending aorta ≥ 40 mm was counted as AAD. The targeted next-generation sequencing of 13 BAV-associated genes were performed on a continuous cohort of 96 unrelated BAV patients. The rare variants with allele frequency < 0.05% were selected and analyzed. Variants frequency was compared against the Exome aggregation consortium database. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics guidelines.

Results: A total of 27 rare nonsynonymous coding variants involving 9 genes were identified in 25 individuals. The burden analysis revealed that variants in GATA5, GATA6, and NOTCH1 were significantly associated with BAV. Eighty percent of the pathogenic variants were detected in root group. The detection rate of rare variants was higher in root dilatation group (71.4%) compared with normal aorta (29.0%) and tubular dilatation groups (29.6%) (P = 0.018). The rare variant was identified as the independent risk factor of root dilatation [P = 0.014, hazard ratio = 23.9, 95% confidence interval (1.9-302.9)].

Conclusions: Our results presented a broad genetic spectrum in BAV patients. The rare variants of BAV genes contribute the most to the root phenotype among BAV patients.
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http://dx.doi.org/10.1186/s12872-021-02215-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404252PMC
August 2021

Mediastinal and subglottic hemangioma in an infant: a case report and literature review.

J Int Med Res 2021 Aug;49(8):3000605211039803

NHC Key Laboratory of Control of Tropical diseases, Hainan Medical University, Haikou, China.

We performed a retrospective analysis of the clinical manifestations, laboratory and imaging examinations, treatment, and prognosis of a male infant who was diagnosed with mediastinal and subglottic hemangioma in our hospital. The clinical features of this patient were coughing, wheezing, and dyspnea. Enhanced computed tomography of the neck and chest showed a diffuse abnormality in the right-upper mediastinum. He was diagnosed with a hemangioma after a physical examination combined with bronchoscopy. The clinical symptoms were relieved by oral propranolol. We also investigated the clinical characteristics, treatment, and prognosis of mediastinal and subglottic hemangioma in infants in the previous literature, and searched for case reports of this disease in China and in other countries. We only identified three previous cases of mediastinal and subglottic hemangioma in infants, indicating that this condition is rare. In the proliferative stage, surrounding organs and tissues are compressed, which can be life-threatening. Most of these children develop wheezing, shortness of breath, dyspnea, cyanosis, and other symptoms within 2 months. Enhanced computed tomography and magnetic resonance imaging combined with soft bronchoscopy can confirm the diagnosis of this disease, and oral propranolol achieves a favorable effect.
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http://dx.doi.org/10.1177/03000605211039803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408903PMC
August 2021

Revealing the heterogeneous activation mechanism of peroxydisulfate by CuO: the critical role of surface-binding organic substrates.

Sci Total Environ 2021 Aug 24;802:149833. Epub 2021 Aug 24.

School of Environmental Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074, China; CAS Key Laboratory of Urban Pollutant Conversion, Department of Environmental Science and Engineering, University of Science and Technology of China, Hefei 230026, China. Electronic address:

Heterogeneous catalytic activation mechanisms of peroxydisulfate (PDS) by transition metal oxides are generally attributed to the interactions between catalysts and PDS, however, the role of the co-existed organic substrate was largely overlooked in the past studies. In this work, phenol was selected as the target organic pollutant in a CuO/PDS system to evaluate its deep-seated role in participating in the effective activation of PDS. First, optimized reaction conditions as pH of 6.0, CuO of 5.96 g·L and PDS of 2.5 mM were obtained by the response surface methodology (RSM) with a phenol degradation efficiency of 84.0%. It was further found that pre-adsorption of phenol or PDS led to obviously different performances in the phenol degradation with/without the radical scavengers. Two different activation pathways of PDS, i.e., the non-radical pathway mediated by surface deprotonated phenol to generate O and the radical pathway mediated by structural Cu(I)/Cu(II) to produce SO, were therefore proposed, and the former was predominant in the CuO/PDS/phenol system. In addition, HCO and HPO could strongly inhibit the phenol degradation while Cl and NO only performed negligible effects. NaOH washing could regenerate the surface hydroxyl groups and recover the catalytic ability of CuO. The result of this study integrated the interactions among the catalyst, oxidant and substrate, providing new insights into environmental-friendly PDS activation processes.
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http://dx.doi.org/10.1016/j.scitotenv.2021.149833DOI Listing
August 2021

Long non-coding RNA TUG1 knockdown promotes autophagy and improves acute renal injury in ischemia-reperfusion-treated rats by binding to microRNA-29 to silence PTEN.

BMC Nephrol 2021 Aug 24;22(1):288. Epub 2021 Aug 24.

Department of Pediatrics, Hainan Maternal and Children's Medical Center, Changbin Road, Xiuying District, Hainan, 571199, Haikou, P.R. China.

Objective: Long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) is increased under the condition of ischemia. This study intended to identify the mechanism of TUG1 in renal ischemia-reperfusion (I/R).

Methods: First, a rat model of acute renal injury induced by I/R was established, followed by the measurement of blood urea nitrogen (BUN), serum creatine (SCr), methylenedioxyphetamine (MDA) and superoxide dismutase (SOD) in the serum of rats. TUG1 was knocked down in I/R rats (ko-TUG1 group). Next, histological staining was used to evaluate the pathological damage and apoptosis of rat kidney. Western blot analysis was used to detect the levels of apoptosis- and autophagy-related proteins and transmission electron microscope was used to observe autophagosomes. Autophagy and apoptosis were evaluated after inhibition of the autophagy pathway using the inhibitor 3-MA. The targeting relation among TUG1, microRNA (miR)-29 and phosphatase and tensin homolog (PTEN) were validated. Lastly, the effects of TUG1 on biological behaviors of renal tubular cells were evaluated in vitro.

Results: In vivo, the levels of BUN, SCr and MDA in the serum of I/R-treated rats were increased while SOD level and autophagosomes were reduced, tubule epithelial cells were necrotic, and TUG1 was upregulated in renal tissues of I/R-treated rats, which were all reversed in rats in the ko-TUG1 group. Autophagy inhibition (ko-TUG1 + 3-MA group) averted the protective effect of TUG1 knockdown on I/R-treated rats. TUG1 could competitively bind to miR-29 to promote PTEN expression. In vitro, silencing TUG1 (sh-TUG1 group) promoted viability and autophagy of renal tubular cells and inhibited apoptosis.

Conclusions: LncRNA TUG can promote PTEN expression by competitively binding to miR-29 to promote autophagy and inhibited apoptosis, thus aggravating acute renal injury in I/R-treated rats.
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http://dx.doi.org/10.1186/s12882-021-02473-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385981PMC
August 2021

LncRNA CRNDE Promotes ATG4B-Mediated Autophagy and Alleviates the Sensitivity of Sorafenib in Hepatocellular Carcinoma Cells.

Front Cell Dev Biol 2021 2;9:687524. Epub 2021 Aug 2.

Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China.

Autophagy is closely related to the growth and drug resistance of cancer cells, and autophagy related 4B (ATG4B) performs a crucial role in the process of autophagy. The long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) promotes the progression of hepatocellular carcinoma (HCC), but it is unclear whether the tumor-promoting effect of CRNDE is associated with the regulation of ATG4B and autophagy. Herein, we for the first time demonstrated that CRNDE triggered autophagy via upregulating ATG4B in HCC cells. Mechanistically, CRNDE enhanced the stability of ATG4B mRNA by sequestrating miR-543, leading to the elevation of ATG4B and autophagy in HCC cells. Moreover, sorafenib induced CRNDE and ATG4B as well as autophagy in HCC cells. Knockdown of CRNDE sensitized HCC cells to sorafenib and . Collectively, these results reveal that CRNDE drives ATG4B-mediated autophagy, which attenuates the sensitivity of sorafenib in HCC cells, suggesting that the pathway CRNDE/ATG4B/autophagy may be a novel target to develop sensitizing measures of sorafenib in HCC treatment.
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http://dx.doi.org/10.3389/fcell.2021.687524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365422PMC
August 2021

A Novel Occlusion-aware Vote Cost for Light Field Depth Estimation.

IEEE Trans Pattern Anal Mach Intell 2021 Aug 18;PP. Epub 2021 Aug 18.

Conventional light field depth estimation methods build a cost volume that measures the photo-consistency of pixels refocused to a range of depths, which works well in most regions but usually generates blurry edges in the estimated depth map due to occlusions. Existing occlusion handling methods rely on complex edge-aided processing and post-refinement, and this reliance limits the resultant depth accuracy and impacts on the computational performance. In this paper, we propose a novel occlusion-aware vote cost (OAVC) which is able to accurately preserve edges in the depth map. Instead of using photo-consistency as an indicator of the correct depth, we construct a novel cost from a new perspective that counts the number of refocused pixels whose deviations from the central-view pixel is less than a small threshold, and utilizes that number to select the correct depth. The pixels from occluders are thus excluded in determining the correct depth. Without the use of any explicit occlusion handling methods, the proposed method can inherently preserve edges and produces high-quality depth estimates. Experimental results show that the proposed OAVC outperforms state-of-the-art light field depth estimation methods in terms of depth estimation accuracy and the computational performance.
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http://dx.doi.org/10.1109/TPAMI.2021.3105523DOI Listing
August 2021

A Simple Gas-Solid Treatment for Surface Modification of Li-Rich Oxides Cathodes.

Angew Chem Int Ed Engl 2021 Oct 15;60(43):23248-23255. Epub 2021 Sep 15.

Department of Chemical Engineering, University of Sichuan, Chengdu, 610065, P. R. China.

Li-rich layered oxides with high capacity are expected to be the next generation of cathode materials. However, the irreversible and sluggish anionic redox reaction leads to the O loss in the surface as well as the capacity and voltage fading. In the present study, a simple gas-solid treatment with ferrous oxalate has been proposed to uniformly coat a thin spinel phase layer with oxygen vacancy and simultaneously realize Fe-ion substitution in the surface. The integration of oxygen vacancy and spinel phase suppresses irreversible O release, prevents electrolyte corrosion, and promotes Li-ion diffusion. In addition, the surface doping of Fe-ion can further stabilize the structure. Accordingly, the treated Feox-2 % cathode exhibits superior capacity retention of 86.4 % and 85.5 % at 1 C and 2 C to that (75.3 % and 75.0 %) of the pristine sample after 300 cycles, respectively. Then, the voltage fading is significantly suppressed to 0.0011 V per cycle at 2 C especially. The encouraging results may play a significant role in paving the practical application of Li-rich layered oxides cathode.
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http://dx.doi.org/10.1002/anie.202107955DOI Listing
October 2021

Atomistic investigation on the kinetic behavior of vapour adsorption and cluster evolution using a statistical rate theory approach.

Phys Chem Chem Phys 2021 Sep 13;23(33):18058-18067. Epub 2021 Aug 13.

Key Laboratory of Low-Grade Energy Utilization Technologies and Systems of Ministry of Education, School of Energy and Power Engineering, Chongqing University, Chongqing 400044, China.

The kinetic behavior of vapor adsorption on a solid surface in an isobaric-isothermal system is investigated by means of molecular dynamics simulations combined with theoretical studies through a statistical rate theory approach. The molecular insights into the formation and evolution of clusters in the adsorbate are presented. Results show that the argon vapor is adsorbed on the silicon surface as different types of clusters. In the initial stage of adsorption, the empty adsorption sites on the surface decrease, and the adsorbed single-molecule-cluster grows rapidly and dominates the interface. The increasing rate of the adsorbed cluster and the declining rate of the empty adsorption site are dependent on the pressure ratio. For a large pressure ratio, the single-molecule-clusters are aggregated to incubate large clusters, and the fraction of a single-molecule-cluster is decreased with time. When the adsorption isotherm is determined, the chemical potential of the adsorbed cluster is expressed from the zeta isotherm model. Then the adsorption kinetics are analyzed through the statistical rate theory. The molecular exchange rate and the instantaneous driving force are calculated. The higher pressure ratio induces the larger chemical potential difference and accelerates the net adsorption rate. The adsorption kinetics derived from MD simulations are in close agreement with the theoretical analysis of the statistical rate theory.
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http://dx.doi.org/10.1039/d1cp02800fDOI Listing
September 2021

Railway Overhead Contact System Point Cloud Classification.

Sensors (Basel) 2021 Jul 21;21(15). Epub 2021 Jul 21.

Faculty of Geoscience and Environmental Engineering, Southwest Jiaotong University, Chengdu 611756, China.

As the railway overhead contact system (OCS) is the key component along the high-speed railway, it is crucial to detect the quality of the OCS. Compared with conventional manual OCS detection, the vehicle-mounted Light Detection and Ranging (LiDAR) technology has advantages such as high efficiency and precision, which can solve the problems of OCS detection difficulty, low efficiency, and high risk. Aiming at the contact cables, return current cables, and catenary cables in the railway vehicle-mounted LiDAR OCS point cloud, this paper used a scale adaptive feature classification algorithm and the DBSCAN (density-based spatial clustering of applications with noise) algorithm considering OCS characteristics to classify the OCS point cloud. Finally, the return current cables, catenary cables, and contact cables in the OCS were accurately classified and extracted. To verify the accuracy of the method presented in this paper, we compared the experimental results of this article with the classification results of TerraSolid, and the classification results were evaluated in terms of four accuracy indicators. According to statistics, the average accuracy of using this method to extract two sets of OCS point clouds is 99.83% and 99.89%, respectively; the average precision is 100% and 99.97%, respectively; the average recall is 99.16% and 99.42%, respectively; and the average overall accuracy is 99.58% and 99.69% respectively, which is overall better than TerraSolid. The experimental results showed that this approach could accurately and quickly extract the complete OCS from the point cloud. It provides a new method for processing railway OCS point clouds and has high engineering application value in railway component detection.
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http://dx.doi.org/10.3390/s21154961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347761PMC
July 2021

Water compatible supramolecular polymers: recent progress.

Chem Soc Rev 2021 Sep 20;50(18):10025-10043. Epub 2021 Sep 20.

Department of Chemistry, The University of Texas at Austin, 105 E. 24th Street A5300, Austin, TX 78712, USA.

Water compatible supramolecular polymers (WCSPs) combine aqueous compatibility with the reversibility and environmental responsiveness of supramolecular polymers. WCSPs have seen application across a number of fields, including stimuli-responsive materials, healable materials, and drug delivery, and are attracting increasing attention from the design, synthesis, and materials perspectives. In this review, we summarize the chemistry of WCSPs from 2016 to mid-2021. For the sake of discussion, we divide WCSPs into five categories based on the core supramolecular approaches at play, namely hydrogen-bonding arrays, electrostatic interactions, large π-conjugated subunits, host-guest interactions, and peptide-based systems, respectively. We discuss both synthesis and polymer structure, as well as the underlying design expectations. The goal of this overview is to deepen our understanding of the strategies that have been exploited to prepare WCSPs, as well as their properties and uses. Thus, a section devoted to potential applications is included in this review.
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http://dx.doi.org/10.1039/d1cs00187fDOI Listing
September 2021

Correlation Analysis between Gut Microbiota and Metabolites in Children with Systemic Lupus Erythematosus.

J Immunol Res 2021 23;2021:5579608. Epub 2021 Jul 23.

Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.

Systemic lupus erythematosus (SLE) is an autoimmune-mediated diffuse connective tissue disease characterized by immune inflammation with an unclear aetiology and pathogenesis. This work profiled the intestinal flora and faecal metabolome of patients with SLE using 16S RNA sequencing and gas chromatography-mass spectrometry (GC-MS). We identified unchanged alpha diversity and partially altered beta diversity of the intestinal flora. Another important finding was the increase in Proteobacteria and Enterobacteriales and the decrease in Ruminococcaceae among SLE patients. For metabolites, amino acids and short-chain fatty acids were enriched when long-chain fatty acids were downregulated in SLE faecal samples. KEGG analysis showed the significance of the protein digestion and absorption pathway, and association analysis revealed the key role of 3-phenylpropanoic acid and . were reported to be less abundant in healthy periodontal sites of SLE patients than in those of HCs, indicating transmission of oral species to the gut. This study contributes to the understanding of the pathogenesis of SLE disease from the perspective of intestinal microorganisms, explains the pathogenesis of SLE, and serves as a basis for exploring potential treatments for the disease.
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http://dx.doi.org/10.1155/2021/5579608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325587PMC
July 2021

The mechanism of treatment of multiple myeloma with metformin by way of metabolism.

Arch Med Sci 2021 29;17(4):1056-1063. Epub 2020 Nov 29.

Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Introduction: Multiple myeloma (MM) is a malignant hematologic tumor. Although many new drugs are currently found to significantly improve the median survival, MM is still not curable due partly to drug resistance recurrence. Epidemiological studies have shown that patients with type 2 diabetes have a high risk of malignancy, and patients' treatment with metformin could reduce the risk of cancer as well as associated mortality.

Material And Methods: We used chemotherapeutics - melphalan combined with metformin or the single drug - to treat RPMI8226 cells and used a series of tests to detect the drug sensitivity, apoptotic rate, DNA damage and the concentration of ATP. SPSS 17.0 was used to analyze the data.

Results: The inhibitory effect of melphalan on RPMI8226 cells was significantly increased after metformin was added ( < 0.05), and the inhibitory effect was enhanced with the increasing concentration of melphalan. The comet assay showed that metformin increased melphalan-induced DNA damage and increased the apoptotic rate from 12.7 ±2.8% to 18.8 ±1.5% ( < 0.05). In the ATP concentration test, the concentration of ATP in the tumor cells was significantly decreased from 0.42 ±0.01 μmol/l to 0.08 ±0.02 μmol/l ( < 0.05).

Conclusions: Metformin can promote DNA damage induced by melphalan and decrease the concentration of ATP in the process of repairing DNA damage to hinder the anti-apoptotic process of tumor cells, which showed the pesticide effect of the enhanced sensitivity of multiple myeloma cells to melphalan.
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http://dx.doi.org/10.5114/aoms.2020.101305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314393PMC
November 2020

A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies.

Acta Neuropathol 2021 09 26;142(3):399-421. Epub 2021 Jul 26.

Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103, Leipzig, Germany.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may-in analogy to pGlu-Aβ peptides in Alzheimer's disease-act as a seed for pathogenic protein aggregation.
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http://dx.doi.org/10.1007/s00401-021-02349-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357657PMC
September 2021
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