Publications by authors named "Le Li"

447 Publications

Agreement of Angiography-Derived and Wire-Based Fractional Flow Reserves in Percutaneous Coronary Intervention.

Front Cardiovasc Med 2021 23;8:654392. Epub 2021 Apr 23.

Department of Cardiology, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Coronary angiography-derived fractional flow reserve (caFFR) measurements have shown good correlations and agreement with invasive wire-based fractional flow reserve (FFR) measurements. However, few studies have examined the diagnostic performance of caFFR measurements before and after percutaneous coronary intervention (PCI). This study sought to compare the diagnostic performance of caFFR measurements against wire-based FFR measurements in patients before and after PCI. Patients who underwent FFR-guided PCI were eligible for the acquisition of caFFR measurements. Offline caFFR measurements were performed by blinded hospital operators in a core laboratory. The primary endpoint was the vessel-oriented composite endpoint (VOCE), defined as a composite of vessel-related cardiovascular death, vessel-related myocardial infarction, and target vessel revascularization. A total of 105 pre-PCI caFFR measurements and 65 post-PCI caFFR measurements were compared against available wire-based FFR measurements. A strong linear correlation was found between wire-based FFR and caFFR measurements ( = 0.77; < 0.001) before PCI, and caFFR measurements also showed a high correlation ( = 0.82; < 0.001) with wire-based FFR measurements after PCI. A total of 6 VOCEs were observed in 61 patients during follow-up. Post-PCI FFR values (≤0.82) in the target vessel was the strongest predictor of VOCE [hazard ratio (HR): 5.59; 95% confidence interval (CI): 1.12-27.96; = 0.036). Similarly, patients with low post-PCI caFFR values (≤0.83) showed an 8-fold higher risk of VOCE than those with high post-PCI caFFR values (>0.83; HR: 8.83; 95% CI: 1.46-53.44; = 0.017). The study showed that the caFFR measurements were well-correlated and in agreement with invasive wire-based FFR measurements before and after PCI. Similar to wire-based FFR measurements, post-PCI caFFR measurements can be used to identify patients with a higher risk for adverse events associated with PCI.
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http://dx.doi.org/10.3389/fcvm.2021.654392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102686PMC
April 2021

Uncertainty Guided Multi-Scale Attention Network for Raindrop Removal From a Single Image.

IEEE Trans Image Process 2021 7;30:4828-4839. Epub 2021 May 7.

Raindrops adhered to a glass window or camera lens appear in various blurring degrees and resolutions due to the difference in the degrees of raindrops aggregation. The removal of raindrops from a rainy image remains a challenging task because of the density and diversity of raindrops. The abundant location and blur level information are strong prior guide to the task of raindrop removal. However, existing methods use a binary mask to locate and estimate the raindrop with the value 1 (adhesion of raindrops) and 0 (no adhesion), which ignores the diversity of raindrops. Meanwhile, it is noticed that different scale versions of a rainy image have similar raindrop patterns, which makes it possible to employ such complementary information to represent raindrops. In this work, we first propose a soft mask with the value in [-1,1] indicating the blurring level of the raindrops on the background, and explore the positive effect of the blur degree attribute of raindrops on the task of raindrop removal. Secondly, we explore the multi-scale fusion representation for raindrops based on the deep features of the input multi-scale images. The framework is termed uncertainty guided multi-scale attention network (UMAN). Specifically, we construct a multi-scale pyramid structure and introduce an iterative mechanism to extract blur-level information about raindrops to guide the removal of raindrops at different scales. We further introduce the attention mechanism to fuse the input image with the blur-level information, which will highlight raindrop information and reduce the effects of redundant noise. Our proposed method is extensively evaluated on several benchmark datasets and obtains convincing results.
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http://dx.doi.org/10.1109/TIP.2021.3076283DOI Listing
May 2021

MicroRNA-338 inhibition protects against focal cerebral ischemia and preserves mitochondrial function in vitro in astrocytes and neurons via COX4I1.

Mitochondrion 2021 Apr 30;59:105-112. Epub 2021 Apr 30.

Dept of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Brain-enriched microRNA-338 (miR-338) is known to play a central role in brain mitochondrial function, however the role of miR-338 in stroke injury remains unknown. This study investigated the role of miR-338 in injury from transient focal cerebral ischemia in mice, and in cell survival and mitochondrial function after in vitro ischemia in astrocyte and neuronal cultures. Pre-treatment of mice with intracerebroventricular injection of miR-338 antagomir 24 h prior to 1 h of middle cerebral artery occlusion (MCAO) significantly reduced infarct size and improved neurological score at both 24 h and 7d after injury. Levels of the miR-338 target cytochrome-c oxidase subunit 4I1 (COX4I1), which plays an essential role in maintaining brain mitochondrial ATP production, were increased in miR-338 antagomir-treated mice. Mouse primary astrocyte cell cultures subjected to glucose deprivation exhibited increased cell survival when pre-treated with miR-338 inhibitor, and greater cell death with miR-338 mimic. Decreased miR-338 levels were associated with increased ATP production, augmented cytochrome c oxidative (CcO) activity and preservation of COX4I1. In vitro protection with miR-338 inhibitor was blocked by concurrent knockdown of COX4I1 with small interfering RNA. Parallel studies in mouse neuronal N2a cultures resulted in preserved ATP content and CcO activity with miR-338 inhibition, indicating a shared miR-338-dependent response to ischemic stress between brain cell types. These results suggest that miR-338 inhibition and/or COX4I1-targeted therapies may be novel clinical strategies to protect against stroke injury via preservation of mitochondrial function in multiple cell types.
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http://dx.doi.org/10.1016/j.mito.2021.04.013DOI Listing
April 2021

Sliding State Analysis of Fractal Rough Interface Based on the Finite Element Method.

Materials (Basel) 2021 Apr 22;14(9). Epub 2021 Apr 22.

The Key Laboratory of Modem Measurement and Control Technology in Ministry of Education, Beijing Information Science & Technology University, Beijing 100192, China.

Local high temperature, stress concentration, and abnormal friction coefficients will appear at the friction pair in a wet clutch as a result of surface topography real-time changing. In order to improve the reliability of clutch friction components and reduce the failure phenomenon, the three-dimensional fractal surface topography data of the actual rough surface asperities are scanned, extracted, and processed successively, and then the finite element model of the rotary sliding friction pair is established considering the micro surface topography. Based on the finite element model, the variation of surface stress and strain is analyzed, and the friction coefficient measured experimentally is taken as the model input. It is concluded that when the rough surface and smooth surface make contact with each other, the maximum stress and plastic strain appear at the inner radius edge. Therefore, this research has a guiding significance for the structural design and processing technology of the friction components in a vehicle clutch.
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http://dx.doi.org/10.3390/ma14092121DOI Listing
April 2021

Large-Scale Preparation of Highly Stable Recombinant Human Acidic Fibroblast Growth Factor in BL21(DE3) plysS Strain.

Front Bioeng Biotechnol 2021 13;9:641505. Epub 2021 Apr 13.

Wenzhou Medical University, Chashan University Park, Wenzhou, China.

In this study, the optimum human gene encoding haFGF was cloned in pET3c and transferred to BL21(DE3) plysS. To enhance the yield of fermentation and the expression level of the target protein, the fermentation parameters, including temperature, pH, dissolved oxygen, glucose concentration, ammonium chloride concentration, induction time, and inducer (IPTG) concentration, were optimized. The optimized fermentation parameters were used in large-scale fermentation (30 L). Ion-exchange and heparin-affinity column chromatography techniques were used for separation and purification of rhaFGF protein. HPLC, isoelectric focusing electrophoresis, and mass spectrometry were used to detect the purity, isoelectric point, and molecular weight and peptide map of rhaFGF protein, respectively. Mitogenic activity of rhaFGF protein was detected in NIH-3T3 cells and a full-thickness injury wound diabetic rat model. The production and expression level of rhaFGF in the 30-L scale fermentation reached 80.4 ± 2.7 g/L culture and 37.8% ± 1.8%, respectively. The RP-HPLC and SDS-PAGE purity of the final rhaFGF product almost reached 100%, and the final pure protein yield was 158.6 ± 6.8 mg/L culture. Finally, the cell and animal experiments showed that rhaFGF retained a potent mitogenic activity. The large-scale process of rhaFGF production reported herein is relatively stable and time-saving, and thus, it can be used as an efficient and economic strategy for the synthesis of rhaFGF at the industrial level.
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http://dx.doi.org/10.3389/fbioe.2021.641505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072344PMC
April 2021

The feasibility and safety of same-day surgery for diaphragmatic eventration by minithoracotomy in children.

Pediatr Surg Int 2021 Apr 17. Epub 2021 Apr 17.

Department of Pediatric Thoracic Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China.

Purpose: The diaphragmatic plication procedure by thoracoscopy has gradually become standard treatment for diaphragmatic eventration (DE). However, thoracoscopic diaphragmatic plication is difficult to manipulate and the surgical learning curve is long. This study aimed to demonstrate the feasibility and safety of same-day surgery for DE by minithoracotomy in children.

Methods: From December 2017 to December 2019, we included 22 patients who underwent diaphragmatic plication of DE in the Department of Pediatric Thoracic Surgery at the Guangzhou Women and Children's Medical Center. A total of 10 patients underwent diaphragmatic plication by minithoracotomy and 12 patients underwent thoracoscopic plication. The perioperative condition and postoperative follow-up were evaluated, respectively.

Results: The age, sex, and weight were no different in the minithoracotomy group versus the thoracoscopy group (P > 0.05). The intraoperative time, blood loss volume, and postoperative hospital stay of the minithoracotomy group were significantly less than that of the thoracoscopy group (31.10 ± 4.70 min vs. 72.08 ± 22.8 min; 1.20 ± 0.42 ml vs. 2.58 ± 1.67 ml; and 1.00 ± 0.00 days vs. 6.00 ± 2.95 days, respectively, all P < 0.05). The eventration levels in these two groups were significantly different in the perioperative and postoperative periods as detected by chest X-ray. No chest tubes were inserted and no recurrence of DE occurred in the thoracoscopy group through the postoperative follow-up of at least 6 months.

Conclusion: Same-day surgery by minithoracotomy as a treatment for DE was feasible and safe with less operative time, less blood loss, and low recurrence. Same-day surgery for DE was attributed to a quick recovery. More prospective studies are necessary to further explore the consequences of same-day surgery for DE by minithoracotomy.
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http://dx.doi.org/10.1007/s00383-021-04907-0DOI Listing
April 2021

3D CT airway evaluation-guided intraluminal placement of endobronchial blocker in pediatric patients: a randomized controlled study.

Transl Pediatr 2021 Mar;10(3):625-634

Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

Background: The aim of the present study was to propose a new approach for 3D computed tomography (CT) airway evaluation-guided endobronchial blocker placement in pediatric patients, and to determine its efficiency in clinical application.

Methods: A total of 127 pediatric patients aged 0.5-3 years who were scheduled for elective thoracic surgery using one-lung ventilation (OLV) were randomized into the bronchoscopy (BRO) group and the CT group. The degree of lung collapse, postoperative airway mucosal injury, pulmonary infection within 72 h after surgery, and hoarseness after tracheal extubation; duration of postoperative mechanical ventilation, intensive care unit (ICU) stay and hospitalization; success rate of first blocker positioning; and required time and repositioning for successful blocker placement were compared between the 2 groups.

Results: The degree of lung collapse, postoperative airway mucosal injury, pulmonary infection within 72 h after surgery, and hoarseness after tracheal extubation; duration of postoperative mechanical ventilation, ICU stay and hospitalization; success rate of first blocker positioning; and required time and repositioning for successful blocker placement were similar between the 2 groups (all P>0.05).

Conclusions: For pediatric patients undergoing surgery with OLV, preoperative 3D CT airway evaluation could be used to guide endobronchial blocker placement, with a blocking efficiency similar to that of BRO-guided blocker placement.
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http://dx.doi.org/10.21037/tp-21-33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039777PMC
March 2021

Inhomogeneous and anisotropic mechanical properties of the triceps surae muscles and aponeuroses in vivo during submaximal muscle contraction.

J Biomech 2021 Mar 24;121:110396. Epub 2021 Mar 24.

Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan. Electronic address:

This study aimed to identify characteristics of the triceps surae muscles and aponeuroses stiffness in vivo, during graded isometric submaximal plantarflexion efforts. A total of twelve healthy male subjects (age: 27 ± 4 years) participated and were required to stay at rest (0% MVC) and perform isometric submaximal plantar flexion contractions (20%, 40%, 60% of MVC) on a dynamometer. Young's modulus of triceps surae muscles and the adjoining aponeuroses between gastrocnemii and soleus at the proximal and distal sites were obtained in the longitudinal direction (along muscle's line of action) during at rest and submaximal plantar flexions. Additionally, Young's modulus of adjoining aponeuroses in the transverse direction at the distal sites was also calculated. Young's modulus of LG (lateral gastrocnemius), SOL-lat (lateral part of soleus) and LPS (superficial aponeurosis of LG) at the proximal site showed significant (p < 0.001) graded increase response to the submaximal contraction levels. Besides, in the lateral side, significant differences in the Young's modulus of aponeuroses were observed between longitudinal and transverse directions at rest and during contractions (p < 0.002). Changes of aponeuroses length were significantly correlated with Young's modulus changes of the proximal gastrocnemii muscle bellies (r = 0.43-0.45, p = 0.006-0.008) and superficial aponeuroses (r = 0.49-0.60, p < 0.002). The results further indicate that the triceps surae muscles and aponeuroses showed inhomogeneous and anisotropic mechanical properties during submaximal muscle contractions, and the stiffening effect of muscle belly possibly make influence on the mechanical properties of aponeuroses during muscle contractions, especially for the lateral gastrocnemius.
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http://dx.doi.org/10.1016/j.jbiomech.2021.110396DOI Listing
March 2021

Application of 2D Materials to Potassium-Ion Hybrid Capacitors.

ChemSusChem 2021 May 7;14(9):1974-1986. Epub 2021 Apr 7.

College of Medicine, Yan'an University, Yan'an, 716000, P. R. China.

Metal-ion hybrid supercapacitors (MICs) are a new type of electrochemical energy storage (EES) device, consisting of a battery-type electrode and a supercapacitor (SC)-type electrode. Exhibiting the advantages of both batteries and SCs (e. g., good energy density, excellent power density and long cycle life), these advanced energy storage devices have considerable commercial application prospects. Among MICs, potassium-ion hybrid supercapacitors (PICs) have several further advantages, including abundancy of resources, low standard electrode potential, and low cost. PICs are regarded as potential substitutes for lithium- or sodium-ion hybrid supercapacitors. However, the practical applications of PICs remain limited, owing to the imbalance of kinetics and capacity between the electrodes, the slow ion/electron diffusion rate, and the poor electrode structural stability. Recently, 2D materials with distinct structures and fascinating features have elicited widespread attention for application in PICs, thus achieving significant enhancements, ranging from charge storage capacity to reaction kinetics. This Review discusses research progress in 2D materials for PICs. Firstly, the energy storage principle and development requirements of MICs are introduced. The pivotal advantages and significant roles of 2D materials in the fabrication of PICs are then discussed in detail. Lastly, the challenges and prospects of the application of 2D materials to high-performance PICs are presented.
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http://dx.doi.org/10.1002/cssc.202100255DOI Listing
May 2021

The importance of intervertebral disc material model on the prediction of mechanical function of the cervical spine.

BMC Musculoskelet Disord 2021 Apr 2;22(1):324. Epub 2021 Apr 2.

Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, Canada.

Background: Linear elastic, hyperelastic, and multiphasic material constitutive models are frequently used for spinal intervertebral disc simulations. While the characteristics of each model are known, their effect on spine mechanical response requires a careful investigation. The use of advanced material models may not be applicable when material constants are not available, model convergence is unlikely, and computational time is a concern. On the other hand, poor estimations of tissue's mechanical response are likely if the spine model is oversimplified. In this study, discrepancies in load response introduced by material models will be investigated.

Methods: Three fiber-reinforced C2-C3 disc models were developed with linear elastic, hyperelastic, and biphasic behaviors. Three different loading modes were investigated: compression, flexion and extension in quasi-static and dynamic conditions. The deformed disc height, disc fluid pressure, range of motion, and stresses were compared.

Results: Results indicated that the intervertebral disc material model has a strong effect on load-sharing and disc height change when compression and flexion were applied. The predicted mechanical response of three models under extension had less discrepancy than its counterparts under flexion and compression. The fluid-solid interaction showed more relevance in dynamic than quasi-static loading conditions. The fiber-reinforced linear elastic and hyperelastic material models underestimated the load-sharing of the intervertebral disc annular collagen fibers.

Conclusion: This study confirmed the central role of the disc fluid pressure in spinal load-sharing and highlighted loading conditions where linear elastic and hyperelastic models predicted energy distribution different than that of the biphasic model.
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http://dx.doi.org/10.1186/s12891-021-04172-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017640PMC
April 2021

Newcastle Disease Virus Entry into Chicken Macrophages via a pH-Dependent, Dynamin and Caveola-Mediated Endocytic Pathway That Requires Rab5.

J Virol 2021 Mar 24. Epub 2021 Mar 24.

Division of Avian Infectious Diseases, the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, the People's Republic of China

The cellular entry pathways and the mechanisms of Newcastle disease virus (NDV) entry into cells are poorly characterized. In this study, we demonstrated that chicken interferon-induced transmembrane protein 1 (chIFITM1) which is located in the early endosomes could limit the replication of NDV in chicken macrophage cell line HD11, suggesting the endocytic entry of NDV into chicken macrophages. Then, we presented a systematic study about the entry mechanism of NDV into chicken macrophages. First, we demonstrated that a low-pH condition and dynamin were required during NDV entry. However, NDV entry into chicken macrophages was independent of clathrin-mediated endocytosis. We also found that NDV entry was dependent on membrane cholesterol. The NDV entry and replication were significantly reduced by nystatin and Phorbol 12-myristate 13-acetate treatment, overexpression of dominant negative (DN) caveolin-1 or knockdown of caveolin-1, suggesting that NDV entry depends on caveola-mediated endocytosis. However, macropinocytosis did not play a role in NDV entry into chicken macrophages. Additionally, we found that Rab5, rather than Rab7, was involved in the entry and traffic of NDV. The colocalization of NDV with Rab5 and early endosome suggested that NDV virion was transported to early endosomes in a Rab5-dependent manner after internalization. Of particular note, the caveola-mediated endocytosis was also utilized by NDV to enter primary chicken macrophages. And NDV entered different cell types using different pathways. Collectively, our findings demonstrate for the first time that NDV virion enters chicken macrophages via a pH-dependent, dynamin and caveola-mediated endocytosis pathway and Rab5 is involved in the traffic and location of NDV.Although the pathogenesis of Newcastle disease virus (NDV) has been extensively studied, the detailed mechanism of NDV entry into host cells is largely unknown. Macrophages are the first-line defenders of host defense against infection of pathogens. Chicken macrophages are considered as one of the main types of target cells during NDV infection. Here, we comprehensively investigated the entry mechanism of NDV in chicken macrophages. This is the first report to demonstrate that NDV enters chicken macrophages via a pH-dependent, dynamin and caveola-mediated endocytosis pathway that requires Rab5. The result is important for our understanding of the entry of NDV in chicken macrophages, which will further advance the knowledge of NDV pathogenesis and provide useful clues for the development of novel preventive or therapeutic strategies against NDV infection. In addition, this information will contribute to our further understanding of pathogenesis with regard to other numbers of genus in family.
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http://dx.doi.org/10.1128/JVI.02288-20DOI Listing
March 2021

The role and mechanisms of polycomb repressive complex 2 on the regulation of osteogenic and neurogenic differentiation of stem cells.

Cell Prolif 2021 May 23;54(5):e13032. Epub 2021 Mar 23.

Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.

The stem cells differentiate into osteoblasts or neurocytes is the key process for treatment of bone- or neural tissue-related diseases which is caused by ageing, fracture, injury, inflammation, etc Polycomb group complexes (PcGs), especially the polycomb repressive complex 2 (PRC2), act as pivotal epigenetic regulators by modifying key developmental regulatory genes during stem cells differentiation. In this review, we summarize the core subunits, the variants and the potential functions of PRC2. We also highlight the underlying mechanisms of PRC2 associated with the osteogenic and neurogenic differentiation of stem cells, including its interaction with non-coding RNAs, histone acetyltransferases, histone demethylase, DNA methyltransferase and polycomb repressive complex 1. This review provided a substantial information of epigenetic regulation mediated by PRC2 which leads to the osteogenic and neurogenic differentiation of stem cells.
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http://dx.doi.org/10.1111/cpr.13032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088470PMC
May 2021

in Qinghai-Tibet plateau: population structure and confirmation of additional endemic areas.

Parasitology 2021 Mar 24:1-8. Epub 2021 Mar 24.

State Key Laboratory of Veterinary Etiological Biology/National Professional Laboratory for Animal Echinococcosis/Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, CAAS, Lanzhou730046, Gansu Province, People's Republic of China.

Echinococcus shiquicus is currently limited to the Qinghai–Tibet plateau, a large mountainous region in China. Although the zoonotic potential remains unknown, progress is being made on the distribution and intermediate host range. In this study, we report E. shiquicus within Gansu and Qinghai provinces in regions located not only around the central areas but also the southeast edge of the plateau and describe their genetic relationship with previous isolates from the plateau. From 1879 plateau pikas examined, 2.39% (95% CI 1.79–3.18) were infected with E. shiquicus. The highest prevalence of 10.26% (4.06–23.58) was recorded in Makehe town, Qinghai province. Overall the prevalence was marginally higher in Qinghai (2.5%, CI 1.82–3.43) than in Gansu (2%, CI 1.02–3.89). The cox1 and nad1 genes demonstrated high and low haplotype and nucleotide diversities, respectively. The median-joining network constructed by the cox1–nad1 gene sequences demonstrated a star-like configuration with a median vector (unsampled haplotype) occupying the centre of the network. No peculiar distinction or common haplotype was observed in isolates originating from the different provinces. The presence of E. shiquicus in regions of the southeast and northeast edges of the Qinghai–Tibet plateau and high genetic variation warrants more investigation into the haplotype distribution and genetic polymorphism by exploring more informative DNA regions of the mitochondrial genome to provide epidemiologically useful insight into the population structure of E. shiquicus across the plateau and its axis.
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http://dx.doi.org/10.1017/S0031182021000512DOI Listing
March 2021

Investigation of multidrug-resistance mutations of hepatitis B virus (HBV) in a large cohort of chronic HBV-infected patients with treatment of nucleoside/nucleotide analogs.

Antiviral Res 2021 May 9;189:105058. Epub 2021 Mar 9.

Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. Electronic address:

Multidrug-resistance hepatitis B virus (MDR HBV), defined as those with mutations resistant to both nucleoside analogs lamivudine/telbivudine/entecavir (LAM/LdT/ETV) and nucleotide analog adefovir (ADV), has potential to cause treatment difficulty. To clarify clinical prevalence and virological features of MDR HBV, we investigated serum samples from 28,236 chronic HBV-infected patients with treatment of nucleoside/nucleotide analogs. All patients underwent resistance testing in the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2019. MDR mutations were screened by direct sequencing; MDR strains (with mutations co-located on the same viral genome) were verified by clonal sequencing (≥20 clones/sample) and subjected to phenotypic analysis if necessary. MDR mutations were detected in 0.81% (229/28,236) patients. MDR strains were verified in 83.0% (190/229) of MDR mutation-positive patients. As ETV-resistance mutation (ETVr) had additional mutation(s) on LAMr conferring more resistance, MDR mutations fell into LAMr + ADVr and ETVr + ADVr subsets. Sixteen mutation patterns of MDR strains were verified, including eight with LAMr + ADVr and eight with ETVr + ADVr. Refractory to sequential therapies of LAM/LdT/ETV and ADV were closely linked with MDR HBV development. Ten representative MDR strains (five LAMr + ADVr and five ETVr + ADVr) tested all had decrease in replication capacity compared to wild-type strains and decrease extent was positively related with the number of primary resistance on viral genome. Compared to ADV + ETV, TDF/TDF + ETV showed higher inhibitory rates on MDR HBV, especially for the five ETVr + ADVr strains (74.5%-97.6% vs. 60.2%-79.5%, all P < 0.05). This study significantly extends the knowledge on MDR HBV and has clinical implications for resistance management.
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http://dx.doi.org/10.1016/j.antiviral.2021.105058DOI Listing
May 2021

Cortical Representations of Transversus Abdominis and Multifidus Muscles Were Discrete in Patients with Chronic Low Back Pain: Evidence Elicited by TMS.

Neural Plast 2021 18;2021:6666024. Epub 2021 Feb 18.

Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.

Introduction: The transversus abdominis (TVA) and multifidus (MF) muscles are the main segmental spinal stabilizers that are controlled by the primary motor cortex of the brain. However, relocations of the muscle representation in the motor cortex may occur after chronic lower back pain (cLBP); it still needs more evidence to be proven. The current study was aimed at applying transcranial magnetic stimulation (TMS) to investigate the changes of representation of TVA and MF muscles at the cortical network in individuals with cLBP.

Methods: Twenty-four patients with cLBP and 12 age-matched healthy individuals were recruited. Responses of TVA and MF to TMS during muscle contraction were monitored and mapped over the contralateral cortex using a standardized grid cap. Maps of the center of gravity (CoG), area, volume, and latency were analyzed, and the asymmetry index was also computed and compared.

Results: The locations of MF CoG in cLBP individuals were posterior and lateral to the CoG locations in healthy individuals. In the healthy group, the locations of TVA and MF CoG were closed to each other in both the left and right hemispheres. In the cLBP group, these two locations were next to each other in the right hemisphere but discrete in the left hemisphere. In the cLBP group, the cortical motor map of TVA and MF were mutually symmetric in five out of eleven (45.5%) subjects and leftward asymmetric in four out of ten (40.0%) subjects.

Conclusions: Neural representations of TVA and MF muscles were closely organized in both the right and left motor cortices in the healthy group but were discretely organized in the left motor cortex in the cLBP group. This provides strong support for the neural basis of pathokinesiology and clinical treatment of cLBP.
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http://dx.doi.org/10.1155/2021/6666024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906820PMC
February 2021

Molecular characterization and expression analysis of Japanese flounder (Paralichthys olivaceus) chemokine receptor CXCR2 in comparison with CXCR1.

Dev Comp Immunol 2021 Jul 26;120:104047. Epub 2021 Feb 26.

Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, Konan 4-5-7, Minato-ku, Tokyo, 108-8477, Japan.

Chemokines are categorized into five families; one of the families is the CXC chemokines, which are critical in the pro-inflammatory process. CXC chemokines transmit signals and mediate a cell's biological activities by binding to cell surface receptors known as chemokine receptors (CXCRs). In this study, the CXCR2 from Japanese flounder (Paralichthys olivaceus) (JfCXCR2) was identified and characterized at the molecular level. The JfCXCR2 gene has a 1077 bp open reading frame that encodes a protein of 359 amino acid residues with seven transmembrane domains. Phylogenetic analysis of JfCXCR2 revealed that it belonged to the fish CXCR2 subfamily. Furthermore, JfCXCR2 was compared with the previously identified Japanese flounder CXCR1 (JfCXCR1). The expression analysis of uninfected Japanese flounder showed that JfCXCR1 and JfCXCR2 were expressed in all the tissues and organs tested but mainly in immune-related organs, including the kidney and spleen. Infection by Streptococcus iniae significantly increased the level of JfCXCR1 and JfCXCR2 mRNA in the kidney at days 1 and 3 post-infection. On the other hand, VHSV (viral hemorrhagic septicemia virus) and Edwardsiella tarda infection significantly increased JfCXCR2 mRNA levels in the kidney at days 3 and 6 post-infection, respectively. Conversely, JfCXCR1 expression was not significantly changed by either E. tarda or VHSV infection. Additionally, the peripheral blood leukocytes (PBLs) stimulated by recombinant proteins rCXCL8_L1a and rCXCL8_L1b were found to have significantly increased levels of JfCXCR1 and JfCXCR2 mRNA. Interestingly, even higher levels of JfCXCR1 and JfCXCR2 expression were observed in PBLs stimulated with rCXCL8_L1a and rCXCL8_L1b than in PBLs stimulated with either recombinant protein. These data suggest that bacterial infections may activate JfCXCR1. By contrast, JfCXCR2 may be activated by both bacterial and viral infection to mediate the immune response. These data can contribute to further understanding the functions of CXCR1 and CXCR2 in the fish immune system.
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http://dx.doi.org/10.1016/j.dci.2021.104047DOI Listing
July 2021

Surgical Treatment for Asymptomatic Congenital Pulmonary Airway Malformations in Children: Waiting or Not?

Eur J Pediatr Surg 2021 Feb 28. Epub 2021 Feb 28.

College of Life Science, Jining Medical University, Jining, Shandong, China.

Introduction:  Infection is undoubtedly the most important factor in influencing the timing and surgical strategy of congenital pulmonary airway malformation (CPAM) surgery. However, there have been no studies on the optimal timing of surgery for patients based on the probability of infection. The aim of this study was performed to explore the optimal timing of surgery of CPAM in children from the risk of infection.

Materials And Methods:  The correlation of age distribution and pulmonary infection of 237 children diagnosed by pathology from January 2012 to January 2020 in Guangzhou Women and Children's Medical Center were analyzed retrospectively. We defined the cases with preoperative computed tomographic findings of infection, pathological findings of large number of neutrophils, tissue cells, and abscess formation as the infection group.

Results:  The rate of infection in patients less than 2 years old was significantly lower than in patients over 2 years old (11.4% vs. 45.7%,  < 0.001). And the pulmonary lobectomy rate of patients with infection (29.0%) was significantly higher than in noninfected patients (17.2%) and whole patients (36.3%),  = 0.033. Patients with infection lose more blood during surgery (noninfected patients: 81.76 ± 13.14 mL, infected patients: 145.10 ± 25.39 mL,  = 0.027). The univariate analysis revealed that the infection rate of patients over 2 years old was 3.084 times that of patients ≤2 years old (odds ratio [OR]: 3.084, 95% confidence interval [CI]: 1.196-7.954;  = 0.020). The infection rate of CPAM types III and IV patients is lower than types I and II (OR: 0.531, 95% CI: 0.307-0.920;  = 0.024).

Conclusion:  In consideration of the high risk of infection, lower minimally invasive surgery rate, an increased rate of pulmonary lobectomy, and more blood loss in patients over 2 years old, our study also supports early surgical treatment. Therefore, we suggest that for asymptomatic patients with CPAM I and CPAM II, surgical treatment should be performed when they are less than 2 years old, providing more options for surgical strategies and monitoring of CPAM patients.
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http://dx.doi.org/10.1055/s-0040-1719057DOI Listing
February 2021

Eight-week antidepressant treatment reduces functional connectivity in first-episode drug-naïve patients with major depressive disorder.

Hum Brain Mapp 2021 Jun 27;42(8):2593-2605. Epub 2021 Feb 27.

CAS Key Laboratory of Behavioral Science, Institute of Psychology, Beijing, China.

Previous neuroimaging studies have revealed abnormal functional connectivity of brain networks in patients with major depressive disorder (MDD), but findings have been inconsistent. A recent big-data study found abnormal intrinsic functional connectivity within the default mode network in patients with recurrent MDD but not in first-episode drug-naïve patients with MDD. This study also provided evidence for reduced default mode network functional connectivity in medicated MDD patients, raising the question of whether previously observed abnormalities may be attributable to antidepressant effects. The present study (ClinicalTrials.gov identifier: NCT03294525) aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Forty-one first-episode drug-naïve MDD patients were administrated antidepressant medication (escitalopram or duloxetine) for 8 weeks, with resting-state functional connectivity compared between posttreatment and baseline. To assess the replicability of the big-data finding, we also conducted a cross-sectional comparison of resting-state functional connectivity between the MDD patients and 92 matched healthy controls. Both Network-Based Statistic analyses and large-scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, indicating considerable antidepressant effects. Neither Network-Based Statistic analyses nor large-scale network analyses detected significant functional connectivity differences between treatment-naïve patients and healthy controls. In short, antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD.
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http://dx.doi.org/10.1002/hbm.25391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090770PMC
June 2021

Associations between gene polymorphisms and neuroblastoma susceptibility in Chinese children.

Transl Pediatr 2021 Jan;10(1):146-152

Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

Background: Previous studies have revealed that WTAP is related to multiple types of cancer. Recently, WTAP has been reported as an independent prognostic factor in patients with neuroblastoma.

Methods: To explore the association between three polymorphisms (rs9457712 G>A, rs1853259 A>G and rs7766006 G>T) and neuroblastoma susceptibility in Chinese populations, we performed this case-control study including 898 neuroblastoma cases and 1,734 controls. We genotyped these potentially functional single nucleotide polymorphisms (SNPs) by TaqMan assays. The odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression models were used to assess the relationship between SNPs and the risk of neuroblastoma.

Results: No significant associations were observed in the overall analysis between any of the three polymorphisms and the risk of neuroblastoma. However, in the age ≤18 months subgroup, we found that the rs1853259 AG/GG genotype exerted protective effects against neuroblastoma (adjusted OR =0.77, 95% CI: 0.59-0.998, P=0.048), whereas the presence of 1-2 combined risk genotypes significantly increased the risk of neuroblastoma (adjusted OR =1.32, 95% CI: 1.02-1.71, P=0.036).

Conclusions: gene polymorphisms only have a weak impact on the risk of neuroblastoma in the Chinese children. Further case-control studies, preferable on larger sample sizes, are needed to validate our results.
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http://dx.doi.org/10.21037/tp-20-168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882302PMC
January 2021

Alternative splicing: An important regulatory mechanism in colorectal carcinoma.

Mol Carcinog 2021 04 25;60(4):279-293. Epub 2021 Feb 25.

Department of Pathology, Harbin Medical University, Harbin, China.

Alternative splicing (AS) is a process that produces various mRNA splicing isoforms via different splicing patterns of mRNA precursors (pre-mRNAs). AS is the primary mechanism for increasing the types and quantities of proteins to improve biodiversity and influence multiple biological processes, including chromatin modification, signal transduction, and protein expression. It has been reported that AS is involved in the tumorigenesis and development of colorectal carcinoma (CRC). In this review, we delineate the concept, types, regulatory processes, and technical advances of AS and focus on the role of AS in CRC initiation, progression, treatment, and prognosis. This summary of the current knowledge about AS will contribute to our understanding of CRC initiation and development. This study will help in the discovery of novel biomarkers and therapeutic targets for CRC prognosis and treatment.
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http://dx.doi.org/10.1002/mc.23291DOI Listing
April 2021

Mechanistic Insights into the Co-Aggregation of Aβ and hIAPP: An All-Atom Molecular Dynamic Study.

J Phys Chem B 2021 03 22;125(8):2050-2060. Epub 2021 Feb 22.

State Key Laboratory of Surface Physics and Department of Physics, Fudan University, 2005 Songhu Road, Shanghai 200438, China.

Patients with Alzheimer's disease (AD) have a high risk of developing Type II diabetes (T2D). The co-aggregation of the two disease-related proteins, Aβ and hIAPP, has been proposed as a potential molecular mechanism. However, the detailed Aβ-hIAPP interactions and structural characteristics of co-aggregates are mostly unknown at atomic level. Here, we explore the conformational ensembles of the Aβ-hIAPP heterodimer and Aβ or hIAPP homodimer by performing all-atom explicit-solvent replica exchange molecular dynamic simulations. Our simulations show that the interaction propensity of Aβ-hIAPP in the heterodimer is comparable with that of Aβ-Aβ/hIAPP-hIAPP in the homodimer. Similar hot spot residues of Aβ/hIAPP in the homodimer and heterodimer are identified, indicating that both Aβ and hIAPP have similar molecular recognition sites for self-aggregation and co-aggregation. Aβ in the heterodimer possesses three high β-sheet probability regions: the N-terminal region E3-H6, the central hydrophobic core region K16-E22, and the C-terminal hydrophobic region I31-A41, which is highly similar to Aβ in the homodimer. More importantly, in the heterodimer, the regions E3-H6, F19-E22, and I31-M35 of Aβ and the amyloid core region N20-T30 of hIAPP display higher β-sheet probability than they do in homodimer, implying their crucial roles in the formation of β-sheet-rich co-aggregates. Our study sheds light on the co-aggregation of Aβ and hIAPP at an atomic level, which will be helpful for an in-depth understanding of the molecular mechanism for epidemiological correlation of AD and T2D.
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http://dx.doi.org/10.1021/acs.jpcb.0c11132DOI Listing
March 2021

Comprehensive phytochemical analysis and sedative-hypnotic activity of two species leaves.

Food Funct 2021 Mar;12(5):2292-2311

College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.

Acanthopanax senticosus leaves (SCL) and Acanthopanax sessiliflorus leaves (SFL), which are usually made into functional teas, possess similar pharmacological activities. With the aim of revealing their chemical compositions and evaluating their sedative-hypnotic effects, comprehensive metabolite profiling analysis based on ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS) and high-performance liquid chromatography with evaporative light scattering detection (HPLC-ELSD) as well as bioassay studies in mice were performed for the first time. Firstly, a total of 75 compounds (including 69 shared components) were identified or briefly characterized. Results indicated that the leaves of the two species were both rich in phytochemicals and contained similar structural types. Secondly, 20 and 7 chemical markers were identified from SCL and SFL, respectively. Five oleanane-type triterpene saponins (ciwujianoside C1, C3, D2, E and saniculoside N) and two lupine-type triterpene saponins (1-deoxychiisanoside and 24-hydroxychiisanoside) may be used for rapid identification of SCL and SFL. Thirdly, the contents of rutin, hederacoside D, ciwujianoside B, -C3, -E and ursolic acid in SCL (0.308%, 0.024%, 0.042%, 0.131%, 0.038%, and 0.255%, respectively) were higher than in SFL (0.067%, 0.005%, 0.012%, 0.015%, 0.002%, and 0.087%, respectively). Fourthly, an in vivo bioassay verified that both SCL and SFL could inhibit autonomous activity, shorten sleep latency and prolong sleep duration in a dose-dependent manner. To a certain degree, SCL showed a higher and more stable effect. The hypnotic effect could be inhibited by flumazenil (FLU). The two leaves not only had an obvious antagonism action of p-chlorophenoxyacetic acid (pCPA) but also showed a synergistic hypnotic effect with 5-hydroxytryptophan (5-HTP). The beneficial bioactivity may be mediated by 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA). Finally, network pharmacology analysis showed that the undifferentiated and differentiated compounds were the material basis for the similar and the different activities of two leaves. Some typical chemical markers (such as saniculoside N, hederacoside D, ciwujianoside C3, -E and ursolic acid, 24-hydroxychiisanoside and 1-deoxyisochiisanoside) were the potential active compounds and could be used as quality markers in the future. The present study furnished a basis for the further development and utilization of the leaves of these two Acanthopanax species.
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http://dx.doi.org/10.1039/d0fo02814bDOI Listing
March 2021

Multiple drug-resistant HBV mutation may contribute to poor response of adefovir + entecavir in entecavir-resistant patients.

J Infect Dev Ctries 2021 Jan 31;15(1):131-140. Epub 2021 Jan 31.

The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China.

Introduction: Adefovir plus entecavir (ADV+ETV) rescue therapy in ETV-resistant patients with chronic hepatitis B virus (HBV) infection is suboptimal in some patients. This study aims to elucidate the evolutionary characteristics of drug-resistant HBV mutants and their association with clinical responses in such patients.

Methodology: Thirty-seven ETV-resistant patients were enrolled, among whom twelve had an inadequate virological response to ADV+ETV rescue therapy. The clonal sequence (³ 20 clones/sample) of HBV reverse transcriptase gene was performed to identify the resistance mutations. Phenotypic analysis was performed to evaluate the replication capacity and drug susceptibility of the mutants.

Results: ETV-resistant mutants were continuously detected in 10 of the 12 patients, and multidrug-resistant (MDR) mutants, including a novel strain (rtL180M+A181V+T184A+S202G+M204V), were detected in two patients. Seven of the 12 patients who subsequently received tenofovir (TDF)-based therapy for 38 (23-60) months all achieved undetectable HBV DNA after treatment, and ETV-resistant mutants converted to wild-type in the four patients' samples. In contrast, the other five patients who did not achieve an adequate virological response had remaining of ETV-resistant mutants. The novel MDR strain exhibited multiple resistances to LAM, ADV, and ETV, and 11.2-fold lower susceptibility to TDF.

Conclusions: This study is the first to demonstrate that MDR HBV mutations may contribute to the poor efficacy of ADV+ETV combination therapy in ETV-resistant patients. Moreover, a novel MDR HBV strain was identified. Our results indicate that a TDF-based rescue therapy would be effective for the treatment of the refractory cases.
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http://dx.doi.org/10.3855/jidc.12643DOI Listing
January 2021

Multiple drug-resistant HBV mutation may contribute to poor response of adefovir + entecavir in entecavir-resistant patients.

J Infect Dev Ctries 2021 Jan 31;15(1):131-140. Epub 2021 Jan 31.

The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China.

Introduction: Adefovir plus entecavir (ADV+ETV) rescue therapy in ETV-resistant patients with chronic hepatitis B virus (HBV) infection is suboptimal in some patients. This study aims to elucidate the evolutionary characteristics of drug-resistant HBV mutants and their association with clinical responses in such patients.

Methodology: Thirty-seven ETV-resistant patients were enrolled, among whom twelve had an inadequate virological response to ADV+ETV rescue therapy. The clonal sequence (³ 20 clones/sample) of HBV reverse transcriptase gene was performed to identify the resistance mutations. Phenotypic analysis was performed to evaluate the replication capacity and drug susceptibility of the mutants.

Results: ETV-resistant mutants were continuously detected in 10 of the 12 patients, and multidrug-resistant (MDR) mutants, including a novel strain (rtL180M+A181V+T184A+S202G+M204V), were detected in two patients. Seven of the 12 patients who subsequently received tenofovir (TDF)-based therapy for 38 (23-60) months all achieved undetectable HBV DNA after treatment, and ETV-resistant mutants converted to wild-type in the four patients' samples. In contrast, the other five patients who did not achieve an adequate virological response had remaining of ETV-resistant mutants. The novel MDR strain exhibited multiple resistances to LAM, ADV, and ETV, and 11.2-fold lower susceptibility to TDF.

Conclusions: This study is the first to demonstrate that MDR HBV mutations may contribute to the poor efficacy of ADV+ETV combination therapy in ETV-resistant patients. Moreover, a novel MDR HBV strain was identified. Our results indicate that a TDF-based rescue therapy would be effective for the treatment of the refractory cases.
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http://dx.doi.org/10.3855/jidc.12643DOI Listing
January 2021

The Effects of Extracorporeal Shock Wave Therapy on Spastic Muscle of the Wrist Joint in Stroke Survivors: Evidence From Neuromechanical Analysis.

Front Neurosci 2020 21;14:580762. Epub 2021 Jan 21.

Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

This study combined neuromechanical modeling analysis, muscle tone measurement from mechanical indentation and electrical impedance myography to assess the neural and peripheral contribution to spasticity post stroke at wrist joint. It also investigated the training effects and explored the underlying mechanism of radial extracorporeal shock wave (rESW) on spasticity. People with first occurrence of stroke were randomly allocated to rESW intervention or control group. The intervention group received one session of rESW therapy, followed by routine therapy which was the same frequency and intensity as the control group. Outcome measures were: (1) NeuroFlexor method measured neural component (NC), elastic component (EC) and viscosity component (VC), and (2) myotonometer measured muscle tone (F) and stiffness (S), (3) electrical impedance myography measured resistance (R), reactance (X) and phase angle (θ); (4) modified Asworth scale; (5) Fugl Meyer Upper limb scale. All outcome measures were recorded at baseline, immediately post rESW and at 1-week follow-up. The differences between the paretic and non-paretic side were assessed by -test. The effectiveness of rESW treatment were analyzed by repeated-measures one-way analysis of variance (ANOVA) at different time points. Twenty-seven participants completed the study. NC, EC, and VC of the Neuroflexor method, F and S from myotonometer were all significantly higher on the paretic side than those from the non-paretic side. R, X, and θ from electrical impedance were significantly lower on the paretic side than the non-paretic side. Immediately after rESW intervention, VC, F, and S were significantly reduced, and X was significantly increased. The clinical scores showed improvements immediate post rESW and at 1-week follow-up. The observed changes in upper limb muscle properties adds further support to the theory that both the neural and peripheral components play a role in muscle spasticity. ESW intervention may be more effective in addressing the peripheral component of spasticity in terms of muscle mechanical properties changes. The clinical management of post stroke spasticity should take into consideration of both the neural and non-neural factors in order to identify optimal intervention regime.
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http://dx.doi.org/10.3389/fnins.2020.580762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859269PMC
January 2021

KLF9 regulates PRDX6 expression in hyperglycemia-aggravated bupivacaine neurotoxicity.

Mol Cell Biochem 2021 May 5;476(5):2125-2134. Epub 2021 Feb 5.

Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.

Background: Neurotoxicity induced by local anesthetics (LAs) is potentially life threatening, especially for patients with underlying diseases like diabetes. The anesthetic bupivacaine (Bup) has been reported to induce neurotoxicity mediated by reactive oxygen species (ROS), which is aggravated by hyperglycemia. Krüppel-like factor 9 (KLF9), an axon growth-suppressing transcription factor, plays a key role in neuronal maturation and promotes oxidative stress. This study was designed to investigate whether and how KLF9 regulates ROS levels related to LA neurotoxicity under hyperglycemic conditions.

Methods: Klf9/GFP ShRNA (LV Sh-Klf9) was used to achieve stable Klf9 knockdown in the SH-SY5Y cell line. KLF9-deficient and normal cells were cultured under normal or high-glucose (HG) culture conditions and then exposed to Bup. Cell viability, intracellular and mitochondrial ROS, and mitochondrial membrane potential (ΔΨm) were detected to examine the role of KLF9. Thereafter, KLF9-deficient and normal cells were pretreated with small-interfering RNA targeting peroxiredoxin 6 (siRNA-Prdx6) to determine if PRDX6 was the target protein in HG-aggravated Bup neurotoxicity.

Results: The mRNA and protein levels of KLF9 were increased after Bup and hyperglycemia treatment. In addition, cell survival and mitochondrial function were significantly improved, and ROS production was decreased after Sh-Klf9 treatment compared with Sh-Ctrl. Furthermore, the expression of PRDX6 was suppressed by Bup in hyperglycemic cultures and was upregulated in the Sh-Klf9 group. Moreover, the protection provided by KLF9 deficiency for cell survival, the increase in ROS production in cells and mitochondria, and the disruption of mitochondrial function were abolished by Prdx6 knockdown.

Conclusions: The results of this study demonstrated that hyperglycemia aggravated Bup neurotoxicity by upregulating KLF9 expression, which repressed the antioxidant PRDX6 and led to mitochondrial dysfunction, ROS burst, and cell death. Understanding this mechanism may, thus, offer valuable insights for the prevention and treatment of neurotoxicity induced by LAs, especially in diabetic patients.
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http://dx.doi.org/10.1007/s11010-021-04059-8DOI Listing
May 2021

Synthesis and Anti-Hepatocarcinoma Effect of Amino Acid Derivatives of Pyxinol and Ocotillol.

Molecules 2021 Feb 3;26(4). Epub 2021 Feb 3.

School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China.

Aiming at seeking an effective anti-hepatocarcinoma drug with low toxicity, a total of 24 amino acid derivatives (20 new along with 4 known derivatives) of two active ocotillol-type sapogenins (pyxinol and ocotillol) were synthesized. Both in vitro and in vivo anti-hepatocarcinoma effects of derivatives were evaluated. At first, the HepG2 human cancer cell was employed to evaluate the anti-cancer activity. Most of the derivatives showed obvious enhanced activity compared with pyxinol or ocotillol. Among them, compound displayed the most excellent activity with an IC value of 11.26 ± 0.43 µM. Next, H22 hepatoma-bearing mice were used to further evaluate the anti-liver cancer activity of compound . It was revealed that the growth of H22 transplanted tumor was significantly inhibited when treated with compound or compound combined with cyclophosphamide (CTX) ( < 0.05, < 0.01), and the inhibition rates of tumor growth were 35.32% and 55.30%, respectively. More importantly, compound caused limited damage to liver and kidney in contrast with CTX causing significant toxicity. Finally, the latent mechanism of compound was explored by serum and liver metabolomics based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. A total of 21 potential metabolites involved in 8 pathways were identified. These results suggest that compound is a promising agent for anti-hepato-carcinoma, and that it also could be used in combination with CTX to increase efficiency and to reduce toxicity.
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http://dx.doi.org/10.3390/molecules26040780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913291PMC
February 2021

Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19.

Theranostics 2021 1;11(5):2170-2181. Epub 2021 Jan 1.

Department of Medicine, the University of Hong Kong, Hong Kong SAR, China.

An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin-converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow. We analysed clinical features in a cohort of 173 children with COVID-19 (0-15 yrs.-old) between January 22, 2020 and March 15, 2020. We systematically examined the expression and distribution of in different developmental stages of children by using a combination of children's lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and SARS-CoV-2 pseudoviral infections. It revealed that infants (< 1yrs.-old), with a weaker potency of immune response, are more vulnerable to develop pneumonia whereas older children (> 1 yrs.-old) are more resistant to lung injury. The expression levels of however do not vary by age in children's lung. is notably expressed not only in Alveolar Type II (AT II) cells, but also in positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants' lungs. The cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children. Infants (< 1 yrs.-old) with SARS-CoV-2 infection are more vulnerable to lung injuries. expression in multiple types of lung cells including positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19. There is a need to continue monitoring lung development in young children who have recovered from SARS-CoV-2 infection.
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http://dx.doi.org/10.7150/thno.53136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797681PMC
February 2021

Modeling paraquat-induced lung fibrosis in reveals KRIT1 as a key regulator of collagen gene transcription.

Aging (Albany NY) 2021 01 20;13(3):4452-4467. Epub 2021 Jan 20.

Department of Emergency, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, China.

Paraquat poisoning causes lung fibrosis, which often results in long-term pulmonary dysfunction. Lung fibrosis has been attributed to collagens accumulation, but the underlying regulatory pathway remains unclear. Here we use the genetically tractable as a model to study collagen gene transcription in response to paraquat. We find that paraquat robustly up-regulates collagen gene transcription, which is dependent on KRI-1, a poorly studied protein homologous to human KRIT1/CCM1. KRI-1 knockdown prevents paraquat from activating the oxidative stress response transcription factor SKN-1/Nrf2, resulting in reduced collagen transcription and increased paraquat sensitivity. Using human lung fibroblasts (MRC-5), we confirm that both KRIT1 and Nrf2 are required for collagen transcription in response to paraquat. Nrf2 hyper-activation by KEAP1 knockdown bypasses KRIT1 to up-regulate collagen transcription. Our findings on the regulation of collagen gene transcription by paraquat could suggest potential strategies to treat pulmonary fibrosis caused by paraquat poisoning.
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http://dx.doi.org/10.18632/aging.202406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906160PMC
January 2021

Detection of bluetongue virus in Culicoides spp. in southern Yunnan Province, China.

Parasit Vectors 2021 Jan 22;14(1):68. Epub 2021 Jan 22.

Yunnan Tropical and Subtropical Animal Virus Diseases Laboratory, Yunnan Animal Science and Veterinary Institute, Kunming, Yunnan Province, China.

Background: Culicoides (Diptera: Ceratopogonidae) are vectors for many arboviruses. At least 20 species are considered as vectors or potential vectors of bluetongue virus (BTV) which cause bluetongue disease in ruminants. A BTV prevalence of 30-50% among cattle and goats in tropical southern Yunnan Province, China, prompted an investigation of the potential BTV vectors in this area.

Methods: Culicoides were collected by light trapping at three sites in the tropical region of Yunnan Province. Species were identified based on morphology and DNA sequences of cytochrome c oxidase subunit 1 (cox1). PCR and quantitative PCR following reverse transcription were used to test for the presence of BTV RNA in these specimens. Phylogenetic analysis was used to analyze the cox1 sequences of Culicoides specimens infected with BTV.

Results: Approximately 67,000 specimens of Culicoides were collected, of which 748 were tested for the presence of BTV. Five specimens, including two of Culicoides jacobsoni, one of C. tainanus and two of C. imicola, were identified as infected with BTV. No specimens of C. (subgenus Trithecoides) or C. oxystoma tested were positive for BTV infection.

Conclusions: To our knowledge this is the first report of C. jacobsoni as a potential BTV vector and the fourth report of an association between C. tainanus and BTV, as well as the first direct evidence of an association between BTV and C. imicola in Asia. A fourth potential cryptic species within C. tainanus was identified in this study. Further analysis is required to confirm the importance of C. jacobsoni and C. tainanus in BTV epidemiology in Asia.
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http://dx.doi.org/10.1186/s13071-020-04518-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821528PMC
January 2021