Publications by authors named "Ying Ding"

448 Publications

Clinical Predictors of Wheezing Among Children Infected With .

Front Pediatr 2021 22;9:693658. Epub 2021 Sep 22.

Department of Respiratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.

(MP) not only was a common pathogen of respiratory tract infections, but also could trigger the exacerbation of asthmatic symptoms in children with or without asthma. This study aimed to identify possible risk factors associated with wheezing among children diagnosed with MP infection. A retrospective analysis of medical records of children aged 28 days to 18 years old who visited the Shanghai Children's Hospital between January 2019 and January 2020 was carried out, and all children were then classified into three groups: two wheezing groups (with or without MP infection) and a non-wheezing group with MP infection. Information including patient's demographics, clinical features, laboratory data, and radiography findings was extracted from the electronic medical record system. Chest radiographs were reviewed independently by two board-certified, blinded pediatric radiologists. A total of 1,512 patients were included in our study, and 21.9% of them belonged to the wheezing group without MP infection. Among 1,181 patients with MP infection, 295 people (25.0%) suffered from wheezing, and males accounted for 61%. Through the multivariable logistic regression analyses, we found that six variables were positively associated with wheezing attacks in children with MP infection: male gender (likelihood ratio [LR] = 2.124, 95% confidence interval [CI]: 1.478-3.053), history of allergy (LR= 3.301, 95% CI: 2.206-4.941), history of wheezing (LR = 7.808, 95% CI: 5.276-11.557), autumn in reference to summer (LR = 2.414, 95% CI: 1.500-3.885), non-end-point infiltration in reference to consolidation or pleural effusion (LR = 1.982, 95% CI: 1.348-2.914), and infiltration scope (LR = 1.773, 95% CI: 1.293-2.432). However, the model showed that the probability of wheezing after MP infection decreased as age increased (LR = 0.257, 95% CI: 0.196-0.337). Moreover, the area under the curve (AUC) of the regression model was as high as 0.901 (0.847-0.955). The model integrated with factors including gender, age, season, radiological patterns, infiltration scope, and history of allergy performed well in predicting wheezing attack after MP infection in children.
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http://dx.doi.org/10.3389/fped.2021.693658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492963PMC
September 2021

Electroacupuncture promotes the survival and synaptic plasticity of hippocampal neurons and improvement of sleep deprivation-induced spatial memory impairment.

CNS Neurosci Ther 2021 Oct 8. Epub 2021 Oct 8.

Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Aims: This study aimed to investigate whether electroacupuncture (EA) promotes the survival and synaptic plasticity of hippocampal neurons by activating brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TrkB)/extracellular signal-regulated kinase (Erk) signaling, thereby improving spatial memory deficits in rats under SD.

Methods: In vivo, Morris water maze (MWM) was used to detect the effect of EA on learning and memory, at the same time Western blotting (WB), immunofluorescence (IF), and transmission electron microscopy (TEM) were used to explore the plasticity of hippocampal neurons and synapses, and the expression of BDNF/TrkB/Erk signaling. In vitro, cultured hippocampal neurons were treated with exogenous BDNF and the TrkB inhibitor K252a to confirm the relationship between BDNF/TrkB/Erk signaling and synaptic plasticity.

Results: Our results showed that EA mitigated the loss of hippocampal neurons and synapses, stimulated hippocampal neurogenesis, and improved learning and memory of rats under SD accompanied by upregulation of BDNF and increased phosphorylation of TrkB and Erk. In cultured hippocampal neurons, exogenous BDNF enhanced the expression of synaptic proteins, the frequency of the postsynaptic currents, and the phosphorylation of TrkB and Erk; these effects were reversed by treatment with K252a.

Conclusions: Electroacupuncture alleviates SD-induced spatial memory impairment by promoting hippocampal neurogenesis and synaptic plasticity via activation of BDNF/TrkB/Erk signaling, which provided evidence for EA as a therapeutic strategy for countering the adverse effects of SD on cognition.
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http://dx.doi.org/10.1111/cns.13722DOI Listing
October 2021

Rapid measurement of SARS-CoV-2 spike T cells in whole blood from vaccinated and naturally infected individuals.

J Clin Invest 2021 09;131(17)

Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore.

Defining the correlates of protection necessary to manage the COVID-19 pandemic requires the analysis of both antibody and T cell parameters, but the complexity of traditional tests limits virus-specific T cell measurements. We tested the sensitivity and performance of a simple and rapid SARS-CoV-2 spike protein-specific T cell test based on the stimulation of whole blood with peptides covering the SARS-CoV-2 spike protein, followed by cytokine (IFN-γ, IL-2) measurement in different cohorts including BNT162b2-vaccinated individuals (n = 112), convalescent asymptomatic and symptomatic COVID-19 patients (n = 130), and SARS-CoV-1-convalescent individuals (n = 12). The sensitivity of this rapid test is comparable to that of traditional methods of T cell analysis (ELISPOT, activation-induced marker). Using this test, we observed a similar mean magnitude of T cell responses between the vaccinees and SARS-CoV-2 convalescents 3 months after vaccination or virus priming. However, a wide heterogeneity of the magnitude of spike-specific T cell responses characterized the individual responses, irrespective of the time of analysis. The magnitude of these spike-specific T cell responses cannot be predicted from the neutralizing antibody levels. Hence, both humoral and cellular spike-specific immunity should be tested after vaccination to define the correlates of protection necessary to evaluate current vaccine strategies.
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http://dx.doi.org/10.1172/JCI152379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409582PMC
September 2021

Fluid-structure interaction: Insights into biomechanical implications of endograft after thoracic endovascular aortic repair.

Comput Biol Med 2021 Sep 23;138:104882. Epub 2021 Sep 23.

State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China. Electronic address:

Thoracic endovascular aortic repair (TEVAR) has developed to be the most effective treatment for aortic diseases. This study aims to evaluate the biomechanical implications of the implanted endograft after TEVAR. We present a novel image-based, patient-specific, fluid-structure computational framework. The geometries of blood, endograft, and aortic wall were reconstructed based on clinical images. Patient-specific measurement data was collected to determine the parameters of the three-element Windkessel. We designed three postoperative scenarios with rigid wall assumption, blood-wall interaction, blood-endograft-wall interplay, respectively, where a two-way fluid-structure interaction (FSI) method was applied to predict the deformation of the composite stent-wall. Computational results were validated with Doppler ultrasound data. Results show that the rigid wall assumption fails to predict the waveforms of blood outflow and energy loss (EL). The complete storage and release process of blood flow energy, which consists of four phases is captured by the FSI method. The endograft implantation would weaken the buffer function of the aorta and reduce mean EL by 19.1%. The closed curve area of wall pressure and aortic volume could indicate the EL caused by the interaction between blood flow and wall deformation, which accounts for 68.8% of the total EL. Both the FSI and endograft have a slight effect on wall shear stress-related-indices. The deformability of the composite stent-wall region is remarkably limited by the endograft. Our results highlight the importance of considering the interaction between blood flow, the implanted endograft, and the aortic wall to acquire physiologically accurate hemodynamics in post-TEVAR computational studies and the deformation of the aortic wall is responsible for the major EL of the blood flow.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104882DOI Listing
September 2021

Effect of additives on the remediation of arsenic and chromium co-contaminated soil by an electrokinetic-permeable reactive barrier.

Environ Sci Pollut Res Int 2021 Sep 23. Epub 2021 Sep 23.

School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, People's Republic of China.

To enhance the remediation efficiency of arsenic (As) and chromium (Cr)co-contaminated soil, the effect of various combinations of reducing and chelating agents on the removal of As and Cr was studied in the present work by using electrokinetic technology coupled with a permeable reactive barrier (EK-PRB). In an experiment with EK-PRB, reducing agents (ascorbic acid and citric acid) and chelating agents (EDTA-2Na) were applied together with CaAl-layered double hydroxide (CaAl-LDH) to pretreat As and Cr co-contaminated soil. The chelating agents increased the removal efficiency of As and Cr, while the reducing agent only improved As removal in co-contaminated soil. The best removal efficiencies of As and Cr were 41.2% and 46.8%, respectively. The reducing agents promoted the production of As(III) and enhanced the migration of As. However, a large amount of Cr(VI) was reduced to Cr(III), which affected the migration of Cr. Although the addition of chelating agents partly increased the migration of Cr(III), the removal of total chromium (TCr) still decreased. In this remediation system, a PRB can effectively capture and fix As and Cr. The results indicated that As was mainly adsorbed on the surface of CaAl-LDH, while the surface adsorption and intercalation of CaAl-LDH were the main mechanisms for Cr.
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http://dx.doi.org/10.1007/s11356-021-16357-1DOI Listing
September 2021

Identification and inference for subgroups with differential treatment efficacy from randomized controlled trials with survival outcomes through multiple testing.

Stat Med 2021 Sep 20. Epub 2021 Sep 20.

Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

With the uptake of targeted therapies, instead of the "one-fits-all" approach, modern randomized controlled trials (RCTs) often aim to develop treatments that target a subgroup of patients. Motivated by analyzing the Age-Related Eye Disease Study (AREDS) data, a large RCT to study the efficacy of nutritional supplements in delaying the progression of an eye disease, age-related macular degeneration (AMD), we develop a simultaneous inference procedure to identify and infer subgroups with differential treatment efficacy in RCTs with time-to-event outcomes. Specifically, we formulate the multiple testing problem through contrasts and construct their simultaneous confidence intervals, which appropriately control both within- and across-marker multiplicity. Realistic simulations are conducted using real genotype data to evaluate the method performance under various scenarios. The method is then applied to AREDS to assess the efficacy of antioxidants and zinc combination in delaying AMD progression. Multiple gene regions including ESRRB-VASH1 on chromosome 14 have been identified with subgroups showing differential efficacy. We further validate our findings in an independent subsequent RCT, AREDS2, by discovering consistent differential treatment responses in the targeted and non-targeted subgroups identified from AREDS. This multiple-testing-based simultaneous inference approach provides a step forward to confidently identify and infer subgroups in modern drug development.
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http://dx.doi.org/10.1002/sim.9196DOI Listing
September 2021

Platelet Endothelial Aggregation Receptor 1 Polymorphism Is Associated With Functional Outcome in Small-Artery Occlusion Stroke Patients Treated With Aspirin.

Front Cardiovasc Med 2021 1;8:664012. Epub 2021 Sep 1.

Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.

The role of genetic polymorphisms is important in defining the patient's prognosis and outcomes in coronary artery disease. The present study aimed to explore the association between platelet endothelial aggregation receptor 1 (PEAR1) rs12041331 polymorphism and the outcomes in patients with acute ischemic stroke treated with aspirin or dual antiplatelet therapy (DAPT) with clopidogrel. A total of 868 ischemic stroke patients admitted to our hospital from January 1, 2016 to December 30, 2018 were retrospectively studied. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification defined stroke subtypes. These patients were treated with aspirin alone or DAPT. The genotype distribution of PEAR1 rs12041331 single-nucleotide polymorphism (AA, AC, and CC) between different TOAST subtypes and treatment groups was assessed, and the clinical impact of genetic variants on functional outcomes defined by the National Institutes of Health Stroke Scale, modified Rankin Scale, and Barthel Index was analyzed using univariate and multivariate logistic regression models. Among the 868 stroke patients, the PEAR1 AA genotype was 16%, GA was 47%, and GG was 36%. Forty-four percent had aspirin alone, and 56% had DAPT. Overall, the distribution of PEAR single-nucleotide polymorphism was not significant among the two treatment groups or subtypes of TOAST. In contrast, in patients treated with aspirin alone, PEAR1 AA tended to be higher in the small-artery occlusion (SAO) subtype when compared with the no-lacunar subtype, including cardioembolism and large-artery atherosclerosis. PEAR1 AA genotype was significantly associated with favorable functional outcomes at day 7 and discharge only in SAO patients treated with aspirin alone compared with the GG genotype. Multivariate regression models further suggested that AA genotype was independently associated with favorable outcomes in this group after being adjusted for three common stroke risk factors such as age, hypertension history, and C-reactive protein level [odds ratio (OR) 0.23, 95% confidence interval (CI), 0.07-0.64, = 0.02 for 7-day National Institutes of Health Stroke Scale; OR 0.2, 95% CI, 0.06-0.66, = 0.03 for 7-day modified Rankin Scale, and OR 0.25, 95% CI, 0.08-0.72, = 0.03 for 7-day Barthel Index, respectively]. The impact of PEAR1 rs12041331 polymorphism on aspirin depends on the TOAST subtype. PEAR1 AA carrier with SAO stroke is most sensitive to aspirin therapy. PEAR1 AA is an independent factor for the short-term functional outcomes in SAO patients treated with aspirin alone. 1800019911.
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http://dx.doi.org/10.3389/fcvm.2021.664012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440843PMC
September 2021

Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.

Cancer Cell 2021 Oct 13;39(10):1404-1421.e11. Epub 2021 Sep 13.

Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA.

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR/HER2 breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
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http://dx.doi.org/10.1016/j.ccell.2021.08.009DOI Listing
October 2021

Inhaled Budesonide vis-à-vis Inhaled Mometasone in Chinese Children with Mild Persistent Asthma: A Single-Center, Retrospective Study.

Pharmacology 2021 Sep 9:1-7. Epub 2021 Sep 9.

Department of Respiratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.

Introduction: A very limited option of inhaled corticosteroids (ICSs) is approved for pediatric use in China because in children the use of ICSs for long periods is associated with dose-dependent growth reduction. Due to the lack of consensus on which is the best ICS-based treatment option to manage mild persistent asthma in children, the present study was performed to evaluate the efficacy and safety of budesonide (BUD)-based therapy vis-à-vis mometasone-based therapy in children with mild persistent asthma.

Methods: A single-center, retrospective study was conducted in asthmatic children aged between 6 and 11 years. BUD and mometasone furoate (MF) were administered as per the approved dosing regimen using pressurized metered-dose inhalers via oral inhalation route for a period of 12 weeks. The study outcome was assessed in terms of the forced expiratory volume in 1 s (FEV1), symptom scores, and nonoccurrence of side effects.

Results: Among the 77 asthmatic children, 71 completed the study treatment and were used in carrying out the analysis. The improvement of spirometric parameters like FEV1, Tiffeneau-Pinelli index (FEV1/forced vital capacity [FVC]), and peak expiratory flow (PEF) values observed in the MF cohort was significantly greater than those of the BUD cohort (p < 0.05 for all). An increase of approximately 12%/child was observed for FEV1/FVC ratios for the BUD cohort and MF cohorts. After the 12-week study, the PEFm and PEFe values increased to about 50 L/min/child for the BUD cohort and about 98 L/min/child for the MF cohort. During the study, no asthma exacerbation event was observed in the MF cohort, whereas 1 child in the BUD cohort had asthma exacerbation in week 4. The use of rescue medication during the study was required for 16.2 and 6% of children, respectively, for BUD and MF cohorts. Owing to low dosing frequency, MF could provide a better treatment approach than BUD due to improved patient compliance.

Conclusions: Although both drugs showed improvement in the quality of life of asthmatic children with manageable treatment-emergent adverse effects, the improvement was augmented in MF-treated children.

Level Of Evidence: The level of evidence was III. Technical Efficacy Stage: The technical efficacy stage was 4.
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http://dx.doi.org/10.1159/000518733DOI Listing
September 2021

miR-337-5p promotes the development of cardiac hypertrophy by targeting Ubiquilin-1 (UBQLN1).

Bioengineered 2021 12;12(1):6771-6781

Electrocardiographic Function Department, Xiangyang Central Hospital, Affiliated Hospital Of Hubei University Of Arts And Science, Xiangyang, Hubei, China.

Cardiac hypertrophy is an adaptive response of the myocardium to the pressure overload of the heart. MicroRNAs (miRNAs/miRs) are shown to be directly involved in the development of cardiac hypertrophy. However, the function of miR-337-5p and its potential contribution to the serine/threonine-protein kinase, a mammalian target of rapamycin (mTOR) signaling in cardiac hypertrophy remains unknown. In the present study, miR-337-5p expression was examined in cardiomyocytes treated with angiotensin II (Ang II). An adenovirus vector system was employed to knockdown miR-337-5p expression to investigate its functions in cardiac hypertrophy. The results revealed a significant increase in the expression of miR-337-5p in cardiomyocytes treated with Ang II as compared with controls. In addition, downregulation of miR-337-5p expression inhibited cardiac hypertrophy both and . Dual-luciferase reporter assays demonstrated Ubiquilin-1 ( as the direct target of miR-337-5p, and revealed its function in the modulation of mTOR signaling. Rescue experiments indicated that overexpression reversed the effects of miR-337-5p, and further verified this interaction. In summary, the results of the present study show that miR-337-5p silencing attenuates cardiac hypertrophy by targeting . Therefore, miR-337-5p plays a critical role in cardiac hypertrophy and may serve as a new therapeutic target.
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http://dx.doi.org/10.1080/21655979.2021.1964892DOI Listing
December 2021

Retraction notice to "The effect of LncRNA SNHG16 on vascular smooth muscle cells in CHD by targeting miRNA-218-5p"[Experimental and Molecular Pathology 118C (2021) 104595].

Exp Mol Pathol 2021 Aug 28;121:104677. Epub 2021 Aug 28.

Department of Cardiovascular Medicine, The Second Affiliated Hospital of NanChang University, Nanchang 330006, Jiangxi Province, China.

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http://dx.doi.org/10.1016/j.yexmp.2021.104677DOI Listing
August 2021

Doped metasurfaces: Etched structure-free flims based on regular spatially doped semiconductor and compatible with general optical ones.

iScience 2021 Aug 27;24(8):102907. Epub 2021 Jul 27.

State Key Laboratory of Optoelectronic Materials and Technologies, School of Materials, Sun Yat-sen University, Guangzhou 510275, China.

The metasurfaces through the reasonable design and arrangement of subwavelength nanostructures to control the spatial light field are expected to replace the traditional lens elements. However, the low light use efficiency (LUE) and difficulty in preparation caused by the etching process restrict the development of its application. Here, an idea of "doped metasurfaces" based on a spatial and regular doping of semiconductor thin films is proposed for the first time. Since the metasurfaces has no etched micro-nano structure, other optical functional films are allowed to be added, which greatly improves and enriches its optical performance. The effectiveness of the design is verified by simulating a suitable metasurface lens. The simulation results show that this designed MIR metalens possesses wide operating range, high transmittance, and high LUE. The method proposed here provides a new idea or perspective for constructing metasurfaces devices compatible with traditional optical thin films.
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http://dx.doi.org/10.1016/j.isci.2021.102907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358693PMC
August 2021

Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A.

Virulence 2021 12;12(1):2149-2161

College of Animal Science, Jilin University, Changchun China.

Drug-resistant pathogenic () has severely threatened human health and arouses widespread concern. Sortase A (SrtA) is an essential virulence factor of , which is responsible for the covalent anchoring of a variety of virulence-related proteins to the cell wall. SrtA has always been regarded as an ideal pharmacological target against infections. In this research, we have determined that orientin, a natural compound isolated from various medicinal plants, can effectively inhibit the activity of SrtA with an IC of 50.44 ± 0.51 µM. We further demonstrated that orientin inhibited the binding of to fibrinogen and diminished biofilm formation and the attaching of Staphylococcal protein A (SpA) to the cell wall . Using the fluorescence quenching assay, we demonstrated a direct interaction between orientin and SrtA. Further mechanistic studies revealed that the residues Glu-105, Thr-93, and Cys-184 were the key sites for the binding of SrtA to orientin. Importantly, we demonstrated that treatment with orientin attenuated virulence of and protected mice against -induced lethal pneumonia. These findings indicate that orientin is a potential drug to counter infections and limit the development of drug resistance.
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http://dx.doi.org/10.1080/21505594.2021.1962138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354611PMC
December 2021

Humic acid characterization and heavy metal behaviour during vermicomposting of pig manure amended with C-labelled rice straw.

Waste Manag Res 2021 Jul 31:734242X211035943. Epub 2021 Jul 31.

Key Laboratory of Hangzhou City for Ecosystem Protection and Restoration, Hangzhou Normal University, Hangzhou, China.

Aiming to reveal the humification process of organic waste and its contribution to the heavy metal behaviour affected by earthworm activity, it was studied about the variation of humic acid (HA) and heavy metal behaviour during vermicomposting of the mixed pig manure and C-labelled rice straw. The results showed that earthworms could well adapt to the culturing environment and feed organic matter for its growth and reproduction, the vermicomposting process increased the content of humic substances (HS), HA, and fulvic acid (FA) in substrate residues, but led to less transformation of HA into FA. The elemental, ultraviolet absorption spectroscopy, Fourier transform infrared (FTIR) and fluorescence excitation-emission matrix (EEM) analysis indicated that vermicomposting led to more aromatic structures and much higher humification degree in HA, whereas less protein, FA-like substances and plastein in HA. Vermicomposting could enhance the total Cu content and decrease Cu/Zn bioavailability in the substrate residues, and vermicomposting especially can help stabilize Cu in the substrate residues by forming more complexed HA-Cu.
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http://dx.doi.org/10.1177/0734242X211035943DOI Listing
July 2021

High-Efficiency Down-Conversion Radiation Fluorescence and Ultrafast Photoluminescence (1.2 ns) at the Interface of Hybrid CsPbBr-CsI Nanocrystals.

J Phys Chem Lett 2021 Aug 29;12(30):7342-7349. Epub 2021 Jul 29.

State Key Laboratory of Optoelectronic Materials and Technologies, School of Materials, Sun Yat-sen University, Guangzhou 510275, China.

The research of fast scintillators in positron emission tomography and other applications based on time-of-flight technology promotes the development of radiation detection. However, because of the current lack of efficient and fast carrier radiation recombination pathways, the research on scintillator radioluminescence (RL) still faces severe challenges. Here, we propose an effective interface carrier transport mechanism: CsI:Na crystal and CsPbBr nanocrystals (NCs) interface to form a new phase and a continuous heterostructure, providing an effective channel for X-ray excited carrier transfer to CsPbBr. Then, the excited carriers realize efficient recombination luminescence through the self-trapped excitons inside CsPbBr. On the basis of this mechanism, the heterostructure composite scintillator composed of CsI:Na/CsPbBr exhibits high-efficiency radiant fluorescence and an ultrafast photoluminescence (PL) decay time of 1.22 ns. The effective interface carrier transport shown in this work provides an optimization idea that can be used for reference in the research of fast scintillators.
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http://dx.doi.org/10.1021/acs.jpclett.1c01615DOI Listing
August 2021

Long noncoding RNA LINC-PINT retards the abnormal growth of airway smooth muscle cells via regulating the microRNA-26a-5p/PTEN axis in asthma.

Int Immunopharmacol 2021 Oct 24;99:107997. Epub 2021 Jul 24.

Department of Respiratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai City 200040, China. Electronic address:

Background: Asthma is a chronic respiratory disease worldwide. This study aimed to explore the functions of the long noncoding RNA LINC-PINT (LINC-PINT) in asthma and to determine its underlying molecular mechanisms.

Methods: Rat asthma model was established with ovalbumin sensitization and challenge. The serum level of IgE, airway hyperresponsiveness (AHR), airway inflammation, and pathological changes of lung were evaluated. Airway smooth muscle cells (ASMCs) were stimulated with platelet-derived growth factor-BB (PDGF-BB) to mimic the asthma-like condition at cellular level. QRT-PCR was performed to detect the expression of LINC-PINT, microRNA-26a-5p (miR-26a-5p), and PTEN. MTT and transwell assays were performed to measure the viability and migration of ASMCs. The protein expression of airway remodelling marker MMP-1 and MMP-9 was measured by western blot. The interactions among LINC-PINT, miR-26a-5p, and PTEN were determined by dual-luciferase reporter assay.

Results: The expression of LINC-PINT and PTEN was decreased, while miR-26a-5p expression was increased in PDGF-BB-stimulated ASMCs. In vivo, overexpression of LINC-PINT decreased the serum level of IgE, AHR, airway inflammation, and pathological changes of lung in asthma rat model. In vitro, up-regulation of LINC-PINT decreased the viability, migration, and MMP-1 and MMP-9 protein expression in PDGF-BB-stimulated ASMCs. Dual-luciferase reporter assay determined that LINC-PINT targeted miR-26a-5p, and miR-26a-5p targeted PTEN in ASMCs. Feedback approaches confirmed that miR-26a-5p up-regulation or PTEN down-regulation reversed the suppressive effect of LINC-PINT overexpression on the abnormal growth of ASMCs.

Conclusions: LINC-PINT overexpression retarded the abnormal growth of ASMCs by regulating the miR-26a-5p/PTEN axis, offering a potential therapeutic target for asthma.
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http://dx.doi.org/10.1016/j.intimp.2021.107997DOI Listing
October 2021

Gastric Cancer Mesenchymal Stem Cells Inhibit NK Cell Function through mTOR Signalling to Promote Tumour Growth.

Stem Cells Int 2021 29;2021:9989790. Epub 2021 Jun 29.

School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.

The dysfunction of natural killer (NK) cells has been increasingly reported in malignancies, especially in solid tumours. Mesenchymal stem cells (MSCs) exhibit pleiotropic functions that include mediating immune cell exhaustion which is implicated in cancer progression. However, the association of MSCs derived from gastric cancer (gastric cancer mesenchymal stem cells: GCMSCs) with the dysfunction of NK cells remains poorly understood. In this study, we demonstrated that GCMSCs effectively contributed to the exhaustion of NK cells through the release of soluble factors. Furthermore, passivation of the antitumour effect in NK cells was closely associated with their dysfunctional state. The GCMSC-conditioned medium prevented the frequency and effector function of infiltrating NK cells in tumour-bearing mouse models, thus promoting tumour growth. Mechanistically, mammalian target of rapamycin (mTOR) signalling, a critical regulator of cellular metabolism that mediates the function of immune cells, was inhibited in NK cells treated with GCMSCs. However, the checkpoint receptor PD-1 was still present at minimal levels with or without GCMSCs. The study results revealed that GCMSCs contributed to dysfunctional NK cells involved at least partially in the inhibition of mTOR signalling, suggesting potential directions for NK cell-based cancer immunotherapy.
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http://dx.doi.org/10.1155/2021/9989790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263240PMC
June 2021

Nickel-Catalyzed Isomerization/Allylic Cyanation of Alkenyl Alcohols.

Org Lett 2021 Aug 23;23(15):6073-6078. Epub 2021 Jul 23.

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.

Herein reported is a nickel-catalyzed isomerization/allylic cyanation of alkenyl alcohols, which complements current methods for the allylic substitution reactions. The specific diphosphite ligand and methanol as the solvent are crucial for the success for this transformation. A gram-scale regioconvergent experiment and formal synthesis of quebrachamine demonstrate the high potential of this methodology.
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http://dx.doi.org/10.1021/acs.orglett.1c02143DOI Listing
August 2021

The Spectrum of C4d Deposition in Renal Biopsies of Lupus Nephritis Patients.

Front Immunol 2021 1;12:654652. Epub 2021 Jul 1.

Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.

Objectives: This study aimed to determine the prevalence and localization of complement factor C4d in renal biopsies from patients with lupus nephritis (LN), as well as its associations with the disease's clinico-pathological features. The correlation between arteriolar C4d deposition and renal microvascular lesions (RVLs) was further analyzed.

Methods: A total of 325 biopsy-proven LN patients were enrolled, and their clinico-pathological data were collected. C4d staining of renal biopsies was performed by immunohistochemistry. The associations between C4d deposition and the clinico-pathological features were further analyzed.

Results: C4d deposition was present in most (98.8%) renal specimens in our cohort. These deposits were localized in the glomeruli (98.2%), tubular basement membrane (TBM) (43.7%), arterioles (31.4%), and peritubular capillary (33.8%). Patients with TBM C4d staining had higher disease activity (measured with the Systemic Lupus Erythematous Disease Activity Index) and higher National Institutes of Health pathological activity and chronicity indices (all < 0.01). Patients with arteriolar C4d deposition were more likely to develop RVLs (91.2%) compared to those with no arteriolar C4d deposition (78.0%; = 0.004), especially with two or more types of RVLs ( < 0.001). During the mean follow-up of 55.8 months, arteriolar C4d was related to worse renal outcomes [hazard ration (HR): 2.074, 95% confidence interval (CI) 1.056-4.075, = 0.034]. Multivariate Cox hazard analysis showed that co-deposition of arteriolar C4d and C3c was an independent risk factor (HR: 3.681, 95% CI 1.519-8.921, = 0.004) for predicting renal outcomes.

Conclusions: C4d deposition was common in renal tissues from LN patients. TBM C4d deposition was related to the disease activity, and arteriolar C4d deposition was associated with RVLs and worse renal outcomes.
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http://dx.doi.org/10.3389/fimmu.2021.654652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281350PMC
September 2021

Differential Cytokine Responses in Hospitalized COVID-19 Patients Limit Efficacy of Remdesivir.

Front Immunol 2021 28;12:680188. Epub 2021 Jun 28.

ASTAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research, Singapore, Singapore.

A significant proportion of COVID-19 patients will progress to critical illness requiring invasive mechanical ventilation. This accentuates the need for a therapy that can reduce the severity of COVID-19. Clinical trials have shown the effectiveness of remdesivir in shortening recovery time and decreasing progression to respiratory failure and mechanical ventilation. However, some studies have highlighted its lack of efficacy in patients on high-flow oxygen and mechanical ventilation. This study uncovers some underlying immune response differences between responders and non-responders to remdesivir treatment. Immunological analyses revealed an upregulation of tissue repair factors BDNF, PDGF-BB and PIGF-1, as well as an increase in ratio of Th2-associated cytokine IL-4 to Th1-associated cytokine IFN-γ. Serological profiling of IgG subclasses corroborated this observation, with significantly higher magnitude of increase in Th2-associated IgG2 and IgG4 responses. These findings help to identify the mechanisms of immune regulation accompanying successful remdesivir treatment in severe COVID-19 patients.
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http://dx.doi.org/10.3389/fimmu.2021.680188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275132PMC
July 2021

Circ_UBR4 Knockdown Alleviates Oxidized Low-Density Lipoprotein-Provoked Growth and Migration of Human Vascular Smooth Muscle Cells by Acting on the miR-637/FOXO4 Pathway.

J Cardiovasc Pharmacol 2021 Oct;78(4):534-543

Department of Cardiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.

Abstract: Excessive proliferation and migration of human vascular smooth muscle cells (HVSMCs) induced by oxidized low-density lipoprotein (ox-LDL) are important pathological features of atherosclerosis. Emerging evidence indicates that circular RNAs deregulation is involved in this pathological process. The objective of this study was to explore the role of circular RNA ubiquitin protein ligase E3 component n-recognin 4 (circ_UBR4) in ox-LDL-treated HVSMCs. The expression of circ_UBR4, microRNA-637 (miR-637), and forkhead box O4 (FOXO4) mRNA was detected by quantitative real-time PCR. Cell cycle progression was examined by flow cytometry assay. Cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell migration was examined by transwell assay. The protein levels of proliferating cell nuclear antigen, matrix metalloproteinase 2, and FOXO4 were measured by western blot. The relationship between miR-637 and circ_UBR4 or FOXO4 was confirmed by dual-luciferase reporter assay. The results presented that the expression of circ_UBR4 was increased in atherosclerosis serum samples and ox-LDL-treated HVSMCs. Cell cycle progression, cell proliferation, and cell migration were promoted by ox-LDL, whereas circ_UBR4 knockdown inhibited HVSMCs proliferation and migration. MiR-637 was a target of circ_UBR4, and FOXO4 was a target of miR-637. Circ_UBR4 positively regulated FOXO4 expression by targeting miR-637. Circ_UBR4 knockdown-inhibited HVSMCs proliferation and migration were recovered by miR-637 inhibition, and miR-637 restoration-inhibited HVSMCs proliferation and migration were recovered by FOXO4 overexpression. In conclusion, circ_UBR4 knockdown inhibited ox-LDL-induced excessive proliferation and migration of HVSMCs by regulating FOXO4 via targeting miR-637.
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http://dx.doi.org/10.1097/FJC.0000000000001098DOI Listing
October 2021

A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects.

Front Pharmacol 2021 17;12:694375. Epub 2021 Jun 17.

Drug Clinical Trial Institution, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.

This study was conducted to compare the pharmacokinetics, safety and immunogenicity of HOT-1010 with bevacizumab (Avastin®) in Chinese healthy male subjects. A single-center, randomized, double-blind, single-dose, parallel trial was performed in 84 Chinese healthy male subjects who randomly (1:1) received a single intravenous infusion of 1 mg/kg HOT-1010 or Avastin® for 90 min and followed up for 85 days. Serum concentrations of bevacizumab were analyzed by enzyme-linked immunosorbent assay. Primary pharmacokinetic parameters, C, AUC and AUC were calculated and evaluated the bioequivalence between HOT-1010 and Avastin®, the safety and immunogenicity of investigational drugs were also assessed. A total of 82 subjects completed the study. The 90% Confidence Intervals for geometric mean ratios of C, AUC and AUC were 91.81-103.64%, 85.19-95.39% and 85.04-95.36%, which were all within the bioequivalence margin. Treatment-emergent adverse events were reported in 27 (65.9%) subjects in HOT-1010 group and 23 (56.1%) subjects in Avastin® group. Most TEAEs were mild or moderate. No TEAEs, Serious Adverse Events or deaths leading to discontinuation was reported. Subjects were all tested negative for Anti-drug Antibody. HOT-1010 exhibited the similar pharmacokinetics, safety and immunogenicity profiles of bevacizumab (Avastin®) in Chinese healthy male subjects. http://www.chinadrugtrials.org.cn/index.html, CTR20181610.
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http://dx.doi.org/10.3389/fphar.2021.694375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245695PMC
June 2021

Toward a Coronavirus Knowledge Graph.

Genes (Basel) 2021 06 29;12(7). Epub 2021 Jun 29.

Department of Library and Information Science, Yonsei University, Seoul 03722, Korea.

This study builds a coronavirus knowledge graph (KG) by merging two information sources. The first source is Analytical Graph (AG), which integrates more than 20 different public datasets related to drug discovery. The second source is CORD-19, a collection of published scientific articles related to COVID-19. We combined both chemo genomic entities in AG with entities extracted from CORD-19 to expand knowledge in the COVID-19 domain. Before populating KG with those entities, we perform entity disambiguation on CORD-19 collections using Wikidata. Our newly built KG contains at least 21,700 genes, 2500 diseases, 94,000 phenotypes, and other biological entities (e.g., compound, species, and cell lines). We define 27 relationship types and use them to label each edge in our KG. This research presents two cases to evaluate the KG's usability: analyzing a subgraph (ego-centered network) from the angiotensin-converting enzyme (ACE) and revealing paths between biological entities (hydroxychloroquine and IL-6 receptor; chloroquine and STAT1). The ego-centered network captured information related to COVID-19. We also found significant COVID-19-related information in top-ranked paths with a depth of three based on our path evaluation.
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http://dx.doi.org/10.3390/genes12070998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307964PMC
June 2021

Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository.

Metabolomics 2021 06 27;17(7):64. Epub 2021 Jun 27.

Department of Pediatrics, Stanford University, 750 Welch Road, Palo Alto, CA, 94304, USA.

Introduction: Acute lymphoblastic leukemia (ALL) is among the most common cancers in children. With improvements in combination chemotherapy regimens, the overall survival has increased to over 90%. However, the current challenge is to mitigate adverse events resulting from the complex therapy. Several chemotherapies intercept cancer metabolism, but little is known about their collective role in altering host metabolism.

Objectives: We profiled the metabolomic changes in plasma of ALL patients initial- and post- induction therapy.

Methods: We exploited a biorepository of non-fasted plasma samples derived from the Dana Farber Cancer Institute ALL Consortium; these samples were obtained from 50 ALL patients initial- and post-induction therapy. Plasma metabolites and complex lipids were analyzed by high resolution tandem mass spectrometry and differential mobility tandem mass spectrometry. Data were analyzed using a covariate-adjusted regression model with multiplicity adjustment. Pathway enrichment analysis and co-expression network analysis were performed to identify unique clusters of molecules.

Results: More than 1200 metabolites and complex lipids were identified in the total of global metabolomics and lipidomics platforms. Over 20% of those molecules were significantly altered. In the pathway enrichment analysis, lipids, particularly phosphatidylethanolamines (PEs), were identified. Network analysis indicated that the bioactive fatty acids, docosahexaenoic acid (DHA)-containing (22:6) triacylglycerols (TAGs), were decreased in the post-induction therapy.

Conclusion: Metabolomic profiling in ALL patients revealed a large number of alterations following induction chemotherapy. In particular, lipid metabolism was substantially altered. The changes in metabolites and complex lipids following induction therapy could provide insight into the adverse events experienced by ALL patients.
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http://dx.doi.org/10.1007/s11306-021-01814-2DOI Listing
June 2021

Doxycycline host-directed therapy in human pulmonary tuberculosis.

J Clin Invest 2021 08;131(15)

Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.
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http://dx.doi.org/10.1172/JCI141895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321570PMC
August 2021

Persistent Symptoms and Association With Inflammatory Cytokine Signatures in Recovered Coronavirus Disease 2019 Patients.

Open Forum Infect Dis 2021 Jun 2;8(6):ofab156. Epub 2021 Apr 2.

National Centre for Infectious Diseases, Singapore.

Background: The complications and sequelae of coronavirus disease 2019 (COVID-19) and their effect on long-term health are unclear, and the trajectory of associated immune dysregulation is poorly understood.

Methods: We conducted a prospective longitudinal multicenter cohort study at 4 public hospitals in Singapore. Patients with COVID-19 were monitored for a median of 6 months after recovery from acute infection. Clinical symptoms and radiologic data were collected, along with plasma samples for quantification of immune mediators. The relationship between clinical symptoms and immune cytokine profiles was investigated.

Results: Two hundred eighty-eight participants were recruited, and follow-up data were available for 183, 175, and 120 participants at days 30, 90, and 180 postsymptom onset, respectively. Symptoms related to COVID-19 were present in 31 (16.9%), 13 (7.4%), and 14 (11.7%) at days 30, 90, and 180. In a multivariable model, age >65 years, non-Chinese ethnicity, and the severity of acute infection were associated with increased likelihood of persistent symptoms. Recovered COVID-19 patients had elevated levels of proinflammatory interleukin (IL)-17A, stem cell factor, IL-12p70, and IL-1β and pro-angiogenic macrophage inflammatory protein 1β, brain-derived neurotrophic factor, and vascular endothelial growth factor at day 180 compared with healthy controls. Higher levels of monocyte chemoattractant protein-1 and platelet-derived growth factor-BB were detected in patients with persistent symptoms, versus symptom-free patients.

Conclusions: Approximately 10% of recovered patients had persistent symptoms 6 months after initial infection. Immune cytokine signatures of the recovered patients reflected ongoing chronic inflammation and angiogenesis. Patients with COVID-19 should be monitored closely for emerging long-term health consequences.
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http://dx.doi.org/10.1093/ofid/ofab156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083585PMC
June 2021

Transdermal Delivery of Lidocaine-Loaded Elastic Nano-Liposomes with Microneedle Array Pretreatment.

Biomedicines 2021 May 23;9(6). Epub 2021 May 23.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.

This study aimed to improve the transdermal delivery of lidocaine hydrochloride (LidH) using elastic nano-liposomes (ENLs) and microneedle (MN) array pretreatment. LidH-containing ENLs were prepared using soybean phosphatidylcholine and cholesterol, with Span 80 or Tween 80, using a reverse-phase evaporation method. The ENL particle size, stability, and encapsulation efficiency (EE) were characterized and optimized based on the component ratio, pH, and type of surfactant used. In vitro transdermal diffusion study was performed on MN-pretreated mouse skin using Franz diffusion cells. The anesthetic effects of LidH in various formulations after dermal application were evaluated in vivo in rats by measuring the tail withdrawal latency after photothermic stimulation. Stable LidH-loaded Tween 80 or Span 80 ENLs were obtained with particle sizes of 115.8 and 146.6 nm and EEs of 27% and 20%, respectively. The formulations did not exert any cytotoxicity in HaCaT cells. Tween 80 and Span 80 ENL formulations showed enhanced LidH delivery on pretreated mice skin in vitro and prolonged the anesthetic effect in vivo compared to that by LidH application alone. LidH-loaded ENLs applied to MN-pretreated skin can shorten the onset time and prolong the anesthetic effect safely, which merits their further optimization and practical application.
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http://dx.doi.org/10.3390/biomedicines9060592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224805PMC
May 2021

Production of viable chicken by allogeneic transplantation of primordial germ cells induced from somatic cells.

Nat Commun 2021 05 20;12(1):2989. Epub 2021 May 20.

Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.

The allogeneic transplantation of primordial germ cells (PGCs) derived from somatic cells overcomes the limitation of avian cloning. Here, we transdifferentiate chicken embryo fibroblasts (CEFs) from black feathered Langshan chickens to PGCs and transplant them into White Plymouth Rock chicken embryos to produce viable offspring with characteristics inherited from the donor. We express Oct4/Sox2/Nanog/Lin28A (OSNL) to reprogram CEFs to induced pluripotent stem cells (iPSCs), which are further induced to differentiate into PGCs by BMP4/BMP8b/EGF. DNA demethylation, histone acetylation and glycolytic activation elevate the iPSC induction efficiency, while histone acetylation and glycolytic inhibition facilitate PGCs formation. The induced PGCs (iPGCs) are transplanted into the recipients, which are self-crossed to produce 189/509 somatic cells derived chicken with the donor's characteristics. Microsatellite analysis and genome sequencing confirm the inheritance of genetic information from the donor. Thus, we demonstrate the feasibility of avian cloning from somatic cells.
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http://dx.doi.org/10.1038/s41467-021-23242-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138025PMC
May 2021

Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke.

Immunity 2021 07 19;54(7):1527-1542.e8. Epub 2021 May 19.

Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA. Electronic address:

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.
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http://dx.doi.org/10.1016/j.immuni.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282725PMC
July 2021

Genome-Wide Association Studies-Based Machine Learning for Prediction of Age-Related Macular Degeneration Risk.

Transl Vis Sci Technol 2021 02;10(2):29

Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Purpose: Because age-related macular degeneration (AMD) is a progressive disorder and advanced AMD is currently hard to cure, an accurate and informative prediction of a person's AMD risk using genetic information is desirable for early diagnosis and potential individualized clinical management. The objective of this study was to develop and validate novel prediction models for AMD risk using large genome-wide association studies datasets with different machine learning approaches.

Methods: Genotype data from 32,215 Caucasian individuals with age of ≥50 years from the International AMD Genomics Consortium in dbGaP were used to establish and test prediction models for AMD risk. Four different machine learning approaches-neural network, lasso regression, support vector machine, and random forest-were implemented. A standard logistic regression model using a genetic risk score was also considered.

Results: All machine learning-based methods achieved satisfactory performance for predicting advanced AMD cases (vs. normal controls) (area under the curve = 0.81-0.82, Brier score = 0.17-0.18 in a separate test dataset) and any stage AMD (vs. normal controls) (area under the curve = 0.78-0.79, Brier score = 0.18-0.20 in a separate test dataset). The prediction performance was further validated in an independent dataset of 783 subjects from UK Biobank (area under the curve = 0.67).

Conclusions: By applying multiple state-of-art machine learning approaches on large AMD genome-wide association studies datasets, the predictive models we established can provide an accurate estimation of an individual's AMD risk profile based on genetic information along with age. The online prediction interface is available at: https://yanq.shinyapps.io/no_vs_amd_NN/.

Translational Relevance: The accurate and individualized risk prediction model interface will greatly improve early diagnosis and enhance tailored clinical management of AMD.
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http://dx.doi.org/10.1167/tvst.10.2.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900884PMC
February 2021
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