Publications by authors named "Zhenzhen Wang"

356 Publications

DNA Origami Frameworks Enabled Self-Protective siRNA Delivery for Dual Enhancement of Chemo-Photothermal Combination Therapy.

Small 2021 Oct 5:e2101780. Epub 2021 Oct 5.

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing, 210023, P. R. China.

Although chemotherapy and photothermal therapy are widely used to combat cancer, their efficacy is often limited by multidrug resistance. Small interfering RNAs (siRNAs) have ability to suppress the expression of target genes, which has been extensively employed for combating the multidrug resistance to chemodrugs and hyperthermia in cancer therapy. However, efficient delivery of siRNAs along with chemo-photothermal agents in vivo is still an enormous challenge. Herein, octahedral DNA origami frameworks (OctDOFs) are constructed as a nanovehicle for precise organization and orchestrated delivery of siRNAs, chemodrugs (doxorubicin, Dox), and photothermal agents (gold nanorods, AuNRs) in combinatorial treatment of cancer. The inner cavity of the rigid OctDOFs structure is able to shield the encapsulated siRNAs during transportation by sterically hindering RNase degradation and protein binding, thus achieving effective downregulation of connective tissue growth factor (CTGF) and heat shock protein 72 (HSP72) for dual sensitization of cancer cells to chemodrugs and hyperthermia. By amplifying chemo-photothermal therapeutic potency with siRNAs, the proposed OctDOFs exhibited superior cytotoxicity and tumor inhibition efficacy in vitro and in vivo. This nanovehicle creates a promising siRNA delivery platform for precise medication and combination therapy.
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http://dx.doi.org/10.1002/smll.202101780DOI Listing
October 2021

Crosstalk Between RPE Cells and Choroidal Endothelial Cells via the ANXA1/FPR2/SHP2/NLRP3 Inflammasome/Pyroptosis Axis Promotes Choroidal Neovascularization.

Inflammation 2021 Oct 1. Epub 2021 Oct 1.

Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China.

One type of age-related macular degeneration (AMD), neovascular (nAMD), characterized by choroidal neovascularization (CNV), accounts for the majority of the severe central vision impairment associated with AMD. Endothelial cells (ECs) in direct contact with retinal pigment epithelial (RPE) cells are more prone to the pathological angiogenesis involved in CNV. Herein, we investigated the effect of crosstalk between RPE cells and choroidal endothelial cells (CECs) via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis on the development of choroidal neovascularization (CNV) in vitro and in vivo. ANXA1 expression and secretion from ARPE-19 cells were upregulated by hypoxia. FPR2 expression, especially on the plasma membrane, in HCECs was upregulated under hypoxic conditions. ANXA1 secreted from ARPE-19 cells inhibited NLRP3 inflammasome activation and NLRP3 inflammasome-mediated pyroptosis in HCECs by activating the FPR2/SHP2 axis. Moreover, ANXA1 secreted by ARPE-19 cells promoted behaviors of HCECs, including proliferation, migration, and tube formation, by activating the FPR2/SHP2 axis and inhibiting NLRP3 inflammasome-mediated pyroptosis. Inhibiting the upregulated ANXA1/FPR2/SHP2/NLRP3 inflammasome/pyroptosis axis decreased the volume of CNV. Our data suggest that the crosstalk between RPE cells and CECs via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis promotes CNV. This finding could identify a potential target for the prevention and treatment of CNV.
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http://dx.doi.org/10.1007/s10753-021-01555-3DOI Listing
October 2021

Topical metformin suppresses angiogenesis pathways induced by pulsed dye laser irradiation in animal models.

Exp Dermatol 2021 Sep 26. Epub 2021 Sep 26.

Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.

Pulsed dye laser (PDL) is the first-line treatment for port-wine stain (PWS). However, only a small portion of the lesions could be completely cleared by PDL treatment, which might be related to the regeneration and revascularization of the vascular structures after laser irradiation. Recently, it is believed that the suppression of regeneration and revascularization of photocoagulated blood vessels can achieve a better therapeutic outcome. We use rabbit ear and SD rat as the animal models to investigate whether PDL-induced angiogenesis can be suppressed by topical metformin. Our results showed that topical application of metformin can effectively suppress the PDL-induced early stage of angiogenesis via inhibition of the AKT/mTOR/P70S6K pathway in animal models.
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http://dx.doi.org/10.1111/exd.14461DOI Listing
September 2021

Multi-species hydrocarbon measurement using TDLAS with a wide scanning range DFG laser.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Aug 28;265:120333. Epub 2021 Aug 28.

Graduate School of Advanced Technology and Science, Tokushima University, Tokushima 770-8501, Japan.

Tunable diode laser absorption spectroscopy (TDLAS) is a widely used diagnostic technique due to its high sensitivity, fast response, low cost, and other merits. Hydrocarbon detection is a field of great interest in the application of tunable diode lasers as hydrocarbons are fundamental molecules in many industrial processes. Many tunable diode lasers are only suitable for single species detection due to the short scanning range and in real situations. However, different hydrocarbon species tend to exist simultaneously. Here we present a laser system based on the difference-frequency generation (DFG) method for simultaneous hydrocarbon mixtures detection. The direct absorption spectra of different hydrocarbons covering various groups (e.g., alkane, olefin, and aromatic) were measured. The measurements of the concentration dependence of absorbance for each molecule were carried out. The R values were larger than 0.997, which demonstrated the system can measure hydrocarbons covering different molecular classes accurately. The mixture components were identified using the independent component analysis and quantitative analysis was performed using the classical least-squares method. Future studies will focus on the validation of the system in actual processes.
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http://dx.doi.org/10.1016/j.saa.2021.120333DOI Listing
August 2021

Expressivity of Interleukin-8 and Gastric Cancer Prognosis Susceptibility: A Systematic Review and Meta-Analysis.

Dose Response 2021 Jul-Sep;19(3):15593258211037127. Epub 2021 Sep 12.

Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Background: The relationship between interleukin-8 (IL-8) expression and the prognosis of gastric cancer (GC) patients has been reported, but the results are contradictory.

Aim: To investigate the effect of IL-8 expression on the prognosis of patients with GC.

Method: A comprehensive search strategy was used to search the PubMed, Web of Science and Cochrane Library databases. The total survival time was analysed using the RevMan 5.4 software. Through extensive search and meta-analysis of relevant studies, studies examining the relationship between IL-8 expression and prognosis in patients with GC were conducted to obtain more accurate estimates.

Findings: Eight studies (1843 patients) were included. The combined results of all the studies showed that high expression of IL-8 was a risk factor for poor prognosis in patients with GC (hazard ratio (HR): 2.08; 95% CI: 1.81-2.39). Sensitivity analysis suggested that the pooled HR was stable, and omitting a single study did not change the significance of the pooled HR. Funnel plots revealed no significant publication bias in the meta-analysis.

Conclusion: High IL-8 expression could be a negative prognostic biomarker for patients with GC.
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http://dx.doi.org/10.1177/15593258211037127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438942PMC
September 2021

Tetrahydroxy stilbene glycoside regulates TGF-β/fractalkine/CX3CR1 based on network pharmacology in APP/PS1 mouse model.

Neuropeptides 2021 Sep 4;90:102197. Epub 2021 Sep 4.

Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China. Electronic address:

Alzheimer's disease (AD) is a serious, progressive neurodegenerative disease that involves irreversible neuronal death. Tetrahydroxy stilbene glycoside (TSG) is an active compound extracted from P. multiflorum, a traditional Chinese herbal medicine, but its role in neuroprotection is unclear. Herein, we aimed to validate the effects of TSG on APP/PS1 model mice and the underlying mechanism. RNA-seq was performed to identify differentially expressed genes in APP/PS1 mouse, with PCR and immunohistochemistry used for validation. Experiments were performed after bioinformatic analysis for verification. Neuronal damage was observed by H&E staining. Key proteins involved in the pathway such as CX3CR1, Iba1 and TGF-β were examined by immunohistochemical analysis. The KEGG analysis suggested that these genes might act by multiple pathways to build the pharmacological network of TSG in AD progression. These data provide the credible evidence that TSG improved neuronal damage and regulated neuroprotective mechanisms. Together, our work has detailed the whole and major genes in APP/PS1 model mouse regulated by TSG, and highlighted the anti-inflammatory function of TSG in mediating CX3CR1 and TGF-β as the TGF-β/fractalkine/CX3XR1 signaling pathway, especially in microglia. Moreover, TSG has potential value in synaptic transmission and neurotrophic action on neurodegenerative diseases. In summary, TSG is a promising candidate for preventing and treating the progression of AD.
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http://dx.doi.org/10.1016/j.npep.2021.102197DOI Listing
September 2021

ZIF/Co-CN with enhanced electrocatalytic reduction of carbon dioxide activity by the photoactivation process.

Nanoscale 2021 Sep 9;13(33):14089-14095. Epub 2021 Aug 9.

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, 215123, China.

Introducing the effect of light into an electrocatalytic system is an effective method to improve electrocatalytic carbon dioxide reduction (CORR). Here, the composite catalyst (ZIF/Co-CN) was prepared for the electrocatalytic reduction of carbon dioxide. The Faraday efficiency of the catalytic reduction of CO to CO under light could reach 90.34% at -0.67 V vs. the RHE (reversible hydrogen electrode), which was 30% higher than that obtained under darkness, and the overpotential was reduced by 200 mV. Chemical kinetics experiments and in-situ transient photovoltage (TPV) tests show that the reason for highly efficient CORR is intermediate CO formed by activated CO in the electrocatalytic system under light. This work offers a deep insight into the photo-activated electrocatalytic reduction of carbon dioxide, and also opens a new way to devise efficient catalysts for CORR.
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http://dx.doi.org/10.1039/d1nr03119hDOI Listing
September 2021

Transcriptome Analysis Reveals the Molecular Immunological Characteristics of Lesions in Patients with Halo Nevi When Compared to Stable Vitiligo, Normal Nevocytic Nevi and Cutaneous Melanoma.

J Inflamm Res 2021 24;14:4111-4124. Epub 2021 Aug 24.

Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, People's Republic of China.

Background: Given their similar appearance and histology, halo nevi (HN) were considered as a type of vitiligo. However, whether HN have stronger immune response than stable vitiligo (VL) remains unclear. In addition, the molecular alterations in HN compared with normal nevocytic nevi (NN) and primary cutaneous melanoma (MM) must be determined. This study aimed to systematically characterize the molecular immunological features of HN.

Methods: Skin samples from patients with HN, VL, NN, and MM were obtained with informed consent. Each of the four groups underwent transcriptome sequencing and data analysis were for pairwise comparison. Quantitative real-time PCR (RT-qPCR) was conducted to confirm the transcriptional expression of some differentially expressed genes (DEGs) that were closely related to immunity.

Results: A total of 441 and 1507 DEGs were found in the HN/NN and HN/MM groups, respectively. Compared with those of VL, HN lesions contained 162 up-regulated DEGs and 12 down-regulated DEGs. Bioinformatics analysis showed that the up-regulated genes in HN were substantially enriched in immune response, immune deficiency, and immune rejection; biological stimulation (virus, bacteria); and proliferation and activation of immune cells. Immune cell composition analysis also confirmed high expression levels of multiple immunocytes in HN.

Conclusion: The molecular immune mechanisms of HN and VL were similar, but the immune activity of HN was stronger than that of VL. Innate and adaptive immunity were involved in the pathogenesis and progression of HN and VL.
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http://dx.doi.org/10.2147/JIR.S321672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403033PMC
August 2021

Quantitative Analysis of Manganese in Underwater Steel Samples Using Long-Short Double-Pulse Laser-Induced Breakdown Spectroscopy.

Appl Spectrosc 2021 Aug 25:37028211038634. Epub 2021 Aug 25.

State Key Laboratory of Multiphase Flow in Power Engineering, Xi'an Jiaotong University, Xi'an, China.

The long-short double-pulse laser-induced breakdown spectroscopy (LS-DP-LIBS) method was applied to qualitative and quantitative analyses of underwater steel samples to improve the detection ability of underwater measurement. The stable plasma intensity and discrete emission lines were detected using LS-DP-LIBS when comparing the measured results of single-pulse LIBS (SP-LIBS) and LS-DP-LIBS. The long pulse produces a cavitation bubble without plasma, and the short pulse induces the plasma of steel samples within the bubble. The detection features of LS-DP-LIBS for underwater steel samples were discussed in different intra-pulse delay time, long-pulse width, and delay time conditions when analyzing the measured spectra, the signal intensity of Fe(I) at 400.524 nm and 402.187 nm, Mn(I) at 404.136 nm, and intensity ratio of Mn(I) 404.136 nm/Fe(I) 402.187 nm. The results indicated that the plasma stability and spectral signal intensity were improved significantly with a long-pulse width of 80 µs in the intra-pulse delay time of 70 µs, which were appropriate for bubble formation and plasma generation. According to the discussion of the delay time effect, the state of generated plasma was almost stable from 650 ns to 850 ns. Manganese (Mn) contents in steel samples were analyzed quantitatively when measuring five steel samples with different Mn contents using LS-DP-LIBS in optimal experimental conditions. A strong linear dependence was observed with =0.9842, which demonstrated the feasibility and appropriateness of quantitative analysis for underwater measurement using LS-DP-LIBS.
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http://dx.doi.org/10.1177/00037028211038634DOI Listing
August 2021

Actoeside mitigated the renal proximal tubule cells damage triggered by high glucose through miR-766/VCAM1/NF-κB signalling pathway.

Arch Physiol Biochem 2021 Aug 2:1-10. Epub 2021 Aug 2.

Department of Endocrinology, Zibo Central Hospital, Zibo City, PR China.

Context: Diabetic nephropathy (DN) triggered by diabetes mellitus is one of the primary causes of end-stage renal failure worldwide.

Objective: This study intends to explore the function and potential mechanism of actoeside on renal proximal tubule (HK-2) cells damage induced by high-glucose (HG).

Methods: The DN model was established in HK-2 cells with 30 mM HG treatment. The viability, apoptosis and inflammation of HK-2 cells were analysed severally via CCK-8, flow cytomery and ELISA. The key factors related to NF-κB were detected by western blotting.

Results: Actoeside attenuated the HG-induced HK-2 cells damage. The differentially expression of miR-766 and VCAM1 in DN patients was reversed by actoeside. Moreover, the increased phosphorylation levels of p65 NF-κB/IκBα induced by HG were attenuated by actoeside.

Conclusions: Actoeside promoted the growth and repressed the apoptosis and inflammation of HK-2 cells via miR-766/VCAM1/NF-κB signalling pathway, affording a promising idea for the treatment of DN.
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http://dx.doi.org/10.1080/13813455.2021.1920983DOI Listing
August 2021

[Development of molecular markers of Mycobacterium tuberculosis rifampicin resistance gene rpoB by PARMS technology].

Sheng Wu Gong Cheng Xue Bao 2021 Jul;37(7):2503-2512

College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang 471023, Henan, China.

The purpose of this study is to provide a simple and reliable genetic typing approach for molecular drug susceptibility test of Mycobacterium tuberculosis, through the developing of fluorescence molecular marker of rifampicin resistance gene rpoB. Eleven fluorescent molecular markers of the rpoB gene were established by using the sequence difference between the amino acid positions 531, 526, 516, 511 and 513 of rpoB gene of rifampicin-resistant strains and the alleles of rifampicin-sensitive strains, combined with the PARMS technique (Penta-primer amplification refractory mutation system). We used 104 clinical isolates of Mycobacterium tuberculosis to validate this marker and it was verified by sequencing as 100% correct. These samples were also tested with proportional drug sensitivity test. The coincidence rate was 94.23%. The molecular markers had high reliability for genotyping of rpoB gene. It can also detect low-concentration drug-resistant samples (511/533 unit point mutations) whose phenotypic susceptibility cannot be detected. The eleven sets of fluorescent molecular markers could cover 92%-96% of rpoB gene mutation types of rifampicin-resistant strains, and provide new idea for rapid detection of rifampin-resistant Mycobacterium tuberculosis.
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http://dx.doi.org/10.13345/j.cjb.200487DOI Listing
July 2021

A multidisciplinary team nursing model in the treatment of patients undergoing transapical mitral valve clamping: a prospective study.

J Cardiothorac Surg 2021 Jul 28;16(1):203. Epub 2021 Jul 28.

Department of Nursing, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou City, Fujian Province, China.

Background: As a new surgical method for older adults with cardiac insufficiency, transapical mitral valve clamp surgery requires the cooperation of practitioners across multiple disciplines to ensure appropriate treatment and nursing care. This study aimed to explore the utility of a multidisciplinary team nursing model in the clinical treatment and nursing care of patients undergoing transapical mitral valve clamping.

Methods: Our sample of ten patients included four men (40%) and six women (60%), with a mean age of 71.4 ± 5.2 years. The multidisciplinary team comprised nurses that specialized in severe illness, cardiac health, rehabilitation, psychology, nutrition, and pain. The team engaged in comprehensive discussions regarding problems specific to the patients undergoing transapical mitral valve surgery, allowing them to formulate individualized nursing measures and implement precise policies.

Results: No serious postoperative complications occurred in any of the ten patients included in this study, and a significant improvement was noted in the cardiac status of all the patients. Color ultrasound findings at discharge indicated that the degree of reflux of all the patients was ≤2+. Among the ten patients, the Activity of Daily Living Scale scores at discharge were significantly higher than before the operation (69.0 ± 4.6 vs. 55.0 ± 5.8). In addition, the 6-min walking test results at discharge were significantly better than those observed before the operation (318.0 ± 21.7 m vs. 295.2 ± 18.4 m).

Conclusions: Utilization of a multidisciplinary team allows nurses across various specialties to provide more comprehensive and systematic care for patients undergoing a mitral valve clamping operation, thus promoting patient recovery.
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http://dx.doi.org/10.1186/s13019-021-01588-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316700PMC
July 2021

The Ionic Liquid-HO Interface: A New Platform for the Synthesis of Highly Crystalline and Molecular Sieving Covalent Organic Framework Membranes.

ACS Appl Mater Interfaces 2021 Aug 26;13(30):36507-36516. Epub 2021 Jul 26.

Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China.

Covalent organic frameworks (COFs) are highly porous crystalline polymers with uniform pores and large surface areas. Combined with their modular design principle and excellent properties, COFs are an ideal candidate for separation membranes. Liquid-liquid interfacial polymerization is a well-known approach to synthesize membranes by reacting two monomers at the interface. However, volatile organic solvents are usually used, which may disturb the liquid-liquid interface and affect the COF membrane crystallinity due to solvent evaporation. Simultaneously, the domain size of the organic solvent-water interface, named the reaction zone, can hardly be regulated, and the diffusion control of monomers for favorable crystallinity is only achieved in the water phase. These drawbacks may limit the widespread applications of liquid-liquid interfacial polymerization to synthesize diverse COF membranes with different functionalities. Here, we report a facile strategy to synthesize a series of imine-linked freestanding COF membranes with different thicknesses and morphologies at tunable ionic liquid (IL)-HO interfaces. Due to the H-bonding of the catalysts with amine monomers and the high viscosity of the ILs, the diffusion of the monomers was simultaneously controlled in water and in ILs. This resulted in the exceptionally high crystallinity of freestanding COF membranes with a Brunauer-Emmett-Teller (BET) surface area up to 4.3 times of that synthesized at a dichloromethane-HO interface. By varying the alkyl chain length of cations in the ILs, the interfacial region size and interfacial tension could be regulated to further improve the crystallinity of the COF membranes. As a result, the as-fabricated COF membranes exhibited ultrahigh permeance toward water and organic solvents and excellent selective rejection of dyes.
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http://dx.doi.org/10.1021/acsami.1c08789DOI Listing
August 2021

Platelet membrane and stem cell exosome hybrid enhances cellular uptake and targeting to heart injury.

Nano Today 2021 Aug 8;39. Epub 2021 Jun 8.

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, and North Carolina State University, Raleigh, North Carolina 27606, United States.

Exosomes from mesenchymal stem cells have been largely studied as therapeutics to treat myocardial infarctions. However, exosomes injected for therapeutic purposes face a number of challenges, including competition from exosomes already in circulation, and the internalization/clearance by the mononuclear phagocyte system. In this study, we hybrid exosomes with platelet membranes to enhance their ability to target the injured heart and avoid being captured by macrophages. Furthermore, we found that encapsulation by the platelet membranes induces macropinocytosis, enhancing the cellular uptake of exosomes by endothelial cells and cardiomyocytes strikingly. studies showed that the cardiac targeting ability of hybrid exosomes in a mice model with myocardial infarction injury. Last, we tested cardiac functions and performed immunohistochemistry to confirm a better therapeutic effect of platelet membrane modified exosomes compared to non-modified exosomes. Our studies provide proof-of-concept data and a universal approach to enhance the binding and accumulation of exosomes in injured tissues.
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http://dx.doi.org/10.1016/j.nantod.2021.101210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294084PMC
August 2021

DysPIA: A Novel Dysregulated Pathway Identification Analysis Method.

Front Genet 2021 5;12:647653. Epub 2021 Jul 5.

Key Laboratory of Tropical Translational Medicine, Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou, China.

Differential co-expression-based pathway analysis is still limited and not widely used. In most current methods, the pathways were considered as gene sets, but the gene regulation relationships were not considered, and the computational speed was slow. In this article, we proposed a novel Dysregulated Pathway Identification Analysis (DysPIA) method to overcome these shortcomings. We adopted the idea of Correlation by Individual Level Product into analysis and performed a fast enrichment analysis. We constructed a combined gene-pair background which was much more sufficient than the background used in Edge Set Enrichment Analysis. In simulation study, DysPIA was able to identify the causal pathways with high AUC (0.9584 to 0.9896). In p53 mutation data, DysPIA obtained better performance than other methods. It obtained more potential dysregulated pathways that could be literature verified, and it ran much faster (∼1,700-8,000 times faster than other methods when 10,000 permutations). DysPIA was also applied to breast cancer relapse dataset and breast cancer subtype dataset. The results show that DysPIA is effective and has a great biological significance. R packages "DysPIA" and "DysPIAData" are constructed and freely available on R CRAN (https://cran.r-project.org/web/packages/DysPIA/index.html and https://cran.r-project.org/web/packages/DysPIAData/index.html), and on GitHub (https://github.com/lemonwang2020).
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http://dx.doi.org/10.3389/fgene.2021.647653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287415PMC
July 2021

Orf Virus ORF120 Protein Positively Regulates the NF-κB Pathway by Interacting with G3BP1.

J Virol 2021 09 9;95(19):e0015321. Epub 2021 Sep 9.

Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin Universitygrid.64924.3d, Changchun, China.

Orf virus (ORFV) is a highly epitheliotropic parapoxvirus with zoonotic significance that induces proliferative lesions in the skin of sheep, goats, and humans. Several viral proteins carried by ORFV, including nuclear factor-κB (NF-κB) inhibitors, play important roles in hijacking host-associated proteins for viral evasion of the host innate immune response. However, the roles of proteins with unknown functions in viral replication and latent infection remain to be explored. Here, we present data demonstrating that the ORF120, an early-late ORFV-encoded protein, activates the NF-κB pathway in the early phase of infection, which implies that ORFV may regulate NF-κB through a biphasic mechanism. A DUAL membrane yeast two-hybrid system and coimmunoprecipitation experiments revealed that the ORF120 protein interacts with Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1). The overexpression of the ORF120 protein can efficiently increase the expression of G3BP1 and nuclear translocation of NF-κB-p65 in primary ovine fetal turbinate (OFTu) and HeLa cells. The knockdown of G3BP1 significantly decreased ORF120-induced NF-κB activation, indicating that G3BP1 is involved in ORF120-induced NF-κB pathway activation. A dual-luciferase reporter assay revealed that ORF120 could positively regulate the NF-κB pathway through the full-length G3BP1 or the domain of G3BP1. In conclusion, we demonstrate, for the first time, that the ORF120 protein is capable of positively regulating NF-κB signaling by interacting with G3BP1, providing new insights into ORFV pathogenesis and a theoretical basis for antiviral drug design. As part of the host innate response, the nuclear factor-κB (NF-κB) pathway plays a partial antiviral role in nature by regulating the innate immune response. Thus, the NF-κB pathway is probably the most frequently targeted intracellular pathway for subversion by anti-immune modulators that are carried by a wide range of pathogens. Various viruses, including poxviruses, carry several proteins that prepare the host cell for viral replication by inhibiting cytoplasmic events, leading to the initiation of NF-κB transcriptional activity. However, NF-κB activity is hypothesized to facilitate viral replication to a great extent. The significance of our research is in the exploration of the activation mechanism of NF-κB induced by the Orf virus (ORFV) ORF120 protein interacting with G3BP1, which helps not only to explain the ability of ORFV to modulate the immune response through the positive regulation of NF-κB but also to show the mechanism by which the virus evades the host innate immune response.
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http://dx.doi.org/10.1128/JVI.00153-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428408PMC
September 2021

PPP1CA/YAP/GS/Gln/mTORC1 pathway activates retinal Müller cells during diabetic retinopathy.

Exp Eye Res 2021 09 17;210:108703. Epub 2021 Jul 17.

Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address:

Diabetic retinopathy (DR) is a vision-loss complication caused by diabetes with high prevalence. During DR, the retinal microvascular injury and neurodegeneration derived from chronic hyperglycemia have attracted global attention to retinal Müller cells (RMCs), the major macroglia in the retina contributes to neuroprotection. Protein Phosphatase 1 Catalytic Subunit Alpha (PPP1CA) dephosphorylates the transcriptional coactivator Yes-associated protein (YAP) to promote the transcription of glutamine synthetase (GS). GS catalyzes the transformation of neurotoxic glutamate (Glu) into nontoxic glutamine (Gln) to activate the mammalian target of rapamycin complex 1 (mTORC1), which promotes the activation of RMCs. In this study, in vitro MIO-M1 cell and in vivo mouse high-fat diet and streptozotocin (STZ)-induced diabetic model to explore the role of the PPP1CA/YAP/GS/Gln/mTORC1 pathway on the activation of MRCs during DR. Results showed that PPP1CA promoted the dephosphorylation and nuclear translocation of YAP in high glucose (HG)-exposed MIO-M1 cells. YAP transcribed GS in HG-exposed MIO-M1 cells in a TEAD1-dependent and PPP1CA-dependent way. GS promoted the biosynthesis of Gln in HG-exposed MIO-M1 cells. Gln activated mTORC1 instead of mTORC2 in HG-exposed MIO-M1 cells. The proliferation and activation of HG-exposed MIO-M1 cells were PPP1CA/YAP/GS/Gln/mTORC1-dependent. Finally, RMC proliferation and activation during DR were inhibited by the PPP1CA/YAP/GS/Gln/mTORC1 blockade. The findings supplied a potential idea to protect RMCs and alleviate the development of DR.
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http://dx.doi.org/10.1016/j.exer.2021.108703DOI Listing
September 2021

Lipophagy: A New Perspective of Natural Products in Type 2 Diabetes Mellitus Treatment.

Diabetes Metab Syndr Obes 2021 30;14:2985-2999. Epub 2021 Jun 30.

Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China.

Autophagy has been reported to involve in the pathogenesis of type 2 diabetes mellitus (T2DM), which protects the insulin target tissues and pancreatic β-cells. However, autophagy is inhibited when the cells are lipid overload. That, in turn, increases the accumulation of fat. Lipotoxicity caused by excessive lipid accumulation contributes to pathogenesis of T2DM. Therefore, it is undeniable to break the vicious circles between lipid excess and autophagy deficiency. Lipophagy, a selective form of autophagy, is characterized by selective breakdown of lipid droplets (LDs). The nutritional status of cells contributes to the way of autophagy (selective or non-selective), while selective autophagy helps to accurately remove excess substances. It seems that lipophagy could be an effective means to decrease abnormal lipid accumulation that leads to insulin resistance and β-cell impairment by removing ectopic LDs. Based on this process, many natural compounds have been reported to decrease lipid accumulation in tissues through autophagy-lysosomal pathway, which gradually highlights the significance of lipophagy. In this review, we focus on the mechanisms that lipophagy improves T2DM and natural products that are applied to induce lipophagy. It is also suggested that natural herbs with rich contents of natural products inducing lipophagy would be potential candidates for alleviating T2DM.
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http://dx.doi.org/10.2147/DMSO.S310166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256822PMC
June 2021

Comparative Proteomic Characterization of Ventral Hippocampus in Susceptible and Resilient Rats Subjected to Chronic Unpredictable Stress.

Front Neurosci 2021 17;15:675430. Epub 2021 Jun 17.

State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy Medical Sciences and Peking Union Medical College, Beijing, China.

Chronic stress is an essential factor leading to depression. However, there exist individual differences in people exposed to the same stressful stimuli. Some people display negative psychology and behavior, while others are normal. Given the importance of individual difference, finding differentially expressed proteins in stress-resistant and stress-susceptible groups has great significance for the study of pathogenesis and treatment of depression. In this study, stress-susceptible rats and stress-resilient rats were first distinguished by sucrose preference test. These stress-susceptible rats also displayed depression-like behaviors in forced swimming test and open field test. Then, we employed label-free quantitative proteomics to analyze proteins in the ventral hippocampus. There were 4,848 proteins totally identified. Based on statistical analysis, we found 276 differentially expressed proteins. Bioinformatics analysis revealed that the biological processes of these differential proteins were related to mitochondrion organization, protein localization, coenzyme metabolic process, cerebral cortex tangential migration, vesicle-mediated transport, and so on. The KEGG pathways were mainly involved in metabolic pathways, axon guidance, autophagy, and tight junction. Furthermore, we ultimately found 20 stress-susceptible proteins and two stress-resilient proteins. These stress-related proteins could not only be potential biomarkers for depression diagnosis but also contribute to finding new therapeutic targets and providing personalized medicine.
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http://dx.doi.org/10.3389/fnins.2021.675430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249003PMC
June 2021

Identification of CH subfamily ZAT genes in Gossypium species reveals GhZAT34 and GhZAT79 enhanced salt tolerance in Arabidopsis and cotton.

Int J Biol Macromol 2021 Aug 29;184:967-980. Epub 2021 Jun 29.

Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou 450000, China; State Key Laboratory of Cotton Biology, Institute of Cotton Research Chinese Academy of Agricultural Science, Anyang, Henan 455000, China. Electronic address:

Soil salinization is a vital factor that restricts the efficient and sustainable development of global agriculture. Studies enlightened that the CH zinc finger proteins (CH-ZFP) were involved in regulating the stress response in plants. However, knowledge of the CH-ZFP subfamily C1 (ZAT; Zinc finger of Arabidopsis thaliana) in cotton is still a mystery. In this study, 47, 45, 94, and 88 ZAT genes were obtained from diploid A2, D5 and tetraploid AD1, AD2 cotton genomes, respectively. The function of hybridization and allopolyploidy in the evolutionary linkage of allotetraploid cotton was explained by the family of ZAT gene in 4 species. Duplication of gene activities indicates that the family of ZAT gene of cotton evolution was under strong purifying selection. The integration of previous transcriptome data related to NaCl stress, strongly suggests the GhZAT34 and GhZAT79 may interact with salt resistance in upland cotton. The expression level of certain ZAT genes, higher seed germination rate of transgenic Arabidopsis and gene- silenced cotton revealed that both genes were involved in the salt tolerance of upland cotton. This study may pave the substantial understandings into the role of ZATs genes in plants as well as suggest appropriate candidate genes for breeding of cotton varieties against salinity tolerance.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.06.166DOI Listing
August 2021

An Online Data Visualization Feedback Protocol for Motor Imagery-Based BCI Training.

Front Hum Neurosci 2021 7;15:625983. Epub 2021 Jun 7.

School of Electronics and Information, Northwestern Polytechnical University, Xi'an, China.

Brain-computer interface (BCI) has developed rapidly over the past two decades, mainly due to advancements in machine learning. Subjects must learn to modulate their brain activities to ensure a successful BCI. Feedback training is a practical approach to this learning process; however, the commonly used classifier-dependent approaches have inherent limitations such as the need for calibration and a lack of continuous feedback over long periods of time. This paper proposes an online data visualization feedback protocol that intuitively reflects the EEG distribution in Riemannian geometry in real time. Rather than learning a hyperplane, the Riemannian geometry formulation allows iterative learning of prototypical covariance matrices that are translated into visualized feedback through diffusion map process. Ten subjects were recruited for MI-BCI (motor imagery-BCI) training experiments. The subjects learned to modulate their sensorimotor rhythm to centralize the points within one category and to separate points belonging to different categories. The results show favorable overall training effects in terms of the class distinctiveness and EEG feature discriminancy over a 3-day training with 30% learners. A steadily increased class distinctiveness in the last three sessions suggests that the advanced training protocol is effective. The optimal frequency band was consistent during the 3-day training, and the difference between subjects with good or low MI-BCI performance could be clearly observed. We believe that the proposed feedback protocol has promising application prospect.
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http://dx.doi.org/10.3389/fnhum.2021.625983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215169PMC
June 2021

Inhibition of MicroRNA-326 in a NOD.H-2 Mouse Model of Autoimmune Thyroiditis.

Front Immunol 2021 1;12:620916. Epub 2021 Jun 1.

Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China.

Background: Previous studies reported that various miRNAs participate in autoimmune diseases, but the potential regulatory mechanism of miRNAs in autoimmune thyroiditis (AIT) needs further exploration.

Objective: This study aimed to further verify that miR-326 contributes to AIT by regulating Th17/Treg balance through Ets-1 using lentiviral gene delivery through tail vein and thyroid injection in NOD.H-2 mice.

Materials And Methods: Five-week-old NOD.H-2 mice were divided randomly into tail vein and thyroid injection groups, and each received either mmu-miR-326 sponge (LV-sponge) or lentiviral vector control. Mice were divided for tail vein injection: the therapeutic LV-ctrl, therapeutic LV-sponge, prophylactic LV-ctrl, and prophylactic LV-sponge groups. The control group was fed high-iodine water without vein injection. The thyroid infiltration of lymphocytes and serum TgAb value were investigated by thyroid hematoxylin and eosin (HE) staining and ELISA, respectively. Ets-1 and lymphocyte counts were measured by RT-PCR, western blotting, and flow cytometry. The thyroid CD4IL-17a cells and CD4Ets-1 cells were detected by immunofluorescence, and the serum cytokines were tested by ELISA.

Results: In the tail vein injection groups, the thyroid inflammatory score and serum TgAb titer were significantly lower in the LV-sponge groups than in the control and LV-ctrl groups while Ets-1 protein expression in mouse spleens was increased in the LV-sponge groups. Moreover, Th17/Treg ratio declined in the LV-sponge group and decreased significantly in the prophylactic LV-sponge group ( = 0.036) tested by flow cytometry. Immunofluorescence showed that, in LV-sponge groups, CD4IL-17a cells were decreased significantly ( = 0.001), while CD4Ets-1 cells were increased significantly in the LV-sponge group ( = 0.029). The serum IL-17/IL-10 was decreased significantly in the LV-sponge group ( < 0.05). In the thyroid injection groups, the thyroid inflammatory score and serum TgAb titer in the LV-sponge group decreased significantly compared with those in the LV-ctrl group ( < 0.05). In addition, in LV-sponge groups, CD4IL-17a cells were decreased, while CD4Ets-1 cells were increased significantly in the inhibition group evaluated by immunofluorescence. Moreover, tail vein injection of LV-sponge resulted in much lower TgAb levels in thyroiditis compared with thyroid injection.

Conclusion: MiR-326 targeted therapy may be a promising approach for AIT. In addition, tail vein injection may achieve a better intervention effect than thyroid injection.
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http://dx.doi.org/10.3389/fimmu.2021.620916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205278PMC
June 2021

Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19.

Nat Nanotechnol 2021 08 17;16(8):942-951. Epub 2021 Jun 17.

Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has grown into a global pandemic, and only a few antiviral treatments have been approved to date. Angiotensin-converting enzyme 2 (ACE2) plays a fundamental role in SARS-CoV-2 pathogenesis because it allows viral entry into host cells. Here we show that ACE2 nanodecoys derived from human lung spheroid cells (LSCs) can bind and neutralize SARS-CoV-2 and protect the host lung cells from infection. In mice, these LSC-nanodecoys were delivered via inhalation therapy and resided in the lungs for over 72 h post-delivery. Furthermore, inhalation of the LSC-nanodecoys accelerated clearance of SARS-CoV-2 mimics from the lungs, with no observed toxicity. In cynomolgus macaques challenged with live SARS-CoV-2, four doses of these nanodecoys delivered by inhalation promoted viral clearance and reduced lung injury. Our results suggest that LSC-nanodecoys can serve as a potential therapeutic agent for treating COVID-19.
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http://dx.doi.org/10.1038/s41565-021-00923-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364483PMC
August 2021

Exosomal circRNA as a novel potential therapeutic target for multiple myeloma-related myocardial damage.

Cancer Cell Int 2021 Jun 13;21(1):311. Epub 2021 Jun 13.

Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 16369 Jingshi Road, Jinan, 250014, China.

Introduction: Myocardial damage is a mostly incurable complication of multiple myeloma (MM) that seriously affects the treatment outcome and quality of life of patients. Exosomal circular RNAs (exo-circRNAs) play an important role in tumor occurrence and development and are considered key factors in MM pathogenesis. However, the role and mechanism of action of exo-circRNAs in MM-related myocardial damage are still unclear. This study aimed to investigate correlations between exo-circRNAs and MM and to preliminarily explore the role of exo-circRNAs in MM-related myocardial damage.

Methods: Six MM patients and five healthy controls (HCs) were included in the study. High-throughput sequencing and qRT-PCR verification were used to obtain a profile of abnormally expressed exo-circRNAs. GO, KEGG, miRanda, TargetScan and Metascape were used for bioinformatics analyses. H9C2 cells treated with exosomes from U266 cells were used in cell experiments. CCK-8, PCR, immunofluorescence and western blotting assays were used to detect cell proliferation and expression of autophagy-related indicators. Electron microscopy was used to observe the number of autophagic vesicles.

Results: Bioinformatics analysis showed that circRNAs with upregulated expression had the potential to promote MM-related myocardial damage. In addition, PCR results confirmed that circ-G042080 was abundantly expressed in the serum exosomes of 20 MM patients. Correlation analysis showed that the expression level of circ-G042080 was positively correlated with the clinical level of MM and MM-related myocardial damage and that circ-G042080 might interfere with MM-related myocardial damage through a downstream miRNA/TLR4 axis. Cell experiments demonstrated that the circ-G042080/hsa-miR-4268/TLR4 axis might exist in H9C2 cells incubated with exosomes and cause abnormal autophagy.

Conclusion: Abnormal expression of serum exo-circRNAs was found to be associated with MM-related myocardial damage, suggesting that exo-circRNAs might become a new diagnostic marker of MM-related myocardial damage and a therapeutic target.
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http://dx.doi.org/10.1186/s12935-021-02011-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201884PMC
June 2021

Unexpected three-state hydrochromism of a donor-acceptor self-complex with fluctuations in relative humidity.

Chem Commun (Camb) 2021 Jul;57(53):6554-6557

School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China and Department of Chemistry, Northwestern University, Evanston, IL, USA.

Water in our environment is ever present, particularly in our atmosphere, from which it may be adsorbed by materials hygroscopically. At the molecular level, the binding of water molecules to various materials is driven by weak interactions but can have profound effects on physical properties, including the donor-acceptor interactions in charge transfer (CT) salts. Herein we present the unexpected three-state hydrochromatic switching of a bipyridinium-based donor-acceptor self-complex with changes in relative humidity (RH) and subsequent stable hydrate formation. RH is typically an overlooked variable that can vary greatly. These findings suggest that care should be taken to consider fluctuations in RH when characterizing the solid state optical band gap and CT absorption bands for organic donor-acceptor CT salt complexes.
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http://dx.doi.org/10.1039/d1cc01972dDOI Listing
July 2021

Epidermolysis Bullosa in Chinese Patients: Genetic Analysis and Mutation Landscape in 57 Pedigrees and Sporadic Cases.

Acta Derm Venereol 2021 Jul 15;101(7):adv00503. Epub 2021 Jul 15.

Shandong Provincial Hospital for Skin Diseases and Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.

Epidermolysis bullosa encompasses a group of inherited blistering skin disorders. The pathogenic mutations in 10-25% of patients with epidermolysis bullosa have not been identified by Sanger sequencing. The aims of this study were to identify the pathogenic sequence alterations in a large cohort of Chinese patients with epidermolysis bullosa and to clarify the relationship between clinical phenotypes and genotypes. Whole-exome sequencing was performed on 44 pedigrees and 13 sporadic cases. The results were further confirmed by Sanger sequencing. In total, 52 mutations, comprising 19 novel and 33 previously reported mutations, were identified in 5 genes, with a mutation detection rate of 100%. A relationship between subtypes and pathogenic genes was established: 12 cases of epidermolysis bullosa simplex were associated with mutations in KRT5/14 and PLEC; one case of junctional epidermolysis bullosa carried mutations in ITGB4; and 44 cases of dystrophic epidermolysis bullosa were caused by mutations in COL7A1. The results of this study support whole-exome sequencing as a promising tool in the genetic diagnosis of epidermolysis bullosa.
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http://dx.doi.org/10.2340/00015555-3843DOI Listing
July 2021

Multifunctional Graphdiyne-Cerium Oxide Nanozymes Facilitate MicroRNA Delivery and Attenuate Tumor Hypoxia for Highly Efficient Radiotherapy of Esophageal Cancer.

Adv Mater 2021 Jun 5;33(24):e2100556. Epub 2021 May 5.

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China.

Radioresistance is an important challenge for clinical treatments. The main causes of radioresistance include hypoxia in the tumor microenvironment, the antioxidant system within cancer cells, and the upregulation of DNA repair proteins. Here, a multiple radiosensitization strategy of high-Z-element-based radiation enhancement is designed, attenuating hypoxia and microRNA therapy. The novel 2D graphdiyne (GDY) can firmly anchor and disperse CeO nanoparticles to form GDY-CeO nanocomposites, which exhibit superior catalase-mimic activity in decomposing H O to O to significantly alleviate tumor hypoxia, promote radiation-induced DNA damage, and ultimately inhibit tumor growth in vivo. The miR181a-2-3p (miR181a) serum levels in patients are predictive of the response to preoperative radiotherapy in locally advanced esophageal squamous cell carcinoma (ESCC) and facilitate personalized treatment. Moreover, miR181a can act as a radiosensitizer by directly targeting RAD17 and regulating the Chk2 pathway. Subsequently, the GDY-CeO nanocomposites with miR181a are conjugated with the iRGD-grafted polyoxyethylene glycol (short for nano-miR181a), which can increase the stability, efficiently deliver miR181a to tumor, and exhibit low toxicity. Notably, nano-miR181a can overcome radioresistance and enhance therapeutic efficacy both in a subcutaneous tumor model and human-patient-derived xenograft models. Overall, this GDY-CeO nanozyme and miR181a-based multisensitized radiotherapy strategy provides a promising therapeutic approach for ESCC.
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http://dx.doi.org/10.1002/adma.202100556DOI Listing
June 2021

Three dimensional band-filling control of complex oxides triggered by interfacial electron transfer.

Nat Commun 2021 Apr 27;12(1):2447. Epub 2021 Apr 27.

Beijing National Laboratory for Condensed Matter Physics and Institute of Physics, Chinese Academy of Sciences, Beijing, China.

The d-band-filling of transition metals in complex oxides plays an essential role in determining their structural, electronic and magnetic properties. Traditionally, at the oxide heterointerface, band-filling control has been achieved via electrostatic modification in the structure of field-effect transistors or electron transfer, which is limited to the quasi-two-dimension at the interface. Here we report a three-dimensional (3D) band-filling control by changing the local lattice coordination in a designed oxide heterostructure. At the LaCoO/LaTiO heterointerface, due to the Fermi level mismatch, electrons transfer from LaTiO to LaCoO. This triggers destabilisation of the CoO octahedrons, i.e. the formation of lattice configurations with a reduced Co valence. The associated oxygen migration results in the 3D topotactic phase transition of LaCoO. Tuned by the thickness of LaTiO, different crystalline phases and band-fillings of Co occur, leading to the emergence of different magnetic ground states.
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http://dx.doi.org/10.1038/s41467-021-22790-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079372PMC
April 2021

Whole exome sequencing improves mutation detection in Hailey-Hailey disease.

J Dermatol 2021 Jul 20;48(7):989-992. Epub 2021 Apr 20.

Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.

Hailey-Hailey disease (HHD) is an autosomal dominant monogenic disease that is defective in the ATP2C1 gene. In previous studies, Sanger sequencing was the main method applied to detect mutations in HHD patients, and no mutations in the ATP2C1 gene were found in 12-55% of those reported. The aim of our study was to carry out whole exome sequencing (WES) for the HHD patients in whom efforts to identify mutations by Sanger sequencing had failed, and to find a new pathogenic gene. WES was performed using genomic DNA from 13 HHD patients and 364 in-house healthy controls. Potential pathogenic mutations were subsequently validated by Sanger sequencing. As a result, eight mutations in the ATP2C1 gene were identified using WES. In the remaining five patients, we found one mutation in the ATP2A2 gene which was the causal gene of Darier's disease. Four patients had no detectable mutations in ATP2C1 and the other ATPase genes. Together with our previous study in 2019, the total mutation rate was calculated to be 47/52 (90.4%). These findings demonstrate that WES is capable of improving the mutation detection sensitivity in HHD compared with Sanger sequencing.
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http://dx.doi.org/10.1111/1346-8138.15828DOI Listing
July 2021
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