Publications by authors named "Zhen Liang"

407 Publications

Lowering the Contact Barriers of 2D Organic F CuPc Field-Effect Transistors by Introducing Van der Waals Contacts.

Small 2021 Mar 19:e2007739. Epub 2021 Mar 19.

School of Materials Science and Engineering, Harbin Institute of Technology, Harbin, 150001, China.

2D organic crystals exhibit efficient charge transport and field-effect characteristics, making them promising candidates for high-performance nanoelectronics. However, the strong Fermi level pinning (FLP) effect and large Schottky barrier between organic semiconductors and metals largely limit device performance. Herein, by carrying out temperature-dependent transport and Kelvin probe force microscopy measurements, it is demonstrated that the introducing of 2D metallic 1T-TaSe with matched band-alignment as electrodes for F CuPc nanoflake filed-effect transistors leads to enhanced field-effect characteristics, especially lowered Schottky barrier height and contact resistance at the contact and highly efficient charge transport within the channel, which are attributed to the significantly suppressed FLP effect and appropriate band alignment at the nonbonding van der Waals (vdW) hetero-interface. Moreover, by taking advantage of the improved contact behavior with 1T-TaSe contact, the optoelectronic performance of F CuPc nanoflake-based phototransistor is drastically improved, with a maximum photoresponsivity of 387 A W and detectivity of 3.7 × 10 Jones at quite a low V of 1 V, which is more competitive than those of the reported organic photodetectors and phototransistors. The work provides an avenue to improve the electrical and optoelectronic properties of 2D organic devices by introducing 2D metals with appropriate work function for vdW contacts.
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http://dx.doi.org/10.1002/smll.202007739DOI Listing
March 2021

Antibody-free enrichment method for proteome-wide analysis of endogenous SUMOylation sites.

Anal Chim Acta 2021 Apr 16;1154:338324. Epub 2021 Feb 16.

CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, 116023, China.

SUMOylation is a reversible post-translational modification that plays crucial roles in numerous cellular processes. Although anti-SUMO antibodies have been applied to analyze exogenous and endogenous SUMOylation, such immunoprecipitation enrichment strategy is applicable only for the enrichment of one specific SUMO type in mammalian cells, unable to map the global landscape of all endogenous SUMOylation simultaneously. To address this issue, we proposed an antibody-free strategy to enrich and profile endogenous SUMO1/2/3-modified peptides simultaneously. Upon trypsin digestion, the SUMO1- and SUMO2/3-modified peptides contained SUMO remnants with 7 and 9 acidic amino acids respectively, which carried more negative charges at high pH and could interact with strong anion exchange (SAX) materials more strongly than non-SUMOylated peptides, thus enabling the specific enrichment of endogenous SUMOylated peptides. Followed by the secondary digestion with Asp-N/Glu-C to generate smaller SUMOylated peptides with proper length for MS identification, off-line high-pH C18 pre-fractionation and low pH nanoRPLC-ESI-MS/MS analysis, 177 SUMO1-modified sites and 74 SUMO2/3-modified sites were unbiasedly identified in HeLa cell lysate. To the best of our knowledge, this was the first antibody-free strategy to comprehensively profile various endogenous SUMOylation sites, demonstrating the great potential in the comprehensive analysis of endogenous SUMOylation across various species and organs, which might further facilitate the understanding of SUMO's function in physiology and pathology.
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http://dx.doi.org/10.1016/j.aca.2021.338324DOI Listing
April 2021

Integrated proteomic sample preparation with combination of on-line high-abundance protein depletion, denaturation, reduction, desalting and digestion to achieve high throughput plasma proteome quantification.

Anal Chim Acta 2021 Apr 19;1154:338343. Epub 2021 Feb 19.

CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, 116023, China.

In this study, we developed an integrated plasma proteome sample preparation system, by which high-abundance proteins from human plasma were first depleted by immunoaffinity column, followed by on-line middle and low-abundance proteins denaturation, reduction, desalting and tryptic digestion. To evaluate the performance of such a system, 20 μL plasma was processed automatically, followed by 1-h gradient liquid chromatography-mass spectrometry analysis (LC-MS). Compared to conventional in-solution protocols, not only the sample preparation time could be shortened from 20 h to 20 min, but also the number of identified proteins were greatly increased by 1.4-2.0 times. Such an integrated system allows us to process 36 human plasma samples per day, with more than 300 proteins and 52 FDA approved disease markers per sample being identified. With combination of such an integrated sample preparation system with label-free single-shot LC-MS/MS, the human plasma proteins could be quantified across more than 6 orders of magnitude of abundance range with high reproducibility (Pearson R = 0.99, n = 9). In addition, the relative quantification of human plasma samples from diabetic retinopathy patients and diabetic patients demonstrated the feasibility of our developed workflow for clinic plasma proteome profiling. All these results demonstrated that our developed integrated plasma proteome sample preparation system would provide a new tool for high throughput biomarker discovery.
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http://dx.doi.org/10.1016/j.aca.2021.338343DOI Listing
April 2021

Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells.

Carcinogenesis 2021 Mar 3. Epub 2021 Mar 3.

Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, China.

Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed, and highly enriched in the processes of cell-cell adhesion, negative regulation of apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in-vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of autophagy, whereas inhibition of autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.
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http://dx.doi.org/10.1093/carcin/bgab019DOI Listing
March 2021

Fully integrated protein absolute quantification platform for analysis of multiple tumor markers in human plasma.

Talanta 2021 May 14;226:122102. Epub 2021 Jan 14.

National Chromatographic Research and Analysis Center, Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, 116023, China.

In this study, we developed a fully integrated protein absolute quantification platform for simultaneous analysis of multiple tumor markers in human plasma, by which multiple target proteins (alpha-fetoprotein, prostate-specific antigen, carcino-embryonic antigen and mucin-1) were firstly enriched by aptamers immobilized capillary column using graphene oxide modified polymer microsphere as the separation matrix, and then the eluted target proteins were online denatured, reduced, desalted and digested by our developed fully automated sample treatment device (FAST), finally the resulting peptides were analyzed by parallel reaction monitoring (PRM) on LTQ-orbitrap velos mass spectrometry. Compared to traditional ELISA assay, the platform exhibited significant advantages such as short analysis time, low limit of detection, and ease of automation. Furthermore, our developed platform was also applied in the absolute quantification of tumor markers from clinical human plasma samples, and the results were comparable to those obtained by clinical immunoassay. All the results demonstrated that such a platform could provide a promising tool for achieving high sensitivity, high accuracy, and high throughput detection of disease related protein markers in the routine physical examination and clinical disease diagnosis.
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http://dx.doi.org/10.1016/j.talanta.2021.122102DOI Listing
May 2021

Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ.

Br J Pharmacol 2021 Mar 4. Epub 2021 Mar 4.

Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China.

Background And Purpose: Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages. Research indicates that activation of PPARγ exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that prevent their clinical application in the treatment of CLD. In this study, we found that tectorigenin alleviates intrahepatic cholestasis in mice by activating PPARγ.

Experimental Approach: Wild-type mice were intragastrically administered α-naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and tectorigenin intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPARγ.

Key Results: Treatment with tectorigenin alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages and by promoting the expression of bile transporters via activation of PPARγ. Furthermore, tectorigenin increased expression of the bile salt export pump (BSEP) through enhanced PPARγ binding to the BSEP promoter. In PPARγ-deficient mice, the hepatoprotective effect of tectorigenin during cholestasis was blocked.

Conclusion And Implications: In conclusion, tectorigenin reduced the recruitment and activation of hepatic macrophages and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that tectorigenin is a candidate compound for cholestasis treatment.
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http://dx.doi.org/10.1111/bph.15429DOI Listing
March 2021

Predicting Individual Pain Thresholds From Morphological Connectivity Using Structural MRI: A Multivariate Analysis Study.

Front Neurosci 2021 10;15:615944. Epub 2021 Feb 10.

School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, China.

Pain sensitivity is highly variable among individuals, and it is clinically important to predict an individual's pain sensitivity for individualized diagnosis and management of pain. Literature has shown that pain sensitivity is associated with regional structural features of the brain, but it remains unclear whether pain sensitivity is also related to structural brain connectivity. In the present study, we investigated the relationship between pain thresholds and morphological connectivity (MC) inferred from structural MRI based on data of 221 healthy participants. We found that MC was highly predictive of an individual's pain thresholds and, importantly, it had a better prediction performance than regional structural features. We also identified a number of most predictive MC features and confirmed the crucial role of the prefrontal cortex in the determination of pain sensitivity. These results suggest the potential of using structural MRI-based MC to predict an individual's pain sensitivity in clinical settings, and hence this study has important implications for diagnosis and treatment of pain.
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http://dx.doi.org/10.3389/fnins.2021.615944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902866PMC
February 2021

The incidence of pulmonary thromboembolism in COVID-19 patients admitted to the intensive care unit: a meta-analysis and meta-regression of observational studies.

J Intensive Care 2021 Feb 22;9(1):20. Epub 2021 Feb 22.

Division of Vascular and Endovascular Surgery, Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Level 9, NUHS Tower Block, 1E Kent Ridge Road, Singapore, 119228, Singapore.

Objectives: Coronavirus disease 2019 (COVID-19) infection is associated with a prothrombotic state. We performed a meta-analysis of proportions to estimate the weighted average incidence of pulmonary thromboembolism (PTE) in COVID-19 patients who were admitted to the intensive care unit (ICU).

Methods: We searched various medical databases for relevant studies from 31 December 2019 till 30 September 2020. We included observational studies that reported the incidence of PTE in COVID-19 patients admitted to the ICU. We extracted data related to study characteristics, patient demographics, and the incidence of PTE. Risk of bias was assessed by using the ROBINS-I tool. Statistical analysis was performed with R 3.6.3.

Results: We included 14 studies with a total of 1182 patients in this study. Almost all patients in this meta-analysis received at least prophylactic anticoagulation. The weighted average incidence of PTE was 11.1% (95% CI 7.7% to 15.7%, I = 78%, Cochran's Q test P < 0.01). We performed univariate and multivariate meta-regression, which identified the proportion of males as a significant source of heterogeneity (P = 0.03, 95% CI 0.00 to - 0.09) CONCLUSION: The weighted average incidence of PTE remains high even after prophylactic anticoagulation. PTE is a significant complication of COVID-19 especially in critically ill patients in the ICU.
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http://dx.doi.org/10.1186/s40560-021-00535-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897892PMC
February 2021

Metabolic Syndrome and Risk of Upper Tract Urothelial Carcinoma: A Case-Control Study From Surveillance, Epidemiology and End Results-Medicare-Linked Database.

Front Oncol 2020 21;10:613366. Epub 2021 Jan 21.

Department of Urology, Tianjin Medical University General Hospital, Tianjin, China.

Background: Metabolic syndrome (MetS) and its components are associated with increased risks of several cancers. However, the relationship between MetS and upper tract urothelial carcinoma (UTUC) has never been investigated before.

Methods: We identified 3,785 UTUC cases aged over 65 years old within the Surveillance, Epidemiology and End Results-Medicare database between 2007 and 2016. For comparison, non-cancer controls (n = 189,953) were selected from the 5% random sample of individuals residing within regions of SEER registries and matched with cases through diagnosis date and pseudo-diagnosis date. MetS and its components were all defined by using ICD-9-CM codes. Multivariate logistic regression models were conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Time trends for MetS and its components were reported and we also performed dose-response effect analysis to test the concomitant effect of these components. The study was presented following the STROBE reporting checklist.

Results: UTUC risk was associated with metabolic syndrome (NCEP-III: OR: 1.669, 95% CI: 1.550-1.792; IDF: OR: 1.924, 95% CI: 1.676-2.172) and its component factors: elevated waist circumference/central adiposity (OR: 1.872, 95% CI: 1.693-2.055), impaired fasting glucose (OR: 1.306, 95% CI: 1.133-1.480), high blood pressure (OR: 1.295, 95% CI: 1.239-1.353), high triglycerides (OR: 1.280, 95% CI: 1.222-1.341), and low high-density lipoprotein cholesterol (OR: 1.354, 95% CI: 1.118-1.592). Consistent associations could also be observed in the subgroup analyses by tumor stages, grades, and tumor size. Additionally, the rates of MetS increased over time in both UTUC and control cohort (NCEP-III criterion; EAPC: +18.1%, 0.001; EAPC: +16.1%, 0.001, respectively). A significantly gradual increase in UTUC rates could be seen as the No. of the MetS components increase (² = 37.239, = 0.000).

Conclusions: Among people aged over 65, MetS and its components were significant risk factors for UTUC with consistent associations in different tumor stages, grades, and tumor size. Even if a subject who did not meet the criteria for MetS had only one of the components, he (she) still had an elevated risk for UTUC. Strategies to control the epidemic of MetS and its components might contribute to a reduction in the UTUC burden. The findings should be considered tentative until ascertained by more researches.
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http://dx.doi.org/10.3389/fonc.2020.613366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859618PMC
January 2021

Bi-functional selection markers assist segregation of transgene-free, genome-edited mutants.

Sci China Life Sci 2021 Jan 27. Epub 2021 Jan 27.

School of Life Science, Shanxi University, Taiyuan, 030006, China.

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http://dx.doi.org/10.1007/s11427-020-1820-9DOI Listing
January 2021

Quantitative proteomics of epigenetic histone modifications in MCF-7 cells under estradiol stimulation.

Anal Methods 2021 02;13(4):469-476

Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.

Estrogen exposure has already been considered to be associated with tumorigenesis and breast cancer progression. To study the epigenetic regulation mechanism in MCF-7 cells under estrogen exposure, which normally results in cell proliferation and malignancy, a stable isotope labeling of amino acid (SILAC) based quantitative proteomics strategy was used to analyse histone post-translational modifications (PTMs) and protein differential expressions. In total, we have unambiguously identified 49 histone variants and quantified 42 of them, in which two differentially expressed proteins were found to be associated with breast cancers. Through the quantitative analysis of 470 histone peptides with a combination of different PTM types, including methylation (mono-, di-, and tri-), acetylation and phosphorylation, 150 of them were found to be differentially expressed. Through the biological analysis of the quantification results of both histone PTMs and proteins in MCF-7 cells, we found that (1) the histone variants H10 and H2AV have an effect on the adjustment of the nucleosome or chromatin structure and activate target genes; (2) after estrogen receptor (ER) activation by estrogen, the recruitment of histone acetyltransferase KAT7 might affect the acetylation at the N terminal of H4 (K5, K8 and K12) and also result in cross-talk between different acetylation sites; (3) different expression of histone deacetylase HDAC2 and its nucleo-cytoplasmic transportation process is important in the regulation of histone acetylation in MCF-7 cells under estrogen exposure.
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http://dx.doi.org/10.1039/d0ay02146fDOI Listing
February 2021

Combination of continuous digestion by peptidase and spectral similarity comparisons for peptide sequencing.

J Sep Sci 2020 Sep 17;43(18):3665-3673. Epub 2020 Aug 17.

CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, P. R. China.

Peptide sequencing is critical to the quality control of peptide drugs and functional studies of active peptides. A combination of peptidase digestion and mass spectrometry technology is common for peptide sequencing. However, such methods often cannot obtain the complete sequence of a peptide due to insufficient amino acid sequence information. Here, we developed a method of generating full peptide ladders and comparing their MS spectral similarities. The peptide ladders, of which each component was different from the next component with one residue, were generated by continuous digestion by peptidase (carboxypeptidase Y and aminopeptidase). Then, based on the characteristics of peptide ladders, complete sequencing was realized by comparing MS spectral similarity of the generated peptide ladders. The complete amino acid sequences of bivalirudin, adrenocorticotropic hormone, and oxytocin were determined with high accuracy. This approach is beneficial to the quality control of drug peptides as well as the identification of novel bioactive peptides.
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http://dx.doi.org/10.1002/jssc.202000459DOI Listing
September 2020

[A Method for Isolating Tumor Cells from Large Volume of Malignant Pleural 
Effusion and Its Efficacy Evaluation].

Zhongguo Fei Ai Za Zhi 2020 Dec;23(12):1080-1086

Daycare Center, Peking University Cancer Hospital and Institute, Beijing 100142, China.

Background: Malignant plural effusion (MPE) is one of the most common specimen for liquid biopsy gene detection. This study aims to explore a method for isolating tumor cells from large volume of MPE and evaluate its efficacy and application prospect in gene detection.

Methods: Pleural effusions (>500 mL) from 20 advanced lung cancer patients were obtained by effusion drainage and used to isolate tumor cells with cell separation media Percoll and Ficoll. Cell number and purity were calculated. DNA was extracted from the supernatant (etDNA), total cells and isolated tumor cells of pleural effusion (ETC-DNA) to detect the mutation of tumor-related genes by next-generation sequencing.

Results: The median number of cells isolated from malignant pleural effusion was 8.50×10⁴ (interquel range: 9.25×10³-3.75×10⁵), 85.50%±5.80% of the cells were identified as tumor cells. The detection rates of epidermal growth factor receptor (EGFR) gene mutation of etDNA, total cell DNA and ETC-DNA were 70.00%, 50.00% and 70.00%, reseparately, while the median EGFR mutation abundance in 3 components was 16.05% (4.78%-43.06%), 1.09% (0.00%-2.39%), and 33.02% (18.50%-76.70%), respectively. ETC-DNA had good consistency with tissue DNA (P>0.999, kappa=1.000) and etDNA (P>0.999, kappa=1.000). ETC-DNA inclined to have higher EGFR mutation than etDNA, but the result was not statistically significant.

Conclusions: Our method can isolate large amount of tumor cells from a large volume of malignant pleural effusion with high purity. Using ETC-DNA as specimen improves the efficacy of gene detection, thus is worth further study.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.103.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786232PMC
December 2020

Injectable Porous Microchips with Oxygen Reservoirs and an Immune-Niche Enhance the Efficacy of CAR T Cell Therapy in Solid Tumors.

ACS Appl Mater Interfaces 2020 Dec 11;12(51):56712-56722. Epub 2020 Dec 11.

Central Laboratory, and Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University; Peking University Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Center for Molecular and Translational Medicine, Peking University Health Science Center, Beijing 100081, P.R. China.

Chimeric antigen receptor (CAR) T cell therapy is a promising new class of hematological malignancy treatment. However, CAR T cells are rarely effective in solid tumor therapy mainly because of the poor trafficking of injected CAR T cells to the tumor site and their limited infiltration and survival in the immunosuppressive and hypoxic tumor microenvironment (TME). Here, we built an injectable immune-microchip (i-G/MC) system to intratumorally deliver CAR T cells and enhance their therapeutic efficacy in solid tumors. In the i-G/MC, oxygen carriers (Hemo) are released to disrupt the TME, and then, CAR T cells migrate from IL-15-laden i-G/MCs into the tumor stroma. The results indicate that Hemo and IL-15 synergistically enhanced CAR T cell survival and expansion under hypoxic conditions, promoting the potency and memory of CAR T cells. This i-G/MC not only serves as a cell carrier but also builds an immune-niche, enhancing the efficacy of CAR T cells.
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http://dx.doi.org/10.1021/acsami.0c15239DOI Listing
December 2020

Bis(zinc(II)-dipicolylamine)-functionalized sub-2 μm core-shell microspheres for the analysis of N-phosphoproteome.

Nat Commun 2020 12 4;11(1):6226. Epub 2020 Dec 4.

CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R & A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023, Dalian, China.

Protein N-phosphorylation plays a critical role in central metabolism and two/multicomponent signaling of prokaryotes. However, the current enrichment methods for O-phosphopeptides are not preferred for N-phosphopeptides due to the intrinsic lability of P-N bond under acidic conditions. Therefore, the effective N-phosphoproteome analysis remains challenging. Herein, bis(zinc(II)-dipicolylamine)-functionalized sub-2 μm core-shell silica microspheres (SiO@DpaZn) are tailored for rapid and effective N-phosphopeptides enrichment. Due to the coordination of phosphate groups to Zn(II), N-phosphopeptides can be effectively captured under neutral conditions. Moreover, the method is successfully applied to an E.coli and HeLa N-phosphoproteome study. These results further broaden the range of methods for the discovery of N-phosphoproteins with significant biological functions.
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http://dx.doi.org/10.1038/s41467-020-20026-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718886PMC
December 2020

A Generalized Encoding System for Alpha Oscillations Through Visual Saliency Analysis.

IEEE Trans Neural Syst Rehabil Eng 2020 12 28;28(12):2731-2743. Epub 2021 Jan 28.

By learning how the brain reacts to external visual stimuli and examining possible triggered brain statuses, we conduct a systematic study on an encoding problem that estimates ongoing EEG dynamics from visual information. A novel generalized system is proposed to encode the alpha oscillations modulated during video viewing by employing the visual saliency involved in the presented natural video stimuli. Focusing on the parietal and occipital lobes, the encoding effects at different alpha frequency bins and brain locations are examined by a real-valued genetic algorithm (GA), and possible links between alpha features and saliency patterns are constructed. The robustness and reliability of the proposed system are demonstrated in a 10-fold cross-validation. The results show that stimuli with different saliency levels can induce significant changes in occipito-parietal alpha oscillations and that alpha at higher frequency bins responded the most in involuntary attention related to bottom-up-based visual processing. This study provides a novel approach to understand the processing of involuntary attention in the brain dynamics and would further be beneficial to the development of brain-computer interfaces and visual design.
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http://dx.doi.org/10.1109/TNSRE.2020.3038789DOI Listing
December 2020

Phosphodiesterase Type 5 Inhibitors and Risk of Skin Cancers in Men: A Meta-Analysis and Trial Sequential Analysis Involving 7,479,852 Subjects.

World J Mens Health 2020 Aug 28. Epub 2020 Aug 28.

Department of Urology, Tianjin Medical University General Hospital, Tianjin, China.

Purpose: We conducted a systematic review and meta-analysis to quantify the association between phosphodiesterase type 5 inhibitors (PDE5Is) use and skin cancers and we also examined whether down-expression of the PDE5A gene was related to worse prognosis for malignant melanoma (MM) patients.

Materials And Methods: The PubMed, Cochrane Library, Web of Science, EMBASE, and ClinicalTrails.gov databases were searched. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the association between PDE5Is use and risk of skin cancers. Cumulative meta-analysis and trial sequential analysis (TSA) were also conducted. Survival outcomes were analyzed online.

Results: After pooling all 8 eligible studies comprising 7,479,852 subjects, we found that PDE5Is use was significantly associated with slightly increased risk of developing MM (OR: 1.13, 95% CI: 1.05 to 1.21, ²=67.1%), basal cell carcinoma (OR: 1.16, 95% CI: 1.13 to 1.19, ²=49.6%), and squamous cell carcinoma (OR: 1.07, 95% CI: 1.01 to 1.13, ²=0.0%). Totally, PDE5Is increased the risk of developing skin cancers (OR: 1.13, 95% CI: 1.09 to 1.17, ²=70.8%). TSA results showed that the sample size was enough to reach a positive conclusion.

Conclusions: The use of PDE5Is may be slightly associated with increased risk of developing skin cancers. There should be a balance between drug benefits and potential safety issues. However, the pooled results should be considered tentative until confounding factors such as sun exposure and lifestyle are well-controlled in further studies.
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http://dx.doi.org/10.5534/wjmh.200082DOI Listing
August 2020

Lung Cancer Combination Treatment: Evaluation of the Synergistic Effect of Cisplatin Prodrug, Vinorelbine and Retinoic Acid When Co-Encapsulated in a Multi-Layered Nano-Platform.

Drug Des Devel Ther 2020 27;14:4519-4531. Epub 2020 Oct 27.

Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Day Oncology Unit, Peking University Cancer Hospital & Institute, Beijing 100142, People's Republic of China.

Purpose: Lung cancer remains the leading cancer-associated deaths worldwide. Cisplatin (CIS) was often used in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). Prodrug is an effective strategy to improve the efficiency of drugs and reduce the toxicity. The aim of this study was to prepare and characterize CIS prodrug, vinorelbine (VNR), and all-trans retinoic acid (ATRA) co-delivered multi-layered nano-platform, evaluating their antitumor activity in vitro and in vivo.

Methods: Cisplatin prodrug (CISP) was synthesized. A multi-layered nano-platform contained CISP, VNR and ATRA were prepared and named CISP/VNR/ATRA MLNP. The physicochemical properties of CISP/VNR/ATRA MLNP were investigated. In vitro cytotoxicity against CIS-resistant NSCLC cells (A549/CIS cells) and Human normal lung epithelial cells (BEAS-2B cells) was investigated, and in vivo anti-tumor efficiency was evaluated on mice bearing A549/CIS cells xenografts.

Results: CISP/VNR/ATRA MLNP were spherical particles with particle size and zeta potential of 158 nm and 12.3 mV. CISP/VNR/ATRA MLNP (81.36%) was uptake by cancer cells in vitro. CISP/VNR/ATRA MLNP could significantly inhibit the in vivo antitumor growth and suspended the tumor volume from 1440 mm to 220 mm.

Conclusion: It could be concluded that the CISP/VNR/ATRA MLNP may be used as a promising system for lung cancer combination treatment.
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http://dx.doi.org/10.2147/DDDT.S251749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602907PMC
October 2020

Designing individual-specific and trial-specific models to accurately predict the intensity of nociceptive pain from single-trial fMRI responses.

Neuroimage 2021 01 27;225:117506. Epub 2020 Oct 27.

School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518060, China; Guangdong Provincial Key Laboratory of Biomedical Measurements and Ultrasound Imaging, Shenzhen, Guangdong 518060, China; Peng Cheng Laboratory, Shenzhen, Guangdong 518055, China. Electronic address:

Using machine learning to predict the intensity of pain from fMRI has attracted rapidly increasing interests. However, due to remarkable inter- and intra-individual variabilities in pain responses, the performance of existing fMRI-based pain prediction models is far from satisfactory. The present study proposed a new approach which can design a prediction model specific to each individual or each experimental trial so that the specific model can achieve more accurate prediction of the intensity of nociceptive pain from single-trial fMRI responses. More precisely, the new approach uses a supervised k-means method on nociceptive-evoked fMRI responses to cluster individuals or trials into a set of subgroups, each of which has similar and consistent fMRI activation patterns. Then, for a new test individual/trial, the proposed approach chooses one subgroup of individuals/trials, which has the closest fMRI patterns to the test individual/trial, as training samples to train an individual-specific or a trial-specific pain prediction model. The new approach was tested on a nociceptive-evoked fMRI dataset and achieved significantly higher prediction accuracy than conventional non-specific models, which used all available training samples to train a model. The generalizability of the proposed approach is further validated by training specific models on one dataset and testing these models on an independent new dataset. This proposed individual-specific and trial-specific pain prediction approach has the potential to be used for the development of individualized and precise pain assessment tools in clinical practice.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117506DOI Listing
January 2021

YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer.

Mol Cancer 2020 10 29;19(1):152. Epub 2020 Oct 29.

Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

Background: N6-methyladenosine (mA) is the most abundant modification in mRNA of humans. Emerging evidence has supported the fact that mA is comprehensively involved in various diseases especially cancers. As a crucial reader, YTHDF2 usually mediates the degradation of mA-modified mRNAs in mA-dependent way. However, the function and mechanisms of mA especially YTHDF2 in prostate cancer (PCa) still remain elusive.

Methods: To investigate the functions and mechanisms of YTHDF2 in PCa, in vitro, in vivo biofunctional assays and epigenetics experiments were performed. Endogenous expression silencing of YTHDF2 and METTL3 was established with lentivirus-based shRNA technique. Colony formation, flow cytometry and trans-well assays were performed for cell function identifications. Subcutaneous xenografts and metastatic mice models were combined with in vivo imaging system to investigate the phenotypes when knocking down YTHDF2 and METTL3. mA RNA immunoprecipitation (MeRIP) sequencing, mRNA sequencing, RIP-RT-qPCR and bioinformatics analysis were mainly used to screen and validate the direct common targets of YTHDF2 and METTL3. In addition, TCGA database was also used to analyze the expression pattern of YTHDF2, METTL3 and the common target LHPP in PCa, and their correlation with clinical prognosis.

Results: The upregulated YTHDF2 and METTL3 in PCa predicted a worse overall survival rate. Knocking down YTHDF2 or METTL3 markedly inhibited the proliferation and migration of PCa in vivo and in vitro. LHPP and NKX3-1 were identified as the direct targets of both YTHDF2 and METTL3. YTHDF2 directly bound to the mA modification sites of LHPP and NKX3-1 to mediate the mRNA degradation. Knock-down of YTHDF2 or METTL3 significantly induced the expression of LHPP and NKX3-1 at both mRNA and protein level with inhibited phosphorylated AKT. Overexpression of LHPP and NKX3-1 presented the consistent phenotypes and AKT phosphorylation inhibition with knock-down of YTHDF2 or METTL3. Phosphorylated AKT was consequently confirmed as the downstream of METTL3/YTHDF2/LHPP/NKX3-1 to induce tumor proliferation and migration.

Conclusion: We propose a novel regulatory mechanism in which YTHDF2 mediates the mRNA degradation of the tumor suppressors LHPP and NKX3-1 in mA-dependent way to regulate AKT phosphorylation-induced tumor progression in prostate cancer. We hope our findings may provide new concepts of PCa biology.
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http://dx.doi.org/10.1186/s12943-020-01267-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599101PMC
October 2020

Structural Engineering of SnS Encapsulated in Carbon Nanoboxes for High-Performance Sodium/Potassium-Ion Batteries Anodes.

Small 2020 Nov 20;16(45):e2005023. Epub 2020 Oct 20.

Research Center for Carbon Nanomaterials, Key Laboratory for Liquid-Solid Structural Evolution & Processing of Materials (Ministry of Education), School of Materials Science and Engineering, Shandong University, Jinan, 250061, China.

Conversion-alloying type anode materials like metal sulfides draw great attention due to their considerable theoretical capacity for sodium-ion batteries (SIBs) and potassium-ion batteries (PIBs). However, poor conductivity, severe volume change, and harmful aggregation of the material during charge/discharge lead to unsatisfying electrochemical performance. Herein, a facile and green strategy for yolk-shell structure based on the principle of metal evaporation is proposed. SnS nanoparticle is encapsulated in nitrogen-doped hollow carbon nanobox (SnS @C). The carbon nanoboxes accommodate the volume change and aggregation of SnS during cycling, and form 3D continuous conductive carbon matrix by close contact. The well-designed structure benefits greatly in conductivity and structural stability of the material. As expected, SnS @C exhibits considerable capacity, superior cycling stability, and excellent rate capability in both SIBs and PIBs. Additionally, in situ Raman technology is unprecedentedly conducted to investigate the phase evolution of polysulfides. This work provides an avenue for facilely constructing stable and high-capacity metal dichalcogenide based anodes materials with optimized structure engineering. The proposed in-depth electrochemical measurements coupled with in situ and ex situ characterizations will provide fundamental understandings for the storage mechanism of metal dichalcogenides.
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http://dx.doi.org/10.1002/smll.202005023DOI Listing
November 2020

Carboxylic acid-functionalized polycarbonates as bone cement additives for enhanced and sustained release of antibiotics.

J Control Release 2021 Jan 12;329:871-881. Epub 2020 Oct 12.

Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore; Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Despite the good clinical outcomes of total joint replacements, prosthetic joint infections still remain a significant cause of implant failure. Primary prophylaxis is key to stemming this burgeoning problem and its associated complications. In this study, a series of bone cement formulations with enhanced antibacterial performance have been developed through the addition of carboxylic acid-functionalized polycarbonate block copolymers to commercially available bone cement. Block copolymer design features were specifically tailored to modulate the acidity for adsorption of antibiotic and phase separation of the copolymers within the polymerizing/hardening of the cement during application. The best performing polymers demonstrated sustained antimicrobial release for more than 259 days and 147 days against S. aureus and P. aeruginosa, respectively, compared to 70 days of activity seen with commercially available gentamicin-containing cement control; whilst in vitro gentamicin release was increased by 8-fold. Total porosity was also increased 3-fold from 4.3% to 12.5%, whilst maintaining the mechanical integrity, working characteristics and osteoblastic biocompatibility of bone cement. Taken together, carboxylic acid-functionalized polycarbonates represent a promising class of bone cement additives that can be used to enhance the antibacterial performance of the bone cement whilst maintaining mechanical strength and cellular biocompatibility.
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http://dx.doi.org/10.1016/j.jconrel.2020.10.018DOI Listing
January 2021

An Autoencoder-based Approach to Predict Subjective Pain Perception from High-density Evoked EEG Potentials.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:1507-1511

Pain is a subjective experience and clinicians need to treat patients with accurate pain levels. EEG has emerged as a useful tool for objective pain assessment, but due to the low signal-to-noise ratio of pain-related EEG signals, the prediction accuracy of EEG-based pain prediction models is still unsatisfactory. In this paper, we proposed an autoencoder model based on convolutional neural networks for feature extraction of pain-related EEG signals. More precisely, we used EEGNet to build an autoencoder model to extract a small set of features from high-density pain-evoked EEG potentials and then establish a machine learning models to predict pain levels (high pain vs. low pain) from extracted features. Experimental results show that the new autoencoder-based approach can effectively identify pain-related features and can achieve better classification results than conventional methods.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176644DOI Listing
July 2020

Removal of eye-blinking artifacts by ICA in cross-modal long-term EEG recording.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:217-220

Independent Component Analysis (ICA) has became the most popular method to remove eye-blinking artifacts from electroencephalogram (EEG) recording. For long term EEG recording, ICA was commonly considered to costing a lot of computation time. Furthermore, with no ground truth, the discussion about the quality of ICA decomposition in a nonstationary environment was specious. In this study, we investigated the "signal" (P300 waveform) and the "noise" (averaged eye-blinking artifacts) on a cross-modal long-term EEG recording to evaluate the efficiency and effectiveness of different methods on ICA eye-blinking artifacts removal. As a result, it was found that, firstly, down sampling is an effective way to reduce the computation time in ICA. Appropriate down sampling ratio could speed up ICA computation 200 times and keep the decomposition performance stable, in which the computation time of ICA decomposition on a 2800 s EEG recording was less than 5 s. Secondly, dimension reduction by PCA was also a way to improve the efficiency and effectiveness of ICA. Finally, the comparison by cropping the dataset indicated that performing ICA on each run of the experiment separately would achieve a better result for eye-blinking artifacts removal than using all the EEG data input for ICA.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176711DOI Listing
July 2020

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics.

Adv Sci (Weinh) 2020 Sep 21;7(17):2001374. Epub 2020 Jul 21.

Institute of Bioengineering and Nanotechnology 31 Biopolis Way, The Nanos Singapore 138669 Singapore.

In order to mitigate antibiotic resistance, a new strategy to increase antibiotic potency and reverse drug resistance is needed. Herein, the translocation mechanism of an antimicrobial guanidinium-functionalized polycarbonate is leveraged in combination with traditional antibiotics to afford a potent treatment for drug-resistant bacteria. Particularly, this polymer-antibiotic combination approach reverses rifampicin resistance phenotype in demonstrating a 2.5 × 10-fold reduction in minimum inhibitory concentration (MIC) and a 4096-fold reduction in minimum bactericidal concentration (MBC). This approach also enables the repurposing of auranofin as an antibiotic against multidrug-resistant (MDR) Gram-negative bacteria with a 512-fold MIC and 128-fold MBC reduction, respectively. Finally, the in vivo efficacy of polymer-rifampicin combination is demonstrated in a MDR bacteremia mouse model. This combination approach lays foundational ground rules for a new class of antibiotic adjuvants capable of reversing drug resistance phenotype and repurposing drugs against MDR Gram-negative bacteria.
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http://dx.doi.org/10.1002/advs.202001374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503100PMC
September 2020

A natural product solution to aging and aging-associated diseases.

Pharmacol Ther 2020 12 11;216:107673. Epub 2020 Sep 11.

Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address:

Aging is a natural biological progress accompanied by the gradual decline in physiological functions, manifested by its close association with an increased incidence of human diseases and higher vulnerability to death. Those diseases include neurological disorders, cardiovascular diseases, diabetes, and cancer, many of which are currently without effective cures. Even though aging is inevitable, there are still interventions that can be developed to prevent/delay the onset and progression of those aging-associated diseases and extend healthspan and/or lifespan. Here, we review decades of research that reveals the molecular pathways underlying aging and forms the biochemical basis for anti-aging drug development. Importantly, due to the vast chemical space of natural products and the rich history of herb medicines in treating human diseases documented in different cultures, natural products have played essential roles in aging research. Using several of the most promising natural products and their derivatives as examples, we discuss how natural products serve as an inspiration resource that helped the identification of key components/pathways underlying aging, their mechanisms of action inside the cell, and the functional scaffolds or targeting mechanisms that can be learned from natural products for drug engineering and optimization. We argue that natural products might eventually provide a solution to aging and aging-associated diseases.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107673DOI Listing
December 2020

Emergency Hand and Reconstructive Microsurgery in the COVID-19-Positive Patient.

J Hand Surg Am 2020 09 29;45(9):869-875. Epub 2020 Jul 29.

Department of Hand and Reconstructive Microsurgery, National University Hospital, Singapore.

The case spectrum in hand surgery is one of extremes-purely elective day surgery cases under local anesthesia to mangling limb injuries that require immediate, and frequently, lengthy, surgery. Despite the cancellation of most elective orthopedic and plastic surgical procedures, hand surgeons around the world continue to see a steady stream of limb-threatening cases such as severe trauma and infections that require emergent surgical care. With the increase in community-spread, an increasing number of COVID-19-infected patients may be asymptomatic or have mild, nonspecific or atypical symptoms. Some of them may already have an ongoing, severe infection. The time-sensitive nature of some of these cases means that hand surgeons may need to operate urgently on patients who may be suspected of COVID-19 infections, often before confirmatory test results are available. General guidelines for perioperative care of the COVID-19-positive patient have been published. However, our practices differ from those of general orthopedic and plastic surgery, primarily because of the focus on trauma. This article discusses the perioperative and technical considerations that are essential to manage the COVID-19 patient requiring emergency care, without compromising clinical outcomes and while ensuring the safety of the attending staff.
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http://dx.doi.org/10.1016/j.jhsa.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388858PMC
September 2020

The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions.

Front Neurol 2020 31;11:703. Epub 2020 Jul 31.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.

Ischemic stroke is a multi-factorial cerebrovascular disease with high worldwide morbidity and mortality. In the past few years, multiple studies have revealed the underlying mechanism of ischemia/reperfusion injury, including calcium overload, amino acid toxicity, oxidative stress, and inflammation. Connexin 43 (Cx43), the predominant connexin protein in astrocytes, has been recently proven to display non-substitutable roles in the pathology of ischemic stroke development and progression through forming gap junctions and hemichannels. Under normal conditions, astrocytic Cx43 could be found in hemichannels or in the coupling with other hemichannels on astrocytes, neurons, or oligodendrocytes to form the neuro-glial syncytium, which is involved in metabolites exchange between communicated cells, thus maintaining the homeostasis of the CNS environment. In ischemic stroke, the phosphorylation of Cx43 might cause the degradation of gap junctions and the opening of hemichannels, contributing to the release of inflammatory mediators. However, the remaining gap junctions could facilitate the exchange of protective and harmful metabolites between healthy and injured cells, protecting the injured cells to some extent or damaging the healthy cells depending on the balance of the exchange of protective and harmful metabolites. In this study, we review the changes in astrocytic Cx43 expression and distribution as well as the influence of these changes on the function of astrocytes and other cells in the CNS, providing new insight into the pathology of ischemic stroke injury; we also discuss the potential of astrocytic Cx43 as a target for the treatment of ischemic stroke.
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http://dx.doi.org/10.3389/fneur.2020.00703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411525PMC
July 2020

Anisotropic Signal Processing with Trigonal Selenium Nanosheet Synaptic Transistors.

ACS Nano 2020 08 7;14(8):10018-10026. Epub 2020 Aug 7.

Department of Applied Physics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 999077, People's Republic of China.

Hardware implementation of an artificial neural network requires neuromorphic devices to process information with low energy consumption and high heterogeneity. Here we demonstrate an electrolyte-gated synaptic transistor (EGT) based on a trigonal selenium (-Se) nanosheet. Due to the intrinsic low conductivity of the Se channel, the -Se synaptic transistor exhibits ultralow energy consumption, less than 0.1 pJ per spike. More importantly, the intrinsic low symmetry of -Se offers a strong anisotropy along its - and -axis in electrical conductance with a ratio of up to 8.6. The multiterminal EGT device exhibits an anisotropic response of filtering behavior to the same external stimulus, which enables it to mimic the heterogeneous signal transmission process of the axon-multisynapse biostructure in the human brain. The proof-of-concept device in this work represents an important step to develop neuromorphic electronics for processing complex signals.
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http://dx.doi.org/10.1021/acsnano.0c03124DOI Listing
August 2020