scATAC-Ref: a reference of scATAC-seq with known cell labels in multiple species.

Chromatin accessibility profiles at single cell resolution can reveal cell type-specific regulatory programs, help dissect highly specialized cell functions and trace cell origin and evolution. Accurate cell type assignment is critical for effectively gaining biological and pathological insights, but is difficult in scATAC-seq. Hence, by extensively reviewing the literature, we designed scATAC-Ref (https://bio.liclab.net/scATAC-Ref/), a manually curated scATAC-seq database aimed at providing a comprehensive, high-quality source of chromatin accessibility profiles with known cell labels across broad cell types. Currently, scATAC-Ref comprises 1 694 372 cells with known cell labels, across various biological conditions, >400 cell/tissue types and five species. We used uniform system environment and software parameters to perform comprehensive downstream analysis on these chromatin accessibility profiles with known labels, including gene activity score, TF enrichment score, differential chromatin accessibility regions, pathway/GO term enrichment analysis and co-accessibility interactions. The scATAC-Ref also provided a user-friendly interface to query, browse and visualize cell types of interest, thereby providing a valuable resource for exploring epigenetic regulation in different tissues and cell types.

CRdb: a comprehensive resource for deciphering chromatin regulators in human.

Chromatin regulators (CRs) regulate epigenetic patterns on a partial or global scale, playing a critical role in affecting multi-target gene expression. As chromatin immunoprecipitation sequencing (ChIP-seq) data associated with CRs are rapidly accumulating, a comprehensive resource of CRs needs to be built urgently for collecting, integrating, and processing these data, which can provide abundant annotated information on CR upstream and downstream regulatory analyses as well as CR-related analysis functions. This study established an integrative CR resource, named CRdb (http://cr.liclab.net/crdb/), with the aim of curating a large number of available resources for CRs and providing extensive annotations and analyses of CRs to help biological researchers clarify the regulation mechanism and function of CRs. The CRdb database comprised a total of 647 CRs and 2,591 ChIP-seq samples from more than 300 human tissues and cell types. These samples have been manually curated from NCBI GEO/SRA and ENCODE. Importantly, CRdb provided the abundant and detailed genetic annotations in CR-binding regions based on ChIP-seq. Furthermore, CRdb supported various functional annotations and upstream regulatory information on CRs. In particular, it embedded four types of CR regulatory analyses: CR gene set enrichment, CR-binding genomic region annotation, CR-TF co-occupancy analysis, and CR regulatory axis analysis. CRdb is a useful and powerful resource that can help in exploring the potential functions of CRs and their regulatory mechanism in diseases and biological processes.

SEdb 2.0: a comprehensive super-enhancer database of human and mouse.

Super-enhancers (SEs) are cell-specific DNA cis-regulatory elements that can supervise the transcriptional regulation processes of downstream genes. SEdb 2.0 (http://www.licpathway.net/sedb) aims to provide a comprehensive SE resource and annotate their potential roles in gene transcriptions. Compared with SEdb 1.0, we have made the following improvements: (i) Newly added the mouse SEs and expanded the scale of human SEs. SEdb 2.0 contained 1 167 518 SEs from 1739 human H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) samples and 550 226 SEs from 931 mouse H3K27ac ChIP-seq samples, which was five times that of SEdb 1.0. (ii) Newly added transcription factor binding sites (TFBSs) in SEs identified by TF motifs and TF ChIP-seq data. (iii) Added comprehensive (epi)genetic annotations of SEs, including chromatin accessibility regions, methylation sites, chromatin interaction regions and topologically associating domains (TADs). (iv) Newly embedded and updated search and analysis tools, including 'Search SE by TF-based', 'Differential-Overlapping-SE analysis' and 'SE-based TF-Gene analysis'. (v) Newly provided quality control (QC) metrics for ChIP-seq processing. In summary, SEdb 2.0 is a comprehensive update of SEdb 1.0, which curates more SEs and annotation information than SEdb 1.0. SEdb 2.0 provides a friendly platform for researchers to more comprehensively clarify the important role of SEs in the biological process.

SEanalysis 2.0: a comprehensive super-enhancer regulatory network analysis tool for human and mouse.

Super-enhancers (SEs) play an essential regulatory role in various biological processes and diseases through their specific interaction with transcription factors (TFs). Here, we present the release of SEanalysis 2.0 (http://licpathway.net/SEanalysis), an updated version of the SEanalysis web server for the comprehensive analyses of transcriptional regulatory networks formed by SEs, pathways, TFs, and genes. The current version added mouse SEs and further expanded the scale of human SEs, documenting 1 167 518 human SEs from 1739 samples and 550 226 mouse SEs from 931 samples. The SE-related samples in SEanalysis 2.0 were more than five times that in version 1.0, which significantly improved the ability of original SE-related network analyses ('pathway downstream analysis', 'upstream regulatory analysis' and 'genomic region annotation') for understanding context-specific gene regulation. Furthermore, we designed two novel analysis models, 'TF regulatory analysis' and 'Sample comparative analysis' for supporting more comprehensive analyses of SE regulatory networks driven by TFs. Further, the risk SNPs were annotated to the SE regions to provide potential SE-related disease/trait information. Hence, we believe that SEanalysis 2.0 has significantly expanded the data and analytical capabilities of SEs, which helps researchers in an in-depth understanding of the regulatory mechanisms of SEs.

Role of laminin and collagen chains in human spermatogenesis - Insights from studies in rodents and scRNA-Seq transcriptome profiling.

Studies have demonstrated that biologically active fragments are generated from the basement membrane and the Sertoli cell-spermatid adhesion site known as apical ectoplasmic specialization (apical ES, a testis-specific actin-based anchoring junction) in the rat testis. These bioactive fragments or peptides are produced locally across the seminiferous epithelium through proteolytic cleavage of constituent proteins at the basement membrane and the apical ES. Studies have shown that they are being used to modulate and coordinate cellular functions across the seminiferous epithelium during different stages of the epithelial cycle of spermatogenesis. In this review, we briefly summarize recent findings based on studies using rat testes as a study model regarding the role of these bioactive peptides that serve as a local regulatory network to support spermatogenesis. We also used scRNA-Seq transcriptome datasets in the public domain for OA (obstructive azoospermia) and NAO (non-obstructive azoospermia) human testes versus testes from normal men for analysis in this review. It was shown that there are differential expression of different collagen chains and laminin chains in these testes, suggesting the possibility of a similar local regulatory network in the human testis to support spermatogenesis, and the possible disruption of such network in men is associated with OA and/or NOA.

GREAP: a comprehensive enrichment analysis software for human genomic regions.

The rapid development of genomic high-throughput sequencing has identified a large number of DNA regulatory elements with abundant epigenetics markers, which promotes the rapid accumulation of functional genomic region data. The comprehensively understanding and research of human functional genomic regions is still a relatively urgent work at present. However, the existing analysis tools lack extensive annotation and enrichment analytical abilities for these regions. Here, we designed a novel software, Genomic Region sets Enrichment Analysis Platform (GREAP), which provides comprehensive region annotation and enrichment analysis capabilities. Currently, GREAP supports 85 370 genomic region reference sets, which cover 634 681 107 regions across 11 different data types, including super enhancers, transcription factors, accessible chromatins, etc. GREAP provides widespread annotation and enrichment analysis of genomic regions. To reflect the significance of enrichment analysis, we used the hypergeometric test and also provided a Locus Overlap Analysis. In summary, GREAP is a powerful platform that provides many types of genomic region sets for users and supports genomic region annotations and enrichment analyses. In addition, we developed a customizable genome browser containing >400 000 000 customizable tracks for visualization. The platform is freely available at http://www.liclab.net/Greap/view/index.

TF-Marker: a comprehensive manually curated database for transcription factors and related markers in specific cell and tissue types in human.

Transcription factors (TFs) play key roles in biological processes and are usually used as cell markers. The emerging importance of TFs and related markers in identifying specific cell types in human diseases increases the need for a comprehensive collection of human TFs and related markers sets. Here, we developed the TF-Marker database (TF-Marker, http://bio.liclab.net/TF-Marker/), aiming to provide cell/tissue-specific TFs and related markers for human. By manually curating thousands of published literature, 5905 entries including information about TFs and related markers were classified into five types according to their functions: (i) TF: TFs which regulate expression of the markers; (ii) T Marker: markers which are regulated by the TF; (iii) I Marker: markers which influence the activity of TFs; (iv) TFMarker: TFs which play roles as markers and (v) TF Pmarker: TFs which play roles as potential markers. The 5905 entries of TF-Marker include 1316 TFs, 1092 T Markers, 473 I Markers, 1600 TFMarkers and 1424 TF Pmarkers, involving 383 cell types and 95 tissue types in human. TF-Marker further provides a user-friendly interface to browse, query and visualize the detailed information about TFs and related markers. We believe TF-Marker will become a valuable resource to understand the regulation patterns of different tissues and cells.

Decoding subject's own name in the primary auditory cortex.

Current studies have shown that perception of subject's own name (SON) involves multiple multimodal brain regions, while activities in unimodal sensory regions (i.e., primary auditory cortex) and their interaction with multimodal regions during the self-processing remain unclear. To answer this, we combined multivariate pattern analysis and dynamic causal modelling analysis to explore the regional activation pattern and inter-region effective connection during the perception of SON. We found that SON and other names could be decoded from the activation pattern in the primary auditory cortex. In addition, we found an excitatory effect of SON on connections from the anterior insula/inferior frontal gyrus to the primary auditory cortex, and to the temporoparietal junction. Our findings extended the current knowledge of self-processing by showing that primary auditory cortex could discriminate SON from other names. Furthermore, our findings highlighted the importance of influence of the insula on the primary auditory cortex during self-processing.

TRlnc: a comprehensive database for human transcriptional regulatory information of lncRNAs.

Long noncoding RNAs (lncRNAs) have been proven to play important roles in transcriptional processes and biological functions. With the increasing study of human diseases and biological processes, information in human H3K27ac ChIP-seq, ATAC-seq and DNase-seq datasets is accumulating rapidly, resulting in an urgent need to collect and process data to identify transcriptional regulatory regions of lncRNAs. We therefore developed a comprehensive database for human regulatory information of lncRNAs (TRlnc, http://bio.licpathway.net/TRlnc), which aimed to collect available resources of transcriptional regulatory regions of lncRNAs and to annotate and illustrate their potential roles in the regulation of lncRNAs in a cell type-specific manner. The current version of TRlnc contains 8 683 028 typical enhancers/super-enhancers and 32 348 244 chromatin accessibility regions associated with 91 906 human lncRNAs. These regions are identified from over 900 human H3K27ac ChIP-seq, ATAC-seq and DNase-seq samples. Furthermore, TRlnc provides the detailed genetic and epigenetic annotation information within transcriptional regulatory regions (promoter, enhancer/super-enhancer and chromatin accessibility regions) of lncRNAs, including common SNPs, risk SNPs, eQTLs, linkage disequilibrium SNPs, transcription factors, methylation sites, histone modifications and 3D chromatin interactions. It is anticipated that the use of TRlnc will help users to gain in-depth and useful insights into the transcriptional regulatory mechanisms of lncRNAs.

Sitravatinib is a potential EGFR inhibitor and induce a new death phenotype in Glioblastoma.

Glioblastoma (GBM) is a highly lethal neurological tumor that presents significant challenge for clinicians due to its heterogeneity and high mortality rate. Despite extensive research, there is currently no effective drug treatment available for GBM. Research evidence has consistently demonstrated that the epidermal growth factor receptor (EGFR) promotes tumor progression and is associated with poor prognosis in several types of cancer. In glioma, EGFR abnormal amplification is reported in approximately 40% of GBM patients, with overexpression observed in 60% of cases, and deletion or mutation in 24% to 67% of patients. In our study, Sitravatinib, a potential EGFR inhibitor, was identified through molecular docking screening based on protein structure. The targeting of EGFR and the tumor inhibitory effect of Sitravatinib on glioma were verified through cellular and in vivo experiments, respectively. Our study also revealed that Sitravatinib effectively inhibited GBM invasive and induced DNA damage and cellular senescence. Furthermore, we observed a novel cell death phenotype induced by Sitravatinib, which differed from previously reported programmed death patterns such as apoptosis, pyroptosis, ferroptosis, and necrosis.

An artificial optoelectronic synapse based on MoOxfilm.

Artificial optoelectronic synapses have the advantages of large bandwidth, low power consumption and low crosstalk, and are considered to be the basic building blocks of neuromorphic computing. In this paper, a two-terminal optoelectronic synaptic device with ITO-MoOx-Pt structure is prepared by magnetron sputtering. The performance of resistive switching (RS) and the photo plastic properties of the device are analyzed and demonstrated. Electrical characterization tests show that the device has a resistive HRS/LRS ratio of about 90, stable endurance, and retention characteristics of more than 104s (85 °C). The physical mechanism of the device is elucidated by a conducting filament composed of oxygen vacancies. Furthermore, the function of various synaptic neural morphologies is successfully mimicked using UV light as the stimulation source. Including short-term/long-term memory, paired-pulse facilitation, the transition from short-term to long-term memory, and 'learning-experience' behavior. Integrated optical sensing and electronic data storage devices have great potential for future artificial intelligence, which will facilitate the rapid development of retina-like visual sensors and low-power neuromorphic systems.

Multiomics analysis of male infertility†.

Infertility affects 8-12% of couples globally, and the male factor is a primary cause in ~50% of couples. Male infertility is a multifactorial reproductive disorder, which can be caused by paracrine and autocrine factors, hormones, genes, and epigenetic changes. Recent studies in rodents and most notably in humans using multiomics approach have yielded important insights into understanding the biology of spermatogenesis. Nonetheless, the etiology and pathogenesis of male infertility are still largely unknown. In this review, we summarized and critically evaluated findings based on the use of advanced technologies to compare normal and obstructive azoospermic versus nonobstructive azoospermic men, including whole-genome bisulfite sequencing, single-cell RNA-seq, whole-exome sequencing, and transposase-accessible chromatin using sequencing. It is obvious that the multiomics approach is the method of choice for basic research and clinical studies including clinical diagnosis of male infertility.

Defects of microtubule cytoskeletal organization in NOA human testes.

The importance of actin and microtubule (MT) cytoskeletons in testis function in rodents is known to some extent, but its role in the etiology of azoospermia in humans remains unexplored. Here, we examined if MT cytoskeleton was defective in NOA (non-obstructive azoospermia) testes versus normal human testes based on histopathological, immunofluorescence (IF), and scRNA-Seq transcriptome profiling. Testis biopsy samples from n = 6 normal men versus n = 3 Sertoli cell only (SCO) and n = 3 MA (meiotic arrest) of NOA patients were used for histopathological analysis. IF analysis was also used to examine MT organization across the seminiferous epithelium, investigating the likely involvement of microtubule-associated proteins (MAPs). scRNA-Seq transcriptome profiling datasets from testes of 3 SCO patients versus 3 normal men in public domain in Gene Expression Omnibus (GEO) Sample (GSM) with identifiers were analyzed to examine relevant genes that regulate MT dynamics. NOA testes of MA and SCO patients displayed notable defects in MT organization across the epithelium with extensive truncation, mis-alignments and appeared as collapsed structures near the base of the tubules. These changes are in contrast to MTs in testes of normal men. scRNA-Seq analyses revealed considerable loss of spermatogenesis capacity in SCO testes of NOA patients versus normal men. An array of genes that support MT dynamics displayed considerable changes in expression and in spatial distribution. In summary, defects in MT cytoskeleton were noted in testes of NOA (SCO) patients, possibly mediated by defective spatial expression and/or distribution of MAPs. These changes, in turn, may impede spermatogenesis in SCO testes of NOA patients.

Establishment and validation of a clinical model for diagnosing solitary pulmonary nodules.

OBJECTIVES: The main purpose of this study was to develop and validate a clinical model for estimating the risk of malignancy in solitary pulmonary nodules (SPNs). METHODS: A total of 672 patients with SPNs were retrospectively reviewed. The least absolute shrinkage and selection operator algorithm was applied for variable selection. A regression model was then constructed with the identified predictors. The discrimination, calibration, and clinical validity of the model were evaluated by the area under the receiver-operating-characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: Ten predictors, including gender, age, nodule type, diameter, lobulation sign, calcification, vascular convergence sign, mediastinal lymphadenectasis, the natural logarithm of carcinoembryonic antigen, and combination of cytokeratin 19 fragment 21-1, were incorporated into the model. The prediction model demonstrated valuable prediction performance with an AUC of 0.836 (95% CI: 0.777-0.896), outperforming the Mayo (0.747, p = 0.024) and PKUPH (0.749, p = 0.018) models. The model was well-calibrated according to the calibration curves. The DCA indicated the nomogram was clinically useful over a wide range of threshold probabilities. CONCLUSION: This study proposed a clinical model for estimating the risk of malignancy in SPNs, which may assist clinicians in identifying the pulmonary nodules that require invasive procedures and avoid the occurrence of overtreatment.

Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces. But known drugs for IPF are far from meeting clinical demands, validation of drug targets against pulmonary fibrosis is in urgent demand. Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling. In this study we designed and synthesized a new indazole derivative XBLJ-13, and identified XBLJ-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities. We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients. Then we showed that XBLJ-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM, respectively. Among a panel of 34 kinases tested, XBLJ-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1, as well as Abl kinase that had high homology with DDRs. Extensive profiling of XBLJ-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice. Furthermore, pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBLJ-13 (30, 60, 90 mg·kg-1·d-1, i.g.) for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis. Together, this study confirms that DDRs kinase is a potential target for PF, Particularly, compound XBLJ-13 is a highly potent and specific DDRs inhibitor, along with good pharmacokinetics profiles, and preferable in vivo efficacy, suggesting that it is a potential candidate for the treatment of PF.

Species Diversification of the Coniferous Pathogenic Fungal Genus Coniferiporia (Hymenochaetales, Basidiomycota) in Association with Its Biogeography and Host Plants.

Coniferiporia, belonging to Hymenochaetaceae and now segregated from Phellinidium, is a wood-inhabiting fungal genus with three species, each having a specific geographic distribution and a strong host specificity as a forest pathogen of coniferous trees. In this study, the species diversity of Coniferiporia is further clarified with the aid of a wider sampling and multilocus-based phylogenetic analysis, which reveals a new species Coniferiporia uzbekistanensis. The molecular clock and ancestral geographic origin analyses indicate that the ancestor of Coniferiporia emerged in one of the Pinaceae and Cupressaceae, then jumped to the other plant family originated in eastern Eurasia 17.01 million years ago (Mya; 95% highest posterior density: 9.46 to 25.86 Mya), and later extended its distribution to western North America, Central Asia, and eastern Europe. Coniferiporia sulphurascens speciated on Pinaceae in eastern Eurasia 8.78 Mya (9.46 to 25.86 Mya) and then extended its distribution to western North America and eastern Europe. Coniferiporia qilianensis and C. uzbekistanensis speciated on Juniperus przewalskii in eastern Eurasia 3.67 Mya (0.36 to 8.02 Mya) and on Juniperus polycarpos in Central Asia 4.35 Mya (0.94 to 8.37 Mya), respectively. The speciation event of Coniferiporia weirii occurred 4.45 Mya (0.77 to 9.33 Mya) right after the emergence of its host, the endemic Cupressaceae species Thuja plicata, and soon after, this fungus evolved to also inhabit another endemic Cupressaceae species Calocedrus decurrens. In summary, this study for the first time unambiguously clarified and timed the adaptive evolutionary event of Coniferiporia in association with its biogeography and host plants.

[Complete chloroplast genome of Ligustrum lucidum and highly variable marker identification for Ligustrum].

Ligustri Lucidi Fructus, the sun-dried mature fruit of Ligustrum lucidum, is cool, plain, sweet, and bitter, which can be used as both food and medicine, with the effects of improving vision, blacking hair, and tonifying liver and kidney. It takes effect slowly. However, little is known about the genetic information of the medicinal plant and it is still a challenge to distinguish Ligustrum species. In this study, the complete chloroplast genome of L. lucidum was obtained by genome skimming and then compared with that of five other Ligustrum species, which had been reported. This study aims to evaluate the interspecific variation of chloroplast genome within the genus and develop molecular markers for species identification of the genus. The result showed that the chloroplast genome of L. lucidum was 162 162 bp with a circular quadripartite structure of two single-copy regions separated by a pair of inverted repeats. The Ligustrum chloroplast genomes were conserved with small interspecific difference. Comparative analysis of six Ligustrum chloroplast genomes revealed three variable regions(rbcL-accD, ycf1a, and ycf1b), and ycf1a and ycf1b can be used as the species-specific DNA barcode for Ligustrum. Phylogeny analysis provided the best resolution of Ligustrum and supported that L. lucidum was sister to L. gracile. This study clarified the genetic diversity of L. lucidum from provenance, which can serve as a reference for further analysis of pharmacological differences and breeding of excellent varieties with stable drug effects.

Systematic analysis of the lysine malonylome in Sanghuangporus sanghuang.

BACKGROUND: Sanghuangporus sanghuang is a well-known traditional medicinal mushroom associated with mulberry. Despite the properties of this mushroom being known for many years, the regulatory mechanisms of bioactive compound biosynthesis in this medicinal mushroom are still unclear. Lysine malonylation is a posttranslational modification that has many critical functions in various aspects of cell metabolism. However, at present we do not know its role in S. sanghuang. In this study, a global investigation of the lysine malonylome in S. sanghuang was therefore carried out. RESULTS: In total, 714 malonyl modification sites were matched to 255 different proteins. The analysis indicated that malonyl modifications were involved in a wide range of cellular functions and displayed a distinct subcellular localization. Bioinformatics analysis indicated that malonylated proteins were engaged in different metabolic pathways, including glyoxylate and dicarboxylate metabolism, glycolysis/gluconeogenesis, and the tricarboxylic acid (TCA) cycle. Notably, a total of 26 enzymes related to triterpene and polysaccharide biosynthesis were found to be malonylated, indicating an indispensable role of lysine malonylation in bioactive compound biosynthesis in S. sanghuang. CONCLUSIONS: These findings suggest that malonylation is associated with many metabolic pathways, particularly the metabolism of the bioactive compounds triterpene and polysaccharide. This paper represents the first comprehensive survey of malonylation in S. sanghuang and provides important data for further study on the physiological function of lysine malonylation in S. sanghuang and other medicinal mushrooms.

Mat_peptide: comprehensive annotation of mature peptides from polyproteins in five virus families.

MOTIVATION: Sequence repositories have few well-annotated virus mature peptide sequences. Therefore post-translational proteolytic processing of polyproteins into mature peptides (MPs) has been performed in silico, with a new computational method, for over 200 species in 5 pathogenic virus families (Caliciviridae, Coronaviridae, Flaviviridae, Picornaviridae and Togaviridae). RESULTS: Using pairwise alignment with reference sequences, MPs have been annotated and their sequences made available for search, analysis and download. At publication the method had produced 156 216 sequences, a large portion of the protein sequences now available in https://www.viprbrc.org. It represents a new and comprehensive mature peptide collection. AVAILABILITY AND IMPLEMENTATION: The data are available at the Virus Pathogen Resource https://www.viprbrc.org, and the software at https://github.com/VirusBRC/vipr_mat_peptide.

Flexible Ta/TiOx/TaOx/Ru memristive synaptic devices on polyimide substrates.

It is very urgent to build memristive synapses and even wearable devices to simulate the basic functions of biological synapses. The linear conductance modulation is the basis of analog memristor for neuromorphic computing. By optimizing the interface engineering wherein Ta/TiOx/TaOx/Ru was fabricated, all the memristor devices with different TiOxthickness showed electroforming-free property. The short-term and long-term plasticity in both potentiation and depression behaviors can be mimicked when TiOxwas fixed at 25 nm. The presented memristive synapses simulated the stable paired-pulse facilitation and spike-timing dependent plasticity performance. The potentiation and depression in linearity and symmetry improved with the TiOxthickness increasing, which provides the feasibility for the application of artificial neural network. In addition, the device deposited on polyimide (PI) still exhibits the synaptic performance until the bending radii reaches 6 mm. By carefully tuning the interface engineering, this study can provide general revelation for continuous improvement of the memristive performance in neuromorphic applications.