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We examined the neural correlates underlying the semantic processing of native- and nonnative-accented sentences, presented in quiet or embedded in multi-talker noise. Implementing a semantic violation paradigm, 36 English monolingual young adults listened to American-accented (native) and Chinese-accented (nonnative) English sentences with or without semantic anomalies, presented in quiet or embedded in multi-talker noise, while EEG was recorded. After hearing each sentence, participants verbally repeated the sentence, which was coded and scored as an offline comprehension accuracy measure. In line with earlier behavioral studies, the negative impact of background noise on sentence repetition accuracy was higher for nonnative-accented than for native-accented sentences. At the neural level, the N400 effect for semantic anomaly was larger for native-accented than for nonnative-accented sentences, and was also larger for sentences presented in quiet than in noise, indicating impaired lexical-semantic access when listening to nonnative-accented speech or sentences embedded in noise. No semantic N400 effect was observed for nonnative-accented sentences presented in noise. Furthermore, the frequency of neural oscillations in the alpha frequency band (an index of online cognitive listening effort) was higher when listening to sentences in noise versus in quiet, but no difference was observed across the accent conditions. Semantic anomalies presented in background noise also elicited higher theta activity, whereas processing nonnative-accented anomalies was associated with decreased theta activity. Taken together, we found that listening to nonnative accents or background noise is associated with processing challenges during online semantic access, leading to decreased comprehension accuracy. However, the underlying cognitive mechanism (e.g., associated listening efforts) might manifest differently across accented speech processing and speech in noise processing.

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An essential post-translational modification, phosphorylation is intimately related with a wide range of biological activities. The advancement of effective computational methods for correctly recognizing phosphorylation sites is important for in-depth understanding of various physiological phenomena. However, the traditional method of identifying phosphorylation sites experimentally is time-consuming and laborious, which makes it difficult to meet the processing demands of today's big data. This research proposes the use of a novel model, Res-GCN, to recognize the phosphorylation sites of SARS-CoV-2. Firstly, eight feature extraction strategies are utilized to digitize the protein sequence from multiple viewpoints, including amino acid property encodings (AAindex), pseudo-amino acid composition (PseAAC), adapted normal distribution bi-profile Bayes (ANBPB), dipeptide composition (DC), binary encoding (BE), enhanced amino acid composition (EAAC), Word2Vec, and BLOSUM62 matrices. Secondly, elastic net is utilized to eliminate redundant data in the fused matrix. Finally, a combination of graph convolutional network (GCN) and residual network (ResNet) is used to classify the phosphorylated sites and output predictions using a fully connected layer (FC). The performance of Res-GCN is tested by 5-fold cross-validation and independent testing, and excellent results are obtained on S/T and Y datasets. This demonstrates that the Res-GCN model exhibits exceptional predictive performance and generalizability.

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BACKGROUND: To explore the functional and morphological variations of retinal vessels in diabetes with no clinically detectable retinopathy (NDR) and mild non-proliferative diabetic retinopathy (NPDR) and to establish a high-performance mild NPDR diagnostic model. METHODS: Normal subjects and type 2 diabetes patients with NDR and mild NPDR were recruited. Oxygen-saturation-related functional parameter (optical density ratio ODR) and morphological characteristics (fractal dimension Df, vessel area rate VAR, mean vascular diameter Dm, vessel tortuosity τ) of different vascular areas were extracted with single fundus photography and comprehensively analyzed among groups. An interpretable model combining marine predator algorithm (MPA) and support vector machine (SVM) based on characteristic selection was proposed for mild NPDR diagnosis. RESULTS: A total of 91 NDR subjects, 75 mild NPDR subjects, and 111 sex- and age-matched normal controls were analyzed. Increased main vessels ODR, while lower VAR of all areas except outer ring macula, lower Dm of all vessels and decreased τ of all areas were associate with NDR (e.g. main vessels ODR: OR [95%CI] 1.42[1.07-1.89], full macula τ:0.53[0.38-0.74]). Increased ODR of all areas, higher Dm of all areas except inner ring macula, increased inner ring macula τ, while decreased Df of full and inner ring macula, lower VAR of all areas were associate with mild NPDR (e.g. main vessels ODR:5.68[3.03-10.65], inner ring macula VAR: 0.48[0.33-0.69]). The MPA-SVM model with selected characteristics obtained the best diagnosis performance (AUC:0.940 ± 0.014; Accuracy:90.4 ± 3.9%; Sensitivity:89.2 ± 6.4%; Specificity:91.3 ± 6.4%). CONCLUSIONS: More significant retinal vascular variations are associate with the incidence of mild NPDR than NDR. High-precision mild NPDR diagnosis is achieved combining the morphological and functional vascular characteristics based on characteristic selection.

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Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment-resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2-activating transcription factor 4-alanine, serine, cysteine-preferring transporter 2 (GCN2-ATF4-ASCT2) axis. Central to this phenomenon is the stress-induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G-quadruplex structure located within the promoter region of ATF4 (ATF4-G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4-G4. For the first time, the high-resolution structure of the COP-ATF4-G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP-2 alpha (TFAP2A) and ATF4-G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4-G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine-restricted therapy.

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DNA G-quadruplex(G4) is a guanine-rich single-stranded DNA sequence that spontaneously folds into a spherical four-stranded DNA secondary structure in oncogene promoter sequences and telomeres. G4s are highly associated with the occurrence and development of cancer and have emerged as promising anticancer targets. Natural products have long been important sources of anticancer drug development. In recent years, significant progress has been made in the discovery of natural drugs targeting DNA G4s, with many DNA G4s have been confirmed as promising targets of natural products, including MYC-G4, KRAS-G4, PDGFR-ß-G4, BCL-2-G4, VEGF-G4, and telomeric G4. This review summarizes the research progress in discovering natural small molecules that target DNA G4s and their binding mechanisms. It also discusses the opportunities of and challenges in developing drugs targeting DNA G4s. This review will serve as a valuable reference for the research on natural products, particularly in the development of novel antitumor medications.

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The antifouling properties of conductive polymers have received extensive attention for biosensor and bioelectronic applications. Polyethylene glycol (PEG) is a well-known antifouling material, but the controlled regulation of the surface topography of PEG without a template remains a challenge. Here, we show a columnar structure antifouling conductive polymer brush with enhanced antifouling properties and considerable conductivity. The method involves synthesizing the 3,4-ethylenedioxythiophene monomer modified with azide (EDOT-N3), the electropolymerization of PEDOT-N3, and the in situ growth of PEG polymer brushes on PEDOT through double-click reactions. The resultant columnar structure polymer brush exhibits high electrical conductivity (3.5 Ω·cm2), ultrahigh antifouling property, electrochemical stability (capacitance retention was 93.8% after 2000 cycles of CV scans in serum), and biocompatibility.

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BACKGROUND: Rapid on-site detection of infectious diseases is considerably essential for preventing and controlling major epidemics and maintaining social and public safety. However, the complexity of the natural environment in which infectious disease pathogens exist severely disrupts the performance of on-site detection, and rapid detection can become meaningless because of the cumbersome sample pretreatment process. RESULT: Herein, a new detection platform based on a carbon sphere@Fe3O4 micromotor (CS@Fe3O4) in combination with a graphene field-effect transistor (GFET) was designed and used for the on-site detection of SARS-CoV-2 coronavirus pathogens. The CS@Fe3O4 micromotor, surface-modified with anti-SARS-CoV-2 coronavirus antibody, could move at a velocity of 79.4 µm/s in a solution containing hydrogen peroxide (H2O2) and exhibited capture rates of 67.9% and 36.2% for the SARS-CoV-2 pathogen in phosphate buffered saline (PBS) and soil solutions, respectively. After magnetic field separation, the captured micromotor was used for GFET detection, with detection limits of 4.6 and 15.6 ag/mL in PBS and soil solutions, respectively. SIGNIFICANCE AND NOVELTY: This detection platform can be employed to avoid complex sample pretreatment procedures and achieve rapid on-site detection of SARS-CoV-2 coronavirus pathogens in complex environments. This study introduces a novel approach for the on-site detection of infectious diseases.

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CCAAT enhancer binding protein delta (CEBPD) is a transcription factor and plays an important role in apoptosis and oxidative stress, which are the main pathogenesis of ischemic stroke. However, whether CEBPD regulates ischemic stroke through targeting apoptosis and oxidative stress is unclear. Therefore, to answer this question, rat middle cerebral artery occlusion (MCAO) reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) primary cortical neuron were established to mimic ischemic reperfusion injury. We found that CEBPD was upregulated and accompanied with increased neurological deficit scores and infarct size, and decreased neuron in MCAO rats. The siRNA targeted CEBPD inhibited CEBPD expression in rats, and meanwhile lentivirus system was used to blocked CEBPD expression in primary neuron. CEBPD degeneration decreased neurological deficit scores, infarct size and brain water content of MCAO rats. Knockdown of CEBPD enhanced cell viability and reduced apoptosis as well as oxidative stress in vivo and in vitro. CEBPD silencing promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the expression of heme oxygenase 1 (HO-1). Newly, CEBPD facilitated the transcription of cullin 3 (CUL3), which intensified ischemic stroke through Nrf2/HO-1 pathway that was proposed by our team in the past. In conclusion, targeting CEBPD-CUL3-Nrf2/HO-1 axis may be contributed to cerebral ischemia therapy.

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PURPOSE: To develop a MRI-based radiomics model, integrating the intratumoral and peritumoral imaging information to predict axillary lymph node metastasis (ALNM) in patients with breast cancer and to elucidate the model's decision-making process via interpretable algorithms. METHODS: This study included 376 patients from three institutions who underwent contrast-enhanced breast MRI between 2021 and 2023. We used multiple machine learning algorithms to combine peritumoral, intratumoral, and radiological characteristics with the building of radiological, radiomics, and combined models. The model's performance was compared based on the area under the curve (AUC) obtained from the receiver operating characteristic analysis and interpretable machine learning techniques to analyze the operating mechanism of the model. RESULTS: The radiomics model, incorporating features from both intratumoral tissue and the 3 mm peritumoral region and utilizing the backpropagation neural network (BPNN) algorithm, demonstrated superior diagnostic efficacy, achieving an AUC of 0.820. The AUC of the combination of the RAD score, clinical T stage, and spiculated margin was as high as 0.855. Furthermore, we conducted SHapley Additive exPlanations (SHAP) analysis to evaluate the contributions of RAD score, clinical T stage, and spiculated margin in ALNM status prediction. CONCLUSIONS: The interpretable radiomics model we propose can better predict the ALNM status of breast cancer and help inform clinical treatment decisions.

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A new detection platform based on CaCO3-based magnetic micromotor (CaCO3@Fe3O4) integrated with graphene field effect transistor (GFET) was construct and used for on-site SARS-CoV-2 coronavirus pathogen detection. The CaCO3@Fe3O4 micromotor, which was modified with anti-SARS-CoV-2 (labelled antibody, AntiE1), can self-moved in the solution containing hydrochloric acid (HCl) and effective to capture the SARS-CoV-2 coronavirus pathogens. After magnetic field separation, the capture micromotor was detected by GFET, exhibiting a good linear relationship within the range of 1 ag/mL to 100 ng/mL and low detection limit (0.39 ag/mL). Furthermore, the detection platform was also successfully applied to detection of SARS-CoV-2 coronavirus pathogens in soil solution, indicating the potential use in on-site application.

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BACKGROUND: Transcatheter arterial chemoembolization (TACE) is a mainstay treatment for intermediate and advanced hepatocellular carcinoma (HCC), with the potential to enhance patient survival. Preoperative prediction of postoperative response to TACE in patients with HCC is crucial. PURPOSE: To develop a deep neural network (DNN)-based nomogram for the non-invasive and precise prediction of TACE response in patients with HCC. MATERIAL AND METHODS: We retrospectively collected clinical and imaging data from 110 patients with HCC who underwent TACE surgery. Radiomics features were extracted from specific imaging methods. We employed conventional machine-learning algorithms and a DNN-based model to construct predictive probabilities (RScore). Logistic regression helped identify independent clinical risk factors, which were integrated with RScore to create a nomogram. We evaluated diagnostic performance using various metrics. RESULTS: Among the radiomics models, the DNN_LASSO-based one demonstrated the highest predictive accuracy (area under the curve [AUC] = 0.847, sensitivity = 0.892, specificity = 0.791). Peritumoral enhancement and alkaline phosphatase were identified as independent risk factors. Combining RScore with these clinical factors, a DNN-based nomogram exhibited superior predictive performance (AUC = 0.871, sensitivity = 0.844, specificity = 0.873). CONCLUSION: In this study, we successfully developed a deep learning-based nomogram that can noninvasively and accurately predict TACE response in patients with HCC, offering significant potential for improving the clinical management of HCC.

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Dry eye disease (DED) is a widespread, multifactorial, and chronic disorder of the ocular surface with disruption of tear film homeostasis as its core trait. Conjunctival goblet cells (CGCs) are specialised secretory cells found in the conjunctival epithelium that participate in tear film formation by secreting mucin. Changes in both the structure and function of CGCs are hallmarks of DED, and imaging assessment of CGCs is important for the diagnosis, classification, and severity evaluation of DED. Existing imaging methods include conjunctival biopsy, conjunctival impression cytology and in vivo confocal microscopy, which can be used to assess the morphology, distribution, and density of the CGCs. Recently, moxifloxacin-based fluorescence microscopy has emerged as a novel technique that enables efficient, non-invasive and in vivo imaging of CGCs. This article presents a comprehensive overview of both the structure and function of CGCs and their alterations in the context of DED, as well as current methods of CGCs imaging assessment. Additionally, potential directions for the visual evaluation of CGCs are discussed.

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PURPOSE: Ferroptosis has recently been recognized as a mechanism of cerebral ischemia-reperfusion (I/R) injury, attributed to blood-brain barrier (BBB) disruption. Edaravone dexboneol (Eda.B) is a novel neuroprotective agent widely employed in ischemic stroke, which is composed of edaravone (Eda) and dexborneol. This study aimed to investigate the protective effects of Eda.B on the BBB in cerebral I/R and explore its potential mechanisms. METHODS: Transient middle cerebral artery occlusion (tMCAO) Sprague-Dawley-rats model was used. Rats were randomly assigned to sham-operated group (sham, n = 20), model group (tMCAO, n = 20), Eda.B group (Eda.B, n = 20), Eda group (Eda, n = 20) and dexborneol group (dexborneol, n = 20), and Eda.B + Zinc protoporphyria group (Eda.B + ZnPP, n = 5). Infarct area, cellular apoptosis and neurofunctional recovery were accessed through TTC staining, TUNEL staining, and modified Garcia scoring system, respectively. BBB integrity was evaluated via Evans blue staining. Nuclear factor E2 related factor 2 (Nrf-2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) signaling were qualified by Western blot. Transmission electron microscopy (TEM) revealed alterations in ipsilateral brain tissue among groups. Glutathione (GSH) and malondialdehyde (MDA) levels, and Fe2+ tissue content determination were detected. RESULTS: Eda.B effectively improved neurological deficits, diminished infarct area and cellular apoptosis, as well as ameliorated BBB integrity in tMCAO rats. Further, Eda.B significantly inhibited ferroptosis, as evidenced by ameliorated pathological features of mitochondria, down-regulated of MDA and Fe2+ levels and up-regulated GSH content. Mechanistically, Eda.B attenuated BBB disruption via Nrf-2-mediated ferroptosis, promoting nuclear translocation of Nrf-2, increasing HO-1, GPX4 expression, alleviating the loss of zonula occludens 1 (ZO-1) and occludin as well as decreasing 4-hydroxynonenal (4-HNE) level. CONCLUSIONS: This study revealed for the first time that Eda.B safeguarded the BBB from cerebral I/R injury by inhibiting ferroptosis through the activation of the Nrf-2/HO-1/GPX4 axis, providing a novel insight into the neuroprotective effect of Eda.B in cerebral I/R.

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BACKGROUND: Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule-associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. METHODS: The levels of nucleotide-binding oligomerisation domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme-linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test-tube acetylation assay, co-immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau-overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno-associated virus injection. The cognitive functions of Tau-overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba-1 IF staining and [18F]-DPA-714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau-NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. RESULTS: Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg-AD mice, microtubule-associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of 'early' phosphorylated-Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau-K18 domain acetyltransferase activity-dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV-2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau-NLRP3-binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. CONCLUSIONS: In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies.

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Myasthenia gravis is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. However, some patients also experience autonomic dysfunction, anxiety, depression, and other neurological symptoms, suggesting the complex nature of the neurological manifestations. With the aim of explaining the symptoms related to the central nervous system, we utilized a rat model to investigate the impact of dopamine signaling in the central nervous and peripheral circulation. We adopted several screening methods, including western blot, quantitative PCR, mass spectrum technique, immunohistochemistry, immunofluorescence staining, and flow cytometry. In this study, we observed increased and activated dopamine signaling in both the central nervous system and peripheral circulation of myasthenia gravis rats. Furthermore, changes in the expression of two key molecules, Claudin5 and CD31, in endothelial cells of the blood-brain barrier were also examined in these rats. We also confirmed that dopamine incubation reduced the expression of ZO1, Claudin5, and CD31 in endothelial cells by inhibiting the Wnt/ß-catenin signaling pathway. Overall, this study provides novel evidence suggesting that pathologically elevated dopamine in both the central nervous and peripheral circulation of myasthenia gravis rats impair brain-blood barrier integrity by inhibiting junction protein expression in brain microvascular endothelial cells through the Wnt/ß-catenin pathway.

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Three new cucurbitane-type triterpenoid glycosides were separated from the ethyl acetate extract of Citrullus colocynthis by a variety of chromatographic techniques. According to the data of NMR, HR-ESI-MS, and/or comparison with the reported data, the three novel cucurbitane-type triterpenoid glycosides were identified as colocynthenin E(1), colocynthenin G(2), and colocynthenin H(3). The cell inflammation model was established with RAW264.7 macrophages exposed to lipopolysaccharide and then used to determine the anti-inflammatory activities of the three compounds. Compounds 2 and 3 showed mild anti-inflammatory activities with the IC_(50) of 48.21 and 40.11 µmol·L~(-1), respectively, compared with that(IC_(50)=7.57 µmol·L~(-1)) of the positive control dexamethasone.

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The mucosa-interfacing systems based on bioinspired engineering design for sampling/drug delivery have manifested crucial potential for the monitoring of infectious diseases and the treatment of mucosa-related diseases. However, their efficiency and validity are severely restricted by limited contact area for molecular transfer and dissatisfactory capture/detachment capability. Herein, inspired by the multilayer villus structure of the small intestine that enables high nutrient absorption, a trigonometric function-based periodic pattern was fabricated and integrated on the base layer of the microneedle patch, exhibiting a desirable synergistic effect with needle tips for deep sample enrichment and promising molecular transfer, significantly improving the device-mucosa bidirectional interaction. Moreover, mathematical modeling and finite element analysis were adopted to visualize and quantify the microcosmic molecular transmission process, guiding parameter optimization in actual situation. Encouragingly, these intestinal villi-inspired mathematically base-layer engineered microneedles (IMBEMs) have demonstrated distinguished applicability among mucosa tissue with varying surface curvatures, tissue toughness, and local environments, and simultaneously, have gained favorable support from healthy volunteers receiving preliminary test of IMBEMs patches. Overall, validated by numerous in vitro and in vivo tests, the IMBEMs were confirmed to act as a promising candidate to facilitate mucosa-based sampling and topical drug delivery, indicating highly clinical translation potential.

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Mesenchymal stem cells (MSCs) have been officially approved in many countries to treat graft-versus-host disease, autoimmune disorders and those associated with tissue regeneration after hematopoietic stem cell transplantation. Studies in recent years have confirmed that MSC acts mainly through paracrine mechanism, in which extracellular vesicles secreted by MSC (MSC-EV) play a central role. MSC-EV has overwhelming advantages over MSC itself in the setting of adverse effects in clinical application, indicating that MSC-EV might take the place of its parent cells to be a potentially therapeutic tool for "cell-free therapy". The pharmaceutical properties of MSC-EV largely depend upon the practical and optimal techniques including large-scale expansion of MSC, the modification of MSC based on the indications and the in vivo dynamic features of MSC-EV, and the methods for preparing and harvesting large amounts of MSC-EV. The recent progresses on the issues above will be briefly reviewed.

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EGFR tyrosine kinase inhibitors have made remarkable success in targeted cancer therapy. However, therapeutic resistance inevitably occurred and EGFR-targeting therapy has been demonstrated to have limited efficacy or utility in glioblastoma, colorectal cancer, and hepatocellular carcinoma. Therefore, there is a high demand for the development of new targets to inhibit EGFR signaling. Herein, we found that the EGFR oncogene proximal promoter sequence forms a unique type of snap-back loop containing G-quadruplex (G4), which can be targeted by small molecules. For the first time, we determined the NMR solution structure of this snap-back EGFR-G4, a three-tetrad-core, parallel-stranded G4 with naturally occurring flanking residues at both the 5'-end and 3'-end. The snap-back loop located at the 3'-end region forms a stable capping structure through two stacked G-triads connected by multiple potential hydrogen bonds. Notably, the flanking residues are consistently absent in reported snap-back G4s, raising the question of whether such structures truly exist under in vivo conditions. The resolved EGFR-G4 structure has eliminated the doubt and showed distinct structural features that distinguish it from the previously reported snap-back G4s, which lack the flanking residues. Furthermore, we found that the snap-back EGFR-G4 structure is highly stable and can form on an elongated DNA template to inhibit DNA polymerase. The unprecedented high-resolution EGFR-G4 structure has thus contributed a promising molecular target for developing alternative EGFR signaling inhibitors in cancer therapeutics. Meanwhile, the two stacked triads may provide an attractive site for specific small-molecule targeting.

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Purpose: To develop a computational method for oxygen-saturation-related functional parameter analysis of retinal vessels based on traditional color fundus photography, and to explore their characteristic alterations in type 2 diabetes mellitus (DM). Methods: 50 type 2 DM patients with no-clinically detectable retinopathy (NDR) and 50 healthy subjects were enrolled in the study. An optical density ratio (ODR) extraction algorithm based on the separation of oxygen-sensitive and oxygen-insensitive channels in color fundus photography was proposed. With precise vascular network segmentation and arteriovenous labeling, ODRs were acquired from different vascular subgroups, and the global ODR variability (ODRv) was calculated. Student's t-test was used to analyze the differences of the functional parameters between groups, and regression analysis and receiver operating characteristic (ROC) curves were used to explore the discrimination efficiency of DM patients from healthy subjects based on these functional parameters. Results: There was no significant difference in the baseline characteristics between the NDR and healthy normal groups. The ODRs of all vascular subgroups except the micro venule were significantly higher (p<0.05, respectively) while ODRv was significantly lower (p<0.001) in NDR group than that in healthy normal group. In the regression analysis, the increased ODRs except micro venule and decreased ODRv were significantly correlated with the incidence of DM, and the C-statistic for discrimination DM with all ODR is 0.777 (95% CI 0.687-0.867, p<0.001). Conclusion: A computational method to extract the retinal vascular oxygen-saturation-related optical density ratios (ODRs) with single color fundus photography was developed, and increased ODRs and decreased ODRv of retinal vessels could be new potential image biomarkers of DM.