Aflibercept Loaded Eye-Drop Hydrogel Mediated with Cell-Penetrating Peptide for Corneal Neovascularization Treatment.

Corneal neovascularization (CoNV) is a major cause of visual impairment worldwide. Currently, available treatment options have limited efficacy and are associated with adverse effects due to biological barriers and clearance mechanisms. To address this challenge, a novel topical delivery system is developed-Gel 2_1&Eylea-an aflibercept-loaded eye-drop hydrogel mediated with cell-penetrating peptide 1. Gel 2_1&Eylea demonstrates superior membrane permeability, increased stability, and prolonged drug retention time on the ocular surface, and thus may improve drug efficacy. In a rabbit CoNV model, Gel 2_1&Eylea significantly reduces the density of neovascularization with no adverse effects on normal corneoscleral limbal vessels, demonstrating high efficacy and biocompatibility. This work identifies a promising treatment for CoNV which has the potential to benefit other ocular neovascular diseases.

Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition.

BACKGROUND AND AIMS: Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis. APPROACH AND RESULTS: By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus. CONCLUSIONS: ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.

A Stapled Peptide Inhibitor Targeting the Binding Interface of N6-Adenosine-Methyltransferase Subunits METTL3 and METTL14 for Cancer Therapy.

METTL3, a primary methyltransferase catalyzing the RNA N6-methyladenosine (m6A) modification, has been identified as an oncogene in several cancer types and thus nominated as a potentially effective target for therapeutic inhibition. However, current options using this strategy are limited. In this study, we targeted protein-protein interactions at the METTL3-METTL14 binding interface to inhibit complex formation and subsequent catalysis of the RNA m6A modification. Among candidate peptides, RM3 exhibited the highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed a stapled peptide inhibitor (RSM3) with enhanced peptide stability and formation of the α-helical secondary structure required for METTL3 interaction. Functional and transcriptomic analysis in vivo indicated that RSM3 induced upregulation of programmed cell death-related genes while inhibiting cancer-promoting signals. Furthermore, tumor growth was significantly suppressed while apoptosis was enhanced upon RSM3 treatment, accompanied by increased METTL3 degradation, and reduced global RNA methylation levels in two in vivo tumor models. This peptide inhibitor thus exploits a mechanism distinct from other small-molecule competitive inhibitors to inhibit oncogenic METTL3 activity. Our findings collectively highlight the potential of targeting METTL3 in cancer therapies through peptide-based inhibition of complex formation and proteolytic degradation.

Cation-π Interaction Trigger Supramolecular Hydrogelation of Peptide Amphiphiles.

As an important noncovalent interaction, cation-π interaction plays an essential role in a broad area of biology and chemistry. Despite extensive studies in protein stability and molecular recognition, the utilization of cation-π interaction as a major driving force to construct supramolecular hydrogel remains uncharted. Here, a series of peptide amphiphiles are designed with cation-π interaction pairs that can self-assemble into supramolecular hydrogel under physiological condition. The influence of cation-π interaction is thoroughly investigated on peptide folding propensity, morphology, and rigidity of the resultant hydrogel. Computational and experimental results confirm that cation-π interaction could serve as a major driving force to trigger peptide folding, resultant ß-hairpin peptide self-assembled into fibril-rich hydrogel. Furthermore, the designed peptides exhibit high efficacy on cytosolic protein delivery. As the first case of using cation-π interactions to trigger peptide self-assembly and hydrogelation, this work provides a novel strategy to generate supramolecular biomaterials.

Trench-assisted 12-core 5-LP mode fiber with a low refractive index circle and a high refractive index ring.

We propose a homogeneous five-mode twelve-core fiber with a trench-assisted structure, combining a low refractive index circle and a high refractive index ring (LCHR). The 12-core fiber utilizes the triangular lattice arrangement. The properties of the proposed fiber are simulated by the finite element method. The numerical result shows that the worst inter-core crosstalk (ICXT) can achieve at -40.14 dB/100 km, which is lower than the target value (-30 dB/100 km). Since adding the LCHR structure, the effective refractive index difference between LP21 and LP02 mode is 2.8 × 10-3, which illustrates that the LP21 and LP02 modes can be separated. In contrast to without the LCHR, the dispersion of LP01 mode has an apparent dropping, which is 0.16 ps/(nm·km) at 1550 nm. Moreover, the relative core multiplicity factor can reach 62.17, which indicates a large core density. The proposed fiber can be applied to the space division multiplexing system to enhance the fiber transmission channels and capacity.

Weakly coupled graded index heterogeneous nineteen-core few-mode fiber.

We propose a novel heterogeneous nineteen-core four-mode fiber. The heterogeneous core arrangement and trench-assisted structure can significantly suppress inter-core crosstalk (XT). In order to control the number of modes in the core, a low refractive index area is introduced in the core. The number of LP modes and the effective refractive index difference (Δneff) of adjacent modes in the core are controlled by changing the refractive index distribution of the core and the parameters of the low refractive index area in the core. And the mode state of low intra-core crosstalk is successfully realized in the graded index core. After the optimization of fiber parameters, each core can stably transmit four LP modes under the optimal fiber parameters, and the inter-core crosstalk of LP02 mode is less than -60 dB/km. Finally, the effective mode area (Aeff) and dispersion (D) of nineteen-core four-mode fiber in C+L band are described. The results show that the nineteen-core four-mode fiber is suitable for terrestrial and undersea communication systems, data centers, optical sensors and other fields.

Low crosstalk trapezoid-index thirteen-core single-mode fiber for multi-channel and high-density applications.

Multi-core fiber based on space division multiplexing technology provides a practical solution to achieve multi-channel and high-capacity signal transmission. However, long-distance and error-free transmission remains challenging due to the presence of inter-core crosstalk within the multi-core fiber. Here, we propose and prepare a novel trapezoid-index thirteen-core single-mode fiber to solve the problems that MCF has large inter-core crosstalk and the transmission capacity of single-mode fiber approaches the upper limit. The optical properties of thirteen-core single-mode fiber are measured and characterized by experimental setups. The inter-core crosstalk of the thirteen-core single-mode fiber is less than -62.50 dB/km at 1550 nm. At the same time, each core can transmit signals at a data rate of 10 Gb/s and achieve error-free signal transmission. The prepared optical fiber with a trapezoid-index core provides a new and feasible solution for reducing inter-core crosstalk, which can be loaded into current communication systems and applied in large data centers.

Experimental research of 13-core 5-LP mode fiber with high doped graded-index core and stairway-index trench.

A graded-index 13-core 5-LP mode fiber with high doped core and stairway-index trench structure have been successfully prepared by Hole-drilling method and Plasma vapor deposition. This fiber has 104 spatial channels, realizing large capacity information transmission. By building an experimental platform, the 13-core 5-LP mode fiber have been tested and characterized. The core can stably transmit 5 LP modes. The transmission loss is lower than 0.5 dB/km. Inter-core crosstalk (ICXT) of each layer of core is analyzed in detail. The ICXT can be less than -30 dB/100 km. The test results show that this fiber can stably transmit 5 LP modes, and has the characteristics of low loss and low crosstalk, realizing large capacity transmission. This fiber provides a solution to the issue of limited fiber capacity.

Early assessment of acute kidney injury in severe acute pancreatitis with multimodal DWI: an animal model.

OBJECTIVES: To evaluate the feasibility of multimodal diffusion-weighted imaging (DWI) for detecting the occurrence and severity of acute kidney injury (AKI) caused by severe acute pancreatitis (SAP) in rats. METHODS: SAP was induced in thirty rats by the retrograde injection of 5.0% sodium taurocholate through the biliopancreatic duct. Six rats underwent MRI of the kidneys 24 h before and 2, 4, 6, and 8 h after this AKI model was generated. Conventional and functional MRI sequences were used, including intravoxel incoherent motion imaging (IVIM), diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DTI). The main DWI parameters and histological results were analyzed. RESULTS: The fast apparent diffusion coefficient (ADC) of the renal cortex was significantly reduced at 2 h, as was the fractional anisotropy (FA) value of the renal cortex on DTI. The mean kurtosis (MK) values for the renal cortex and medulla gradually increased after model generation. The renal histopathological score was negatively correlated with the medullary slow ADC, fast ADC, and perfusion scores for both the renal cortex and medulla, as were the ADC and FA values of the renal medulla in DTI, whereas the MK values of the cortex and medulla were positively correlated (r = 0.733, 0.812). Thus, the cortical fast ADC, medullary MK, FADTI, and slow ADC were optimal parameters for diagnosing AKI. Of these parameters, cortical fast ADC had the highest diagnostic efficacy (AUC = 0.950). CONCLUSIONS: The fast ADC of the renal cortex is the core indicator of early AKI, and the medullary MK value might serve as a sensitive biomarker for grading renal injury in SAP rats. CLINICAL RELEVANCE STATEMENT: The multimodal parameters of renal IVIM, DTI, and DKI are potential beneficial for the early diagnosis and severity grading of renal injury in SAP patients. KEY POINTS: • The multimodal parameters of renal DWI, including IVIM, DTI, and DKI, may be valuable for the noninvasive detection of early AKI and the severity grading of renal injury in SAP rats. • Cortical fast ADC, medullary MK, FA, and slow ADC are optimal parameters for early diagnosis of AKI, and cortical fast ADC has the highest diagnostic efficacy. • Medullary fast ADC, MK, and FA as well as cortical MK are useful for predicting the severity grade of AKI, and the renal medullary MK value exhibits the strongest correlation with pathological scores.

Predictive Value of the Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio Esophageal Stricture After Endoscopic Submucosal Dissection of Early Esophageal Cancer.

BACKGROUND Endoscopic submucosal dissection (ESD) has become a preferred treatment method for patients with early esophageal cancer (EEC), but it can easily be complicated by esophageal stricture. In this study, we aimed to analyze the predictive value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) for post-ESD esophageal stricture of EEC. MATERIAL AND METHODS A retrospective study of 285 patients with EEC who underwent ESD was conducted. Patients were divided into 2 groups according to whether there were complications of esophageal stricture: the stricture group (n=72) and the non-stricture group (n=213). A t test or chi-squared test was used to compare the clinical differences in different subgroups. Receiver operating characteristic (ROC) curves were plotted to determine and compare the predictive value of NLR, PLR, and MLR in post-ESD esophageal stricture. Spearman correlation was used to detect the relationship between NLR, PLR, and MLR and the severity of esophageal stricture. RESULTS The NLR, PLR, and MLR values in the stricture group were higher than those in the non-stricture group, and there was a positive correlation between NLR and MLR and the severity of stricture according to the Spearman correlation test (P<0.05). ROC analysis showed that the area under the ROC curve value of the combination of NLR, PLR, and MLR (0.850) was higher than the NLR (0.792), PLR (0.774), and MLR (0.768). CONCLUSIONS The combination of NLR, PLR, and MLR could help clinicians to predict post-ESD esophageal stricture in the early stage.

Comparison of the imaging and clinical characteristics between Initial and Recurrent Alcoholic Acute Pancreatitis: a retrospective cross-sectional study.

MATERIALS: Patients with alcoholic acute pancreatitis in our hospital were recruited from Jan 2019 to July 2022 and divided into IAAP and RAAP groups. All patients underwent Contrast-Enhanced Computerized Tomography (CECT) or Magnetic Resonance Imaging (MRI) after administration. Imaging manifestations, local complications, severity scores on the Modified CT/MR Severity Index (MCTSI/MMRSI), Extrapancreatic Inflammation on CT/MR (EPIC/M), clinical severity [Bedside Index for Severity in Acute Pancreatitis (BISAP) Acute Physiology and Chronic Health Evaluation (APACHE-II)], and clinical prognosis were compared between the two groups.Results: 166 patients were recruited for this study, including 134 IAAP (male sex 94%) and 32 RAAP patients (male sex 100%). On CECT or MRI, IAAP patients were more likely to develop ascites and Acute Necrosis collection (ANC) than RAAP patients (ascites:87.3%vs56.2%; P = .01; ANC:38%vs18.7%; P < .05). MCTSI/MMRSI and EPIC/M scores were higher in IAAP than in RAAP patients(MCTSI/MMRSI:6.2vs5.2; P < .05; EPIC/M:5.4vs3.8; P < .05).Clinical severity scores (APACHE-II and BISAP), length of stay, and systemic complications [Systemic Inflammatory Response Syndrome (SIRS), respiratory failure] were higher in the IAAP group than in the RAAP group (P < .05). No mortality outcomes were reported in either group while hospitalized.Conclusions: Patients with IAAP had more severe disease than those with RAAP. These results may be helpful for differentiating care paths for IAAP and RAAP, which are essential for management and timely treatment in clinical practice.

Air-Stable Organoradical Boron Reagents.

Both organic radicals and organoboron reagents have been broadly investigated, but the combination of them via direct C-H borylation as organic radical building blocks has never been achieved. Herein, a series of organoradical boron reagents, such as TTM-Bpin and TTM-BOH, were synthesized through the key step of C-H borylation of substrate TTM-H ((2,6-dichlorophenyl) bis(2,4,6-trichlorophenyl)methyl) radical for the first time. They are air stable enough to be stored in the solid state for several months under dark conditions, and fully investigated through single crystal analysis, EPR and DFT calculations. Furthermore, they can smoothly work in the standard Suzuki-Miyaura coupling (SMC) reaction with retention of the carbon radical center. Meanwhile, these radical species bearing different boron units display fluorescent character and are potentially applied for the collective synthesis of luminescent organic radicals, as well as other functionalized open-shell materials.

Preparation and transmission characteristics of seven-core few-mode fiber with low loss and low inter-core crosstalk.

Seven-core five-mode fiber and single-core five-mode fiber with the same core structure by high and low refractive index double rings are prepared based on plasma chemical vapor deposition. The transmission characteristics of the single-core few-mode fiber and the seven-core few-mode fiber are measured and characterized by building an experimental platform. The prepared single-core few-mode fiber can stably transmit five LP modes at 1550 nm, which not only has low loss characteristics, but also has excellent bending resistance. Furthermore, the transmission loss of the prepared seven-core fiber is lower than 0.4 dB/km, and the inter-core crosstalk is lower than -50 dB/km, which realizes the high-density and low-crosstalk transmission of the multi-core fiber. The prepared seven-core few-mode fiber can solve the capacity limitation of single-mode fiber, which will contribute the development of future communication systems.

Manufacturable low-crosstalk high-RCMF 13-core 5-LP mode fiber with graded-index core and stairway-index trench.

We propose a novel scheme of high doped core and stairway-index trench structure to design a manufacturable graded-index 13-core 5-LP mode fiber with low inter-core crosstalk (ICXT) and large mode differential group delay (MDGD). By using the couple power theory and the finite element method (FEM), the change ICXT of with fiber parameters are investigated. The design of core graded profile and trench structure are optimized to achieve better performance and to meet the fabrication conditions. The numerical result demonstrate that this fiber achieves a low ICXT of lower than -30dB/km (Rb≤500 mm). The bending loss values satisfy the ITU-T recommendation G.655 in 195 µm cladding diameter. Furthermore, the dispersion and the MDGD dependences on wavelength are calculated. The relative core multiplicity factor (RCMF) is obtained as 75.17, which realizes the high density multiplexing. The fabrication methods of this fiber are briefly introduced. The designed fiber may be used for Space-division multiplexing (SDM) system to solve the problem of fiber capacity limitation.

Extracellular pH-manipulated in situ reconfiguration of aptamer functionalized DNA monomer enables specifically improved affinity, detection and drug delivery.

Aptamers are promising in cancer diagnosis and therapy, but their poor affinity under physiological conditions is a challenge. In view of the acidic microenvironment of solid tumors, we herein developed an extracellular pH-manipulated multivalent approach to exclusively improve the affinity to target cells at physiological temperature. Specifically, an aptamer based DNA monomer (AptDM) with split i-motif fragments overhanging was rationally designed, it possessed pH-responsiveness and doxorubicin loading capacity. At neutral pH, AptDMs existed as well dispersed small units, showing weakly undesired binding and internalization. In acidic extracellular conditions, AptDMs tended to crosslink of each other into multivalent DNA assemblies (MDAs) via formation of an intermolecular i-motif structure. Due to the multivalent effect, the resulting MDAs showed greatly enhanced affinity (Kd = 9.96 ± 1.06 nM) and stable binding ability at 37 °C, thus allowing highly sensitive diagnosis, efficient drug delivery, and improved inhibition to target tumor cells, but decreased cytotoxicity to nontarget cells. It is believed that this multivalent approach may boost the development of novel aptamer functionalized nanodevices for clinical validation.

FAM98A promotes cancer progression in endometrial carcinoma.

To investigate the expression status of FAM98A and its potential involvement in endometrial carcinoma, the relative expression of FAM98A in clinical endometrial carcinoma tissues was analyzed by immunohistochemistry and real-time polymerase chain reaction. Endogenous FAM98A protein was determined by Western blotting. The overall survival was calculated by the Kaplan-Meier's analysis. Cell growth/viability/proliferation was evaluated by cell counting, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide assay, and clonogenic assay, respectively. Cell apoptosis was determined by the Annexin V/7-AAD double-staining methods followed by flow cytometry analysis. The regulatory effect of miR-142-3p on FAM98A was interrogated by luciferase reporter assay. Aberrant overexpression of FAM98A was found in endometrial carcinoma both in vitro and in vivo. Furthermore, high level of FMA98A was associated with poor prognosis. FAM98A deficiency in Ishikawa and RL95-2 cells significantly inhibited cell growth, cell viability, and cell proliferation. In addition, FAM98A-knockdown stimulated remarkable cell apoptosis, which might be mediated by down-regulation of BCL2 and up-regulation of BAX. Mechanistically, it was demonstrated that miR-142-3p directly targeted FAM98A, and modulated its expression. In conclusion, we unraveled the oncogenic properties of FAM98A in endometrial carcinoma and highlighted the miR-142-3p-FAM98A signaling in this disease.

Enhanced Imaging of Specific Cell-Surface Glycosylation Based on Multi-FRET.

Cell-surface glycosylation contains abundant biological information that reflects cell physiological state, and it is of great value to image cell-surface glycosylation to elucidate its functions. Here we present a hybridization chain reaction (HCR)-based multifluorescence resonance energy transfer (multi-FRET) method for specific imaging of cell-surface glycosylation. By installing donors through metabolic glycan labeling and acceptors through aptamer-tethered nanoassemblies on the same glycoconjugate, intramolecular multi-FRET occurs due to near donor-acceptor distance. Benefiting from amplified effect and spatial flexibility of the HCR nanoassemblies, enhanced multi-FRET imaging of specific cell-surface glycosylation can be obtained. With this HCR-based multi-FRET method, we achieved obvious contrast in imaging of protein-specific GalNAcylation on 7211 cell surfaces. In addition, we demonstrated the general applicability of this method by visualizing the protein-specific sialylation on CEM cell surfaces. Furthermore, the expression changes of CEM cell-surface protein-specific sialylation under drug treatment was accurately monitored. This developed imaging method may provide a powerful tool in researching glycosylation functions, discovering biomarkers, and screening drugs.

A steady-state Kalman predictor-based filtering strategy for non-overlapping sub-band spectral estimation.

This paper focuses on suppressing spectral overlap for sub-band spectral estimation, with which we can greatly decrease the computational complexity of existing spectral estimation algorithms, such as nonlinear least squares spectral analysis and non-quadratic regularized sparse representation. Firstly, our study shows that the nominal ability of the high-order analysis filter to suppress spectral overlap is greatly weakened when filtering a finite-length sequence, because many meaningless zeros are used as samples in convolution operations. Next, an extrapolation-based filtering strategy is proposed to produce a series of estimates as the substitutions of the zeros and to recover the suppression ability. Meanwhile, a steady-state Kalman predictor is applied to perform a linearly-optimal extrapolation. Finally, several typical methods for spectral analysis are applied to demonstrate the effectiveness of the proposed strategy.

MC1R Peptide Agonist Self-Assembles into a Hydrogel That Promotes Skin Pigmentation for Treating Vitiligo.

Vitiligo, a common skin disease that seriously affects 0.5-2.0% of the worldwide population, lacks approved therapeutics due to a wide range of adverse side effects. As a key regulator of skin pigmentation, MC1R may be an effective therapeutic target for vitiligo. Herein, we report an MC1R peptide agonist that directly self-assembles into nanofibrils that form a hydrogel matrix under normal physiological conditions. This hydrogel exhibits higher stability than free peptides, sustained release, rapid recovery from shear-thinning, and resistance to enzymatic proteolysis. Furthermore, this peptidal MC1R agonist upregulates tyrosinase, tyrosinase-related protein-1 (TYRP-1), and tyrosinase-related protein-2 (TYRP-2) to stimulate melanin synthesis. More importantly, MC1R agonist hydrogel promotes skin pigmentation in mice more potently than free MC1R agonist. This study supports the development of this MC1R agonist hydrogel as a promising pharmacological intervention for vitiligo.

Computed tomography angiography-based radiomics model to identify high-risk carotid plaques.

Background: Extracranial atherosclerosis is one of the major causes of stroke. Carotid computed tomography angiography (CTA) is a widely used imaging modality that allows detailed assessments of plaque characteristics. This study aimed to develop and test radiomics models of carotid plaques and perivascular adipose tissue (PVAT) to distinguish symptomatic from asymptomatic plaques and compare the diagnostic value between radiomics models and traditional CTA model. Methods: A total of 144 patients with carotid plaques were divided into symptomatic and asymptomatic groups. The traditional CTA model was built by the traditional radiological features of carotid plaques measured on CTA images which were screened by univariate analysis and multivariable logistic regression. We extracted and screened radiomics features from carotid plaques and PVAT. Then, a support vector machine was used for building plaque and PVAT radiomics models, as well as a combined model using traditional CTA features and radiomics features. The diagnostic value between radiomics models and traditional CTA model was compared in identifying symptomatic carotid plaques by Delong method. Results: The area under curve (AUC) values of traditional CTA model were 0.624 and 0.624 for the training and validation groups, respectively. The plaque radiomics model and PVAT radiomics model achieved AUC values of 0.766, 0.740 and 0.759, 0.618 in the two groups, respectively. Meanwhile, the combined model of plaque and PVAT radiomics features and traditional CTA features had AUC values of 0.883 and 0.840 for the training and validation groups, respectively, and the receiver operating characteristic curves of combined model were significantly better than those of traditional CTA model in the training group (P<0.001) and validation group (P=0.029). Conclusions: The combined model of the radiomics features of carotid plaques and PVAT and the traditional CTA features significantly contributes to identifying high-risk carotid plaques compared with traditional CTA model.