Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats.

Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.

Stepwise Toward Pure Blue Organic Light-Emitting Diodes by Synergetically Locking and Shielding Carbonyl/Nitrogen-Based MR-TADF Emitters.

Deep-blue multi-resonance (MR) emitters with stable and narrow full-width-at-half-maximum (FWHM) are of great importance for widening the color gamut of organic light-emitting diodes (OLEDs). However, most planar MR emitters are vulnerable to intermolecular interactions from both the host and guest, causing spectral broadening and exciton quenching in thin films. Their emission in the solid state is environmentally sensitive, and the color purity is often inferior to that in solutions. Herein, a molecular design strategy is presented that simultaneously narrows the FWHM and suppresses intermolecular interactions by combining intramolecular locking and peripheral shielding within a carbonyl/nitrogen-based MR core. Intramolecularly locking carbonyl/nitrogen-based bears narrower emission of 2,10-dimethyl-12,12-diphenyl-4H-benzo[9,1]quinolizino[3,4,5,6,7-defg]acridine-4,8(12H)-dione in solution and further with peripheral-shielding groups, deep-blue emitter (12,12-diphenyl-2,10-bis(9-phenyl-9H-fluoren-9-yl)-4H-benzo[9,1]quinolizino[3,4,5,6,7-defg]acridine-4,8(12H)-dione, DPQAO-F) exhibits ultra-pure emission with narrow FWHM (c.a., 24 nm) with minimal variations (∆FWHM ≤ 3 nm) from solution to thin films over a wide doping range. An OLED based on DPQAO-F presents a maximum external quantum efficiency (EQEmax) of 19.9% and color index of (0.134, 0.118). Furthermore, the hyper-device of DPQAO-F exhibits a record-high EQEmax of 32.7% in the deep-blue region, representing the first example of carbonyl/nitrogen-based OLED that can concurrently achieve narrow bandwidth in the deep-blue region and a high electroluminescent efficiency surpassing 30%.

Pathway Activation Analysis for Pan-Cancer Personalized Characterization Based on Riemannian Manifold.

The pathogenesis of carcinoma is believed to come from the combined effect of polygenic variation, and the initiation and progression of malignant tumors are closely related to the dysregulation of biological pathways. Quantifying the alteration in pathway activation and identifying coordinated patterns of pathway dysfunction are the imperative part of understanding the malignancy process and distinguishing different tumor stages or clinical outcomes of individual patients. In this study, we have conducted in silico pathway activation analysis using Riemannian manifold (RiePath) toward pan-cancer personalized characterization, which is the first attempt to apply the Riemannian manifold theory to measure the extent of pathway dysregulation in individual patient on the tangent space of the Riemannian manifold. RiePath effectively integrates pathway and gene expression information, not only generating a relatively low-dimensional and biologically relevant representation, but also identifying a robust panel of biologically meaningful pathway signatures as biomarkers. The pan-cancer analysis across 16 cancer types reveals the capability of RiePath to evaluate pathway activation accurately and identify clinical outcome-related pathways. We believe that RiePath has the potential to provide new prospects in understanding the molecular mechanisms of complex diseases and may find broader applications in predicting biomarkers for other intricate diseases.

CD169+ classical monocyte as an important participant in Graves' ophthalmopathy through CXCL12-CXCR4 axis.

Patients with Graves' disease (GD) can develop Graves' ophthalmopathy (GO), but the underlying pathological mechanisms driving this development remain unclear. In our study, which included patients with GD and GO, we utilized single-cell RNA sequencing (scRNA-seq) and multiplatform analyses to investigate CD169+ classical monocytes, which secrete proinflammatory cytokines and are expanded through activated interferon signaling. We found that CD169+ clas_mono was clinically significant in predicting GO progression and prognosis, and differentiated into CD169+ macrophages that promote inflammation, adipogenesis, and fibrosis. Our murine model of early-stage GO showed that CD169+ classical monocytes accumulated in orbital tissue via the Cxcl12-Cxcr4 axis. Further studies are needed to investigate whether targeting circulating monocytes and the Cxcl12-Cxcr4 axis could alleviate GO progression.

A systemic lupus erythematosus patient with persistent elevated conjugated bilirubin as the initial symptom: A case report.

RATIONALE: While some systemic lupus erythematosus (SLE) patients may experience varying degrees of liver function abnormalities, only a small portion of these cases have clinical significance, and the majority of patients typically exhibit low levels of serum bilirubin. However, in this article, we present a case of a middle-aged female patient with SLE who exhibited persistent skin jaundice as her initial symptom, offering a fresh perspective on diagnosing and treating patients who exhibit unexplained liver dysfunction and SLE combined with liver injury. PATIENT CONCERNS: A 45-year-old woman was initially admitted to the hospital due to yellowing of the skin and sclera, and her symptoms did not improve significantly during treatment. The results were abnormal after relevant immunological tests. DIAGNOSES: Persistent non-conjugated bilirubin elevation due to lupus hepatitis. INTERVENTIONS: The use of methylprednisolone sodium succinate (40 mg/Qd) and mycophenolate mofetil (0.75 g/d) suppressed immunity, polyolefin choline (20 mL/d) and glutathione (0.6 g/Qd) improved liver function, and nutritional support therapy. OUTCOMES: After 2 weeks of treatment, a significant decrease in the yellow skin and sclera of the patient was observed. LESSONS: Most clinicians overlook that liver function abnormalities are the main manifestation of SLE, resulting in many patients not receiving timely treatment. This study highlights the importance that SLE is also a cause of abnormal liver function.

A sequence-based machine learning model for predicting antigenic distance for H3N2 influenza virus.

Introduction: Seasonal influenza A H3N2 viruses are constantly changing, reducing the effectiveness of existing vaccines. As a result, the World Health Organization (WHO) needs to frequently update the vaccine strains to match the antigenicity of emerged H3N2 variants. Traditional assessments of antigenicity rely on serological methods, which are both labor-intensive and time-consuming. Although numerous computational models aim to simplify antigenicity determination, they either lack a robust quantitative linkage between antigenicity and viral sequences or focus restrictively on selected features. Methods: Here, we propose a novel computational method to predict antigenic distances using multiple features, including not only viral sequence attributes but also integrating four distinct categories of features that significantly affect viral antigenicity in sequences. Results: This method exhibits low error in virus antigenicity prediction and achieves superior accuracy in discerning antigenic drift. Utilizing this method, we investigated the evolution process of the H3N2 influenza viruses and identified a total of 21 major antigenic clusters from 1968 to 2022. Discussion: Interestingly, our predicted antigenic map aligns closely with the antigenic map generated with serological data. Thus, our method is a promising tool for detecting antigenic variants and guiding the selection of vaccine candidates.

SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway.

Purpose: To evaluate the expression of sry-box transcription factor 9 (SOX9) in orbital fibroblasts (OFs) of thyroid eye disease (TED) and to find its potential role and underlying mechanism in orbital fibrosis. Methods: OFs were cultured from orbital connective tissues obtained from patients with TED (n = 10) and healthy controls (n = 6). SOX9 was depleted by small interfering RNA or overexpressed through lentivirus transduction in OFs. Fibroblast contractile activity was measured by collagen gel contraction assay and proliferation was examined by EdU assay. Transcriptomic changes were assessed by RNA sequencing. Results: The mRNA and protein levels of SOX9 were significantly higher in OFs cultured from patients with TED than those from healthy controls. Extracellular matrix-related genes were down-regulated by SOX9 knockdown and up-regulated by SOX9 overexpression in TED-OFs. SOX9 knockdown significantly decrease the contraction and the antiapoptotic ability of OFs, whereas the overexpression of SOX9 increased the ability of transformation, migration, and proliferation of OFs. SOX9 knockdown suppressed the expression of phosphorylated ERK1/2, whereas its overexpression showed the opposite effect. Epidermal growth factor receptor (EGFR) is one of the notably down-regulated genes screened out by RNA sequencing. Chromatin immunoprecipitation-qPCR demonstrated SOX9 binding to the EGFR promoter. Conclusions: A high expression of SOX9 was found in TED-OFs. SOX9 can activate OFs via MAPK/ERK1/2 signaling pathway, which in turn promotes proliferation and differentiation of OFs. EGFR was a downstream target gene of SOX9. SOX9/EGFR can be considered as therapeutic targets for the treatment of orbital fibrosis in TED.

Digital health integration for noncommunicable diseases: Comprehensive process mapping for full-life-cycle management.

AIM: To create a systematic digital health process mapping framework for full-life-cycle noncommunicable disease management grounded in key stakeholder engagement. METHODS: A triphasic, qualitative methodology was employed to construct a process mapping framework for digital noncommunicable disease management in Shanghai, China. The first phase involved desk research to examine current guidance and practices. In the second phase, pivotal stakeholders participated in focus group discussions to identify prevalent digital touchpoints across lifetime noncommunicable disease management. In the final phase, the Delphi technique was used to refine the framework based on expert insights and obtain consensus. RESULTS: We identified 60 digital touchpoints across five essential stages of full-life-cycle noncommunicable disease management. Most experts acknowledged the rationality and feasibility of these touchpoints. CONCLUSIONS: This study led to the creation of a comprehensive digital health process mapping framework that encompasses the entire life cycle of noncommunicable disease management. The insights gained emphasize the importance of a systemic strategic, person-centered approach over a fragmented, purely technocentric approach. We recommend that healthcare professionals use this framework as a linchpin for efficient disease management and seamless technology incorporation in clinical practice.

Therapeutic effect and mechanism of action of pterostilbene nano drugs in dry eye models.

Dry eye disease is a multifactorial dysfunction of the tear film and ocular surface, with etiology involving inflammation and oxidative stress on the ocular surface. Pterostilbene (PS) is a secondary metabolite extracted from plants, which possesses remarkable anti-inflammatory and antioxidant effects. However, its application is limited by light instability and very poor water solubility. We modified fat-soluble PS into a biparental pterostilbene-glutaric anhydride-arginine-glycine-aspartic acid (PS-GA-RGD) nanomedicine by prodrug ligation of functional peptides. The aim of this study was to explore the protective effect and potential mechanism of PS-GA-RGD on dry eye disease in vitro and in vivo. We demonstrated good long-term biocompatibility of PS-GA-RGD through rabbit eye stimulation test. Lipopolysaccharide (LPS) was used to induce murine macrophages RAW 264.7 to establish an inflammation and oxidative stress model. In this model, PS-GA-RGD effectively reduced the production of ROS and 8-OHdG, enhancing the expression of antioxidant factor Nrf2 and antioxidant enzyme heme oxygenase-1. In addition, the expression of NF-κB inflammatory pathway significantly increased in LPS-induced RAW 264.7 cells, while PS-GA-RGD could significantly reduce this pathway. Hypertonic saline was utilized to establish a hypertonic model of human corneal epithelial cells. PS-GA-RGD was found to significantly reduce the production of ROS and NLRP3 inflammasomes in this model, exhibiting superior efficacy compared to PS. Experimental dry eye animal models were co-induced with subcutaneous injection of scopolamine and an intelligently controlled environmental system. We demonstrated that PS-GA-RGD nano drugs can prevent and reduce corneal epithelial cell defects and apoptosis, protect conjunctival goblet cells, and have an excellent anti-inflammatory effect. Finally, we demonstrated that RGD sequence in PS-GA-RGD can enhance cellular uptake, corneal retention, and penetration, thereby increasing their bioavailability and efficacy by a cell uptake assay and rabbit corneal drug retention experiment. Overall, this study highlights the potential of PS-GA-RGD nanomedicines in the treatment of dry eyes.

Altered expression of the Plexin-B2 system in tuberous sclerosis complex and focal cortical dysplasia IIb lesions.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.

Scbean: a python library for single-cell multi-omics data analysis.

SUMMARY: Single-cell multi-omics technologies provide a unique platform for characterizing cell states and reconstructing developmental process by simultaneously quantifying and integrating molecular signatures across various modalities, including genome, transcriptome, epigenome, and other omics layers. However, there is still an urgent unmet need for novel computational tools in this nascent field, which are critical for both effective and efficient interrogation of functionality across different omics modalities. Scbean represents a user-friendly Python library, designed to seamlessly incorporate a diverse array of models for the examination of single-cell data, encompassing both paired and unpaired multi-omics data. The library offers uniform and straightforward interfaces for tasks, such as dimensionality reduction, batch effect elimination, cell label transfer from well-annotated scRNA-seq data to scATAC-seq data, and the identification of spatially variable genes. Moreover, Scbean's models are engineered to harness the computational power of GPU acceleration through Tensorflow, rendering them capable of effortlessly handling datasets comprising millions of cells. AVAILABILITY AND IMPLEMENTATION: Scbean is released on the Python Package Index (PyPI) (https://pypi.org/project/scbean/) and GitHub (https://github.com/jhu99/scbean) under the MIT license. The documentation and example code can be found at https://scbean.readthedocs.io/en/latest/.

Celastrol ameliorates experimental autoimmune uveitis through STAT3 targeting and gut microenvironment reprofiling.

BACKGROUND: Extensive research has revealed the favorable effects of celastrol (CEL) against various diseases, but the role of CEL in autoimmune uveitis remains unexplored. METHODS: We first assessed the prophylactical and therapeutical effects of CEL on autoimmune uveitis via rat experimental autoimmune uveitis model. After network pharmacology, functional enrichment and molecular docking analyses, we predicted the potential target of CEL and validated its effect on EAU by clinical and histopathological scores, Evans blue staining, immunofluorescence assay and western blotting. Then we evaluated the role of CEL in the gut environment by 16S rRNA sequencing and untargeted metabolomic analysis. RESULTS: We confirmed that CEL treatment suppressed the pathological TH17 response, inhibited the migration of inflammatory cells, and preserved the integrity of BRB via targeting STAT3-IL17 pathway. Furthermore, CEL was found to reduce the relative abundance of opportunistic pathogenic bacteria including Clostridium_sensu_stricto_1, Parasutterella and GCA-900066575, and enrich the relative abundance of beneficial Oscillospirales and Ruminococcus_torques_group in EAU rats by fecal 16S rRNA sequencing. Meanwhile, CEL treatment reshaped the gut metabolites in the EAU rats by increasing the relative concentrations of cholic acid, progesterone and guggulsterone, and decreasing the relative levels of isoproterenol, creatinine and phenylacetylglutamine. CONCLUSIONS: CEL exerts its ameliorative effects on the experimental autoimmune uveitis through the dual mechanisms of targeting STAT3 and reprofiling the gut microenvironment.

Adapting natural language processing and sentiment analysis methods for an intervention in older adults: Positive perceptions of health and technology.

Background: Older adults frequently participate in behavior change studies, yet it is not clear how to quantify a potential relationship between their perception of the intervention and its efficacy. Research Aim: We assessed the relationship between participant sentiment toward the intervention from follow-up interviews with physical activity and questionnaires for the perception of health. Methods: Sentiment was calculated using the transcripts of exit interviews through a bag of words approach defined as the sum of positive and negative words in 28 older adults with obesity (body mass index ≥30kg/m2). Results: Mean age was 73 years (82% female), and 54% lost ≥5% weight loss. Through linear regression we describe a significant association between positive sentiment about the intervention and weight loss; positive sentiment on technology and change in PROMIS-10 physical health and reduced physical activity time, while controlling for sex and age. Conclusions: This analysis demonstrates that sentiment analysis and natural language processing in program review identified an association between perception and topics with clinical outcomes.

Polarization-multiplexed metasurface enabled tri-functional imaging.

Diffraction-limited focusing imaging, edge-enhanced imaging, and long depth of focus imaging offer crucial technical capabilities for applications such as biological microscopy and surface topography detection. To conveniently and quickly realize the microscopy imaging of different functions, the multifunctional integrated system of microscopy imaging has become an increasingly important research direction. However, conventional microscopes necessitate bulky optical components to switch between these functionalities, suffering from the system's complexity and unstability. Hence, solving the problem of integrating multiple functions within an optical system is a pressing need. In this work, we present an approach using a polarization-multiplexed tri-functional metasurface, capable of realizing the aforementioned imaging functions simply by changing the polarization state of the input and output light, enhancing the system structure's compactness and flexibility. This work offers a new avenue for multifunctional imaging, with potential applications in biomedicine and microscopy imaging.

Supramolecular nanofiber of indomethacin derivative confers highly cyclooxygenase-2 (COX-2) selectivity and boosts anti-inflammatory efficacy.

Herein, we report a facile method for converting carboxylate-containing indomethacin (Idm) into a cyclooxygenase-2 (COX-2) selective inhibitor via the amidation of an unnatural peptide sequence (Nal-Nal-Asp). The resulting indomethacin amides (i.e., Idm-Nal-Nal-Asp) have high selectivity for COX-2, and can self-assemble into a one-component supramolecular hydrogel that acts as a 'self-delivery' system for boosting anti-inflammatory efficacy. Self-assembled Idm-Nal-Nal-Asp hydrogel robustly inhibits COX-2 expression in lipopolysaccharide (LPS)-activated Raw 264.7 macrophages while also exhibits superior anti-inflammatory and antioxidant activities via reactive oxygen species (ROS)-related NF-κB and Nrf2/HO-1 pathways. Moreover, a rabbit model of endotoxin-induced uveitis (EIU) reveals that the Idm-Nal-Nal-Asp hydrogel outperforms clinically used 0.1 wt% diclofenac sodium eye drops in terms of in vivo anti-inflammatory efficacy via topical instillation route. As a rational approach to designing and applying COX-2 selective inhibitors, this work presents a simple method for converting non-selective nonsteriodal anti-inflammatory drugs (NSAIDs) into highly selective COX-2 inhibitors that can self-assemble into supramolecular hydrogel for anti-inflammation applications.

Nano Self-Assemblies of Caffeic Acid-Fibronectin Mimic a Peptide Conjugate for the Treatment of Corneal Epithelial Injury.

Rapid corneal re-epithelialization is important for corneal wound healing. Corneal epithelial cell motility and oxidative stress are important targets for therapeutic intervention. In this study, we covalently conjugated the antioxidant caffeic acid (CA) with a bioactive peptide sequence (PHSRN) to generate a CA-PHSRN amphiphile, which was formulated into nanoparticular eye drops with an average size of 43.21 ± 16 nm. CA-PHSRN caused minimal cytotoxicity against human corneal epithelial cells (HCECs) and RAW264.7 cells, exhibited an excellent free radical scavenging ability, and remarkably attenuated reactive oxygen species (ROS) levels in H2O2-stimulated HCECs. The antioxidant and anti-inflammatory activities of CA-PHSRN were assessed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The results show that CA-PHSRN treatment effectively prevented LPS-induced DNA damage and significantly reduced the levels of LPS-induced pro-inflammatory cytochemokines (i.e., iNOS, NO, TNF-α, IL-6, and COX-2) in a dose-dependent manner. Moreover, using a rabbit corneal epithelial ex vivo migration assay, we demonstrated that the proposed CA-PHSRN accelerated corneal epithelial cell migration and exhibited high ocular tolerance and ocular bioavailability after topical instillation. Taken together, the proposed CA-PHSRN nanoparticular eye drops are a promising therapeutic formulation for the treatment of corneal epithelial injury.

AKAP12 inhibits esophageal squamous carcinoma cell proliferation, migration, and cell cycle via the PI3K/AKT signaling pathway.

Esophageal squamous cell carcinoma (ESCC) consistently ranks as one of the most challenging variants of squamous cell carcinomas, primarily due to the lack of effective early detection strategies. We herein aimed to elucidate the underlying mechanisms and biological role associated with A-kinase anchoring protein 12 (AKAP12) in the context of ESCC. Bioinformatic analysis had revealed significantly lower expression level of AKAP12 in ESCC tissue samples than in their non-cancerous counterparts. To gain deeper insights into the potential role of AKAP12 in the progression of ESCC, we conducted a single-gene set enrichment analysis of AKAP12 on ESCC datasets. Our findings suggested that AKAP12 exhibits functions inhibiting cell cycle progression, tumor proliferation, and epithelial-mesenchymal transition. To further validate our findings, we subjected ESCC cell lines to AKAP12 overexpression using CRISPR/Cas9-SAM. In vitro analyses demonstrated that increased expression of AKAP12 significantly reduced cell proliferation, migration, and cell cycle progression. Simultaneously, genes associated with this biological role undergo corresponding regulatory shifts. These observations provided valuable insights into the biological role played by AKAP12 in ESCC progression. In summary, AKAP12 shows promise as a new potential biomarker for early ESCC diagnosis, offering potential advantages for subsequent therapeutic intervention and disease management.

A biomimetic peptide-drug supramolecular hydrogel as eyedrops enables controlled release of ophthalmic drugs.

The rapid clearance of instilled drugs from the ocular surface due to tear flushing and excretion results in low drug bioavailability, necessitating the development of new drug delivery routes. Here, we generated an antibiotic hydrogel eye drop that can extend the pre-corneal retention of a drug after topical instillation to address the risk of side effects (e.g., irritation and inhibition of enzymes), resulting from frequent and high-dosage administrations of antibiotics used to obtain the desired therapeutic drug concentration. The covalent conjugation of small peptides to antibiotics (e.g., chloramphenicol) first endows the self-assembly ability of peptide-drug conjugate to generate supramolecular hydrogels. Moreover, the further addition of calcium ions, which are also widely present in endogenous tears, tunes the elasticity of supramolecular hydrogels, making them ideal for ocular drug delivery. The in vitro assay revealed that the supramolecular hydrogels exhibited potent inhibitory activities against both gram-negative (e.g., Escherichia coli) and gram-positive (e.g., Staphylococcus aureus) bacteria, whereas they were innocuous toward human corneal epithelial cells. Moreover, the in vivo experiment showed that the supramolecular hydrogels remarkably increased pre-corneal retention without ocular irritation, thereby showing appreciable therapeutic efficacy for treating bacterial keratitis. This work, as a biomimetic design of antibiotic eye drops in the ocular microenvironment, addresses the current issues of ocular drug delivery in the clinic and further provides approaches to improve the bioavailability of drugs, which may eventually open new directions to resolve the difficulty of ocular drug delivery. STATEMENT OF SIGNIFICANCE: Herein, we present a biomimetic design for antibiotic hydrogel eye drops mediated by calcium ions (Ca2+) in the ocular microenvironment, which can extend the pre-corneal retention of antibiotics after topical instillation. The mediation of Ca2+ which is widely present in endogenous tears, tunes the elasticity of hydrogels, making them ideal for ocular drug delivery. Since increasing the ocular retention of antibiotic eye drops enhances its action and reduces its adverse effects, this work may lead to an approach of peptide-drug-based supramolecular hydrogel for ocular drug delivery in clinics to combat ocular bacterial infections.

Dissolvable hybrid microneedle patch for efficient delivery of curcumin to reduce intraocular inflammation.

Intraocular inflammation seriously impairs vision, and the effectiveness of intraocular drug delivery is hampered by various physiological barriers, such as the corneal barrier. In this paper, we present a simple approach to fabricating a dissolvable hybrid microneedles (MNs) patch for the efficient delivery of curcumin to treat intraocular inflammatory disorders. Water-insoluble curcumin was first encapsulated into polymeric micelles with high anti-inflammatory capacities, and then were combined with hyaluronic acid (HA) to create a dissolvable hybrid MNs patch using a simple micromolding method. Curcumin was amorphously dispersed within the MNs patch as indicated by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analyses. According to an in vitro drug release study, the proposed MNs patch provided sustainable drug release over 8 h. Following its in vivo topical application, the MNs patch demonstrated an extended pre-corneal retention time over 3.5 h and exhibited great ocular biocompatibility. Additionally, such MNs patch could reversibly penetrate the corneal epithelium, generating an array of microchannels on the corneal surface, thereby increasing ocular bioavailability. Of greater significance, the use of MNs patch demonstrated the improved therapeutic effectiveness in treating endotoxin-induced uveitis (EIU) in a rabbit model compared to curcumin eye drops via a significant reduction in the infiltration of inflammatory cells such as CD45+ leukocytes and CD68+ macrophages. Overall, the topical application of the MNs patch as an efficient ocular drug delivery system could potentially serve as a promising approach for treating different types of intraocular disorders.

Identification of 5 hub genes for diagnosis of coronary artery disease.

Background: Coronary artery disease (CAD) is a main cause leading to increasing mortality of cardiovascular disease (CVD) worldwide. We aimed to discover marker genes and develop a diagnostic model for CAD. Methods: CAD-related target genes were searched from DisGeNET. Count expression data and clinical information were screened from the GSE202626 dataset. edgeR package identified differentially expressed genes (DEGs). Using online STRING tool and Cytoscape, protein-protein reactions (PPI) were predicted. WebGestaltR package was employed to functional enrichment analysis. We used Metascape to conduct module-based network analysis. VarElect algorithm provided genes-phenotype correlation analysis. Immune infiltration was assessed by ESTIMATE package and ssGSEA analysis. mRNAsi was determined by one class logistic regression (OCLR). A diagnostic model was constructed by SVM algorithm. Results: 162 target genes were screened by intersection 1,714 DEGs and 1,708 CAD related target genes. 137 target genes of the 162 target genes were obtained using PPI analysis, in which those targets were enriched in inflammatory cytokine pathways, such as chemokine signaling pathway, and IL-17 signaling pathway. From the above 137 target genes, four functional modules (MCODE1-4) were extracted. From the 162 potential targets, CAD phenotype were directly and indirectly associated with 161 genes and 22 genes, respectively. Finally, 5 hub genes (CCL2, PTGS2, NLRP3, VEGFA, LTA) were screened by intersections with the top 20, directly and indirectly, and genes in MCODE1. PTGS2, NLRP3 and VEGFA were positively, while LTA was negatively correlated with immune cells scores. PTGS2, NLRP3 and VEGFA were negatively, while LTA was positively correlated with mRNAsi. A diagnostic model was successfully established, evidenced by 92.59% sensitivity and AUC was 0.9230 in the GSE202625 dataset and 94.11% sensitivity and AUC was 0.9706 in GSE120774 dataset. Conclusion: In this work, we identified 5 hub genes, which may be associated with CAD development.