Dual roles of the MPK3 and MPK6 mitogen-activated protein kinases in regulating Arabidopsis stomatal development.

An Arabidopsis (Arabidopsis thaliana) mitogen-activated protein kinase (MAPK) cascade composed of YODA (YDA)-MKK4/MKK5-MPK3/MPK6 plays an essential role downstream of the ERECTA (ER)/ER-LIKE (ERL) receptor complex in regulating stomatal development in the leaf epidermis. STOMAGEN (STO), a peptide ligand produced in mesophyll cells, competes with EPIDERMAL PATTERNING FACTOR2 (EPF2) for binding ER/ERL receptors to promote stomatal formation. In this study, we found that activation of MPK3/MPK6 suppresses STO expression. Using MUTE and STO promoters that confer epidermis- and mesophyll-specific expression, respectively, we generated lines with cell-specific activation and suppression of MPK3/MPK6. The activation or suppression of MPK3/MPK6 in either epidermis or mesophyll cells is sufficient to alter stomatal differentiation. Epistatic analyses demonstrated that STO overexpression can rescue the suppression of stomatal formation conferred by the mesophyll-specific expression of the constitutively active MKK4DD or MKK5DD, but not by the epidermis-specific expression of these constitutively active MKKs. These data suggest that STO is downstream of MPK3/MPK6 in mesophyll cells, but upstream of MPK3/MPK6 in epidermal cells in stomatal development signaling. This function of the MPK3/MPK6 cascade allows it to coordinate plant epidermis development based on its activity in mesophyll cells during leaf development.

Ascle-A Python Natural Language Processing Toolkit for Medical Text Generation: Development and Evaluation Study.

BACKGROUND: Medical texts present significant domain-specific challenges, and manually curating these texts is a time-consuming and labor-intensive process. To address this, natural language processing (NLP) algorithms have been developed to automate text processing. In the biomedical field, various toolkits for text processing exist, which have greatly improved the efficiency of handling unstructured text. However, these existing toolkits tend to emphasize different perspectives, and none of them offer generation capabilities, leaving a significant gap in the current offerings. OBJECTIVE: This study aims to describe the development and preliminary evaluation of Ascle. Ascle is tailored for biomedical researchers and clinical staff with an easy-to-use, all-in-one solution that requires minimal programming expertise. For the first time, Ascle provides 4 advanced and challenging generative functions: question-answering, text summarization, text simplification, and machine translation. In addition, Ascle integrates 12 essential NLP functions, along with query and search capabilities for clinical databases. METHODS: We fine-tuned 32 domain-specific language models and evaluated them thoroughly on 27 established benchmarks. In addition, for the question-answering task, we developed a retrieval-augmented generation (RAG) framework for large language models that incorporated a medical knowledge graph with ranking techniques to enhance the reliability of generated answers. Additionally, we conducted a physician validation to assess the quality of generated content beyond automated metrics. RESULTS: The fine-tuned models and RAG framework consistently enhanced text generation tasks. For example, the fine-tuned models improved the machine translation task by 20.27 in terms of BLEU score. In the question-answering task, the RAG framework raised the ROUGE-L score by 18% over the vanilla models. Physician validation of generated answers showed high scores for readability (4.95/5) and relevancy (4.43/5), with a lower score for accuracy (3.90/5) and completeness (3.31/5). CONCLUSIONS: This study introduces the development and evaluation of Ascle, a user-friendly NLP toolkit designed for medical text generation. All code is publicly available through the Ascle GitHub repository. All fine-tuned language models can be accessed through Hugging Face.

Unconventional Luminescence Polymer with Color-Tunability based on Solvent-induced Electrostatic Potential Distribution of Fluorophore.

Tuning the full-color emission of polymers holds significant promise. However, preparing unconventional luminescence polymers with color-tunability in dilute solution and understanding the relationship between non-covalent interactions and luminescent behavior remains a great challenge. We report two emitters (P1 and P2) incorporating tetracoordinate boron. The P1 with non-conjugated D-π-A structure, exhibited red delayed fluorescence at 645 nm with quantum yield of 9.15% in aggregates. Notably, the emission wavelength of P1 can be tuned from 418 to 588 nm at different solvent. Similarly, the emission wavelength of P2 can also be adjusted by manipulating the interactions between the solvent and fluorophore. Experimental characterization and theoretical calculations indicate that the B←N bond and electronic interactions between solvent and fluorophore significantly regulate the equilibrium the electrostatic potential (ESP) and the intramolecular O···O interactions of P1, thereby modulating its emission wavelength. Additionally, these polymers showed excellent potential in fluoride ions detection. This work provides new insights into the complex effects of intermolecular interactions on luminescent properties.

IL-17A promotes tumorigenesis and upregulates PD-L1 expression in non-small cell lung cancer.

BACKGROUND: The tumor microenvironment plays a key role in non-small cell lung cancer (NSCLC) development and also influences the effective response to immunotherapy. The pro-inflammatory factor interleukin-17A mediates important immune responses in the tumor microenvironment. In this study, the potential role and mechanisms of IL-17A in NSCLC were investigated. METHODS: We detected IL-17A by immunohistochemistry (IHC) in 39 NSCLC patients. Its expression was correlated with the programmed cell death-ligand1 (PD-L1). IL-17A knockdown and overexpression in A549 and SPC-A-1 cell models were constructed. The function of IL-17A was examined in vitro by wound healing, migration, invasion, plate colony formation and T cell killing assay. Western blot analysis, immunofluorescence assay and IHC were performed to investigate the regulation effects of IL-17A on autophagy in A549 and SPC-A-1. The effect of IL-17A on ROS/Nrf2/p62 signaling pathway was detected. Subcutaneous tumor models were established to examine the tumor-promoting effect of IL-17A in vivo and its effect on immunotherapy. RESULTS: We found a prevalent expression of IL-17A in NSCLC tumor tissues and it was positively correlated with PD-L1 expression (r = 0.6121, p < 0.0001). In vitro, IL-17A promotes lung cancer cell migration, invasion and colony formation ability. Moreover, IL-17A upregulated N-cadherin, Twist, and Snail, and downregulated E-cadherin in NSCLC cells. IL-17A enhanced cell survival in the T cell killing assay. Mechanistically, IL-17A induced ROS production and increased Nrf2 and p62 expression, thereby inhibiting autophagy and reducing PD-L1 degradation. In vivo experiments, anti-IL-17A monoclonal antibody alone slowed the growth of subcutaneous tumors in mice. When combined with anti-PD-L1 monoclonal antibody, tumor tissue expression of PD-L1 was reduced and the therapeutic effect was diminished. CONCLUSION: We found that IL-17A promoted NSCLC progression and inhibited autophagy through the ROS/Nrf2/p62 pathway leading to increased PD-L1 expression in cancer cells. Modulation of IL-17A may affect the therapeutic efficacy of immunotherapy.

Involvement of aberrant acinar cell proliferation in scopolamine-induced dry eye mice.

Dry eye is a multifactorial disease that causes dryness, inflammation and damage of ocular surface. Subcutaneous injection of the muscarinic cholinergic antagonist scopolamine under desiccating stress reduces tear production and induces dry eye symptoms in mice. However, the expression profile and pathogenic changes of the lacrimal gland remain incompletely understood. In the present study, we performed comparative transcriptomic analysis of lacrimal glands from the control and scopolamine-treated mice. Primary analysis identified 677 upregulated genes and 269 downregulated genes in the lacrimal gland of mice with scopolamine treatment. Unexpectedly, KEGG pathway and hierarchical clustering analysis showed the enrichment of "DNA replication" and "cell cycle" categories in the upregulated genes. Subsequently, we confirmed that the acinar cells were the major proliferating cells of lacrimal gland, which exhibited significant increasing of the proliferating cell nuclear antigen (PCNA) expression after scopolamine treatment, accompanied with the upregulation of DNA damage marker γ-H2AX. More importantly, both prophylactic and therapeutic administration of the cyclin-dependent kinase (CDK) inhibitor AT7519 rescued the tear reduction and alleviated dry eye severity in the scopolamine-treated mice, including corneal epithelial barrier function, lacrimal and corneal inflammation, and conjunctival goblet cell density. Therefore, we conclude that aberrant acinar cell proliferation is involved in the scopolamine-induced tear reduction and dry eye onset, which can be improved by AT7519 treatment.

Extracellular HSP90α promotes cellular senescence by modulating TGF-ß signaling in pulmonary fibrosis.

Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF-ß signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6-D7, a specific eHSP90α antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α-induced cellular senescence, providing a framework for aging-related fibrosis interventions.

HDM induce airway epithelial cell ferroptosis and promote inflammation by activating ferritinophagy in asthma.

Asthma is a disease characterized by airway epithelial barrier destruction, chronic airway inflammation, and airway remodeling. Repeated damage to airway epithelial cells by allergens in the environment plays an important role in the pathophysiology of asthma. Ferroptosis is a novel form of regulated cell death mediated by lipid peroxidation in association with free iron-mediated Fenton reactions. In this study, we explored the contribution of ferroptosis to house dust mite (HDM)-induced asthma models. Our in vivo and in vitro models showed labile iron accumulation and enhanced lipid peroxidation with concomitant nonapoptotic cell death upon HDM exposure. Treatment with ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1) illuminated the role of ferroptosis and related damage-associated molecular patterns in HDM-treated airway epithelial cells. Furthermore, DFO and Fer-1 reduced HDM-induced airway inflammation in model mice. Mechanistically, NCOA4-mediated ferritin-selective autophagy (ferritinophagy) was initiated during ferritin degradation in response to HDM exposure. Together, these data suggest that ferroptosis plays an important role in HDM-induced asthma and that ferroptosis may be a potential treatment target for HDM-induced asthma.

Hyperbranched Polyborosiloxanes: Non-traditional Luminescent Polymers with Red Delayed Fluorescence.

Non-traditional fluorescent polymers have attracted significant attention for their excellent biocompatibility and diverse applications. However, designing and preparing non-traditional fluorescent polymers that simultaneously possess long emission wavelengths and long fluorescence lifetime remains challenging. In this study, a series of novel hyperbranched polyborosiloxanes (P1-P4) were synthesized. As the electron density increases on the monomer diol, the optimal emission wavelengths of the P1-P4 polymers gradually red-shift to 510, 570, 575, and 640 nm, respectively. In particular, P4 not only exhibits red emission but also demonstrates delayed fluorescence with a lifetime of 9.73 µs and the lowest critical cluster concentration (1.76 mg/mL). The experimental results and theoretical calculations revealed that the synergistic effect of dual heteroatom-induced electron delocalization and through-space O⋅⋅⋅O and O⋅⋅⋅N interaction was the key factor contributing to the red-light emission with delayed fluorescence. Additionally, these polymers showed excellent potential in dual-information encryption. This study provides a universal design strategy for the development of unconventional fluorescent polymers with both delayed fluorescence and long-wavelength emission.

Exogenous melatonin alleviates PEG-induced short-term water deficiency in maize by increasing hydraulic conductance.

BACKGROUND: Water deficiency is likely to become more frequent and intense as a result of global climate change, which may severely impact agricultural production in the world. The positive effects of melatonin (MEL) on alleviation drought or osmotic stress-induced water deficiency in plants has been well reported. However, the underlying mechanism of MEL on the detailed process of plant water uptake and transport under water deficiency condition remains largely unknown. RESULTS: Application of 1 µM MEL led to enhanced tolerance to water deficiency stress in maize seedlings, as evidenced by maintaining the higher photosynthetic parameters, leaf water status and plant transpiration rate. The relatively higher whole-plant hydraulic conductance (Kplant) and root hydraulic conductance (Lpr) in MEL-treated seedlings suggest that exogenous MEL alleviated water deficiency stress by promoting root water absorption. HgCl2 (aquaporin inhibitor) treatment inhibit the transpiration rate in MEL-treated plants greater than those of MEL-untreated; after recovery by dithiothreitol (DTT, anti-inhibitor), the transpiration rate in MEL-treated plants increased much higher than those of untreated plants. Moreover, under water deficiency, the transcription level of aquaporin genes was up-regulated by MEL application, and the H2O2 was less accumulated in MEL-treated root. CONCLUSIONS: Exogenous MEL promoted aquaporin activity, which contributed to the maintaining of Lpr and Kplant under short-term water deficiency. The increased water uptake and transport lead to improved water status and thus increased tolerance to PEG-induced short-term water deficiency in maize seedlings.

The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in Caenorhabditis elegans.

A critical accomplishment in the rapidly developing field of regenerative medicine will be the ability to foster repair of neurons severed by injury, disease, or microsurgery. In C. elegans, individual visualized axons can be laser-cut in vivo and neuronal responses to damage can be monitored to decipher genetic requirements for regeneration. With an initial interest in how local environments manage cellular debris, we performed femtosecond laser axotomies in genetic backgrounds lacking cell death gene activities. Unexpectedly, we found that the CED-3 caspase, well known as the core apoptotic cell death executioner, acts in early responses to neuronal injury to promote rapid regeneration of dissociated axons. In ced-3 mutants, initial regenerative outgrowth dynamics are impaired and axon repair through reconnection of the two dissociated ends is delayed. The CED-3 activator, CED-4/Apaf-1, similarly promotes regeneration, but the upstream regulators of apoptosis CED-9/Bcl2 and BH3-domain proteins EGL-1 and CED-13 are not essential. Thus, a novel regulatory mechanism must be utilized to activate core apoptotic proteins for neuronal repair. Since calcium plays a conserved modulatory role in regeneration, we hypothesized calcium might play a critical regulatory role in the CED-3/CED-4 repair pathway. We used the calcium reporter cameleon to track in vivo calcium fluxes in the axotomized neuron. We show that when the endoplasmic reticulum calcium-storing chaperone calreticulin, CRT-1, is deleted, both calcium dynamics and initial regenerative outgrowth are impaired. Genetic data suggest that CED-3, CED-4, and CRT-1 act in the same pathway to promote early events in regeneration and that CED-3 might act downstream of CRT-1, but upstream of the conserved DLK-1 kinase implicated in regeneration across species. This study documents reconstructive roles for proteins known to orchestrate apoptotic death and links previously unconnected observations in the vertebrate literature to suggest a similar pathway may be conserved in higher organisms.

Optimal perfusion computed tomographic thresholds for ischemic core and penumbra are not time dependent in the clinically relevant time window.

BACKGROUND AND PURPOSE: This study aims to determine whether perfusion computed tomographic (PCT) thresholds for delineating the ischemic core and penumbra are time dependent or time independent in patients presenting with symptoms of acute stroke. METHODS: Two hundred seventeen patients were evaluated in a retrospective, multicenter study. Patients were divided into those with either persistent occlusion or recanalization. All patients received admission PCT and follow-up imaging to determine the final ischemic core, which was then retrospectively matched to the PCT images to identify optimal thresholds for the different PCT parameters. These thresholds were assessed for significant variation over time since symptom onset. RESULTS: In the persistent occlusion group, optimal PCT parameters that did not significantly change with time included absolute mean transit time, relative mean transit time, relative cerebral blood flow, and relative cerebral blood volume when time was restricted to 15 hours after symptom onset. Conversely, the recanalization group showed no significant time variation for any PCT parameter at any time interval. In the persistent occlusion group, the optimal threshold to delineate the total ischemic area was the relative mean transit time at a threshold of 180%. In patients with recanalization, the optimal parameter to predict the ischemic core was relative cerebral blood volume at a threshold of 66%. CONCLUSIONS: Time does not influence the optimal PCT thresholds to delineate the ischemic core and penumbra in the first 15 hours after symptom onset for relative mean transit time and relative cerebral blood volume, the optimal parameters to delineate ischemic core and penumbra.

Automating literature screening and curation with applications to computational neuroscience.

OBJECTIVE: ModelDB (https://modeldb.science) is a discovery platform for computational neuroscience, containing over 1850 published model codes with standardized metadata. These codes were mainly supplied from unsolicited model author submissions, but this approach is inherently limited. For example, we estimate we have captured only around one-third of NEURON models, the most common type of models in ModelDB. To more completely characterize the state of computational neuroscience modeling work, we aim to identify works containing results derived from computational neuroscience approaches and their standardized associated metadata (eg, cell types, research topics). MATERIALS AND METHODS: Known computational neuroscience work from ModelDB and identified neuroscience work queried from PubMed were included in our study. After pre-screening with SPECTER2 (a free document embedding method), GPT-3.5, and GPT-4 were used to identify likely computational neuroscience work and relevant metadata. RESULTS: SPECTER2, GPT-4, and GPT-3.5 demonstrated varied but high abilities in identification of computational neuroscience work. GPT-4 achieved 96.9% accuracy and GPT-3.5 improved from 54.2% to 85.5% through instruction-tuning and Chain of Thought. GPT-4 also showed high potential in identifying relevant metadata annotations. DISCUSSION: Accuracy in identification and extraction might further be improved by dealing with ambiguity of what are computational elements, including more information from papers (eg, Methods section), improving prompts, etc. CONCLUSION: Natural language processing and large language model techniques can be added to ModelDB to facilitate further model discovery, and will contribute to a more standardized and comprehensive framework for establishing domain-specific resources.

Design of a compact and portable space neutron spectrometer based on Monte Carlo.

With the rapid development of space exploration, the detection of space neutron radiation is becoming increasingly important. The currently widely used Bonner sphere spectrometer have drawbacks such as large size and weight, as well as low fault tolerance, when detecting space neutron spectra. This paper describes in detail a new type of space neutron spectrometer (SNS), which has two different specifications to adapt to the directional and non-directional neutron field environment, and can measure the directional neutron energy spectrum. For the directed neutron field, SNS integrates 12 3He thermal neutron counters (diameter 3 cm: 3, diameter 4 cm: 6, diameter 5 cm: 3) and uses cylindrical polyethylene as a moderator. For non-directed neutron fields, SNS integrates 9 3He thermal neutron counters (diameter 3 cm: 4, diameter 4 cm: 3, diameter 5 cm: 2) located in a single structure made of polyethylene, boron-containing polyethylene and gadolinium. The device is capable of providing a strong directional response in the energy range of thermal neutrons up to 20 MeV, with little sensitivity to neutrons coming from directions other than the axis of the cylinder. The Monte Carlo transport code FLUKA was used to determine the final configuration of the instrument, including the arrangement, number, and position of thermal neutron counters. In addition, the response matrix of the instrument was calculated using FLUKA code. This device can replace traditional Bonner sphere spectrometer for measuring space neutrons, and it also provides reference value for downsized and lightweight neutron spectrometers on the ground.

Fission cross-section measurements for the 238U(n,f)97m+gNb, 238U(n,f)133gTe and 238U(n,f)130gSb reactions induced by D-T neutrons.

In this study, we conducted measurements of the independent fission cross-sections of 238U(n, f)97m+gNb, 238U(n, f)133gTe reactions and the cumulative cross section of 238U(n, f)130gSb reactions induced by neutron at energies around 14 MeV, i.e., 14.1 ± 0.3, 14.5 ± 0.3 and 14.7 ± 0.3 MeV. The measurement results were obtained by the neutron activation method in combination with off-line γ-ray spectrometry techniques. The neutron flux was monitored on line by the accompanying α-particle from T(d, n)4He reaction, and the neutron energies were determined by the cross-section ratio of 90Zr(n, 2n)8+gZr to 93Nb(n, 2n)92mNb reactions. The independent fission cross-sections of the fission reactions were obtained by subtracting the influence of precursor nuclei or excited states. The obtained results are as follows: for 238U(n, f)97m+gNb, the independent cross sections are 1.0 ± 0.89, 0.98 ± 0.85 and 0.78 ± 0.70 mb at the specified neutron energy points. For 238U(n, f)133gTe, the independent fission cross-sections are 26.8 ± 2.8, 27.7 ± 2.9 and 20.5 ± 2.3 mb, respectively, at the same neutron energy points. As for 238U(n, f)130gSb, the obtained cumulative fission cross-sections are 5.35 ± 0.58, 5.05 ± 0.53 and 4.03 ± 0.44 mb, respectively, at the specified neutron energy points.

Up-regulation of HSP90α in HDM-induced asthma causes pyroptosis of airway epithelial cells by activating the cGAS-STING-ER stress pathway.

Heat Shock protein 90 α (HSP90α), an main subtype of chaperone protein HSP90, involves important biological functions such as DNA damage repair, protein modification, innate immunity. However, the potential role of HSP90α in asthma occurrence and development is still unclear. This study aimed to elucidate the underlying mechanism of HSP90α in asthma by focusing on the cGAS-STING-Endoplasmic Reticulum stress pathway in inflammatory airway epithelial cell death (i.e., pyroptosis; inflammatory cell death). To accomplish that, we modeled allergen exposure in C57/6BL mice and bronchial epithelial cells with house dust mite. Protein technologies and immunofluorescence utilized to study the expression of HSP90α, activation of cGAS-STING pathway and pyroptosis. The effect of inhibitors on HDM-exposed mice detected by histological techniques and examination of bronchoalveolar lavage fluid. Results showed that HSP90α promotes asthma inflammation via pyroptosis and activation of the cGAS-STING-ER stress pathway. Treatment with the HSP90 inhibitor tanespimycin (17-AAG) significantly relieved airway inflammation and abrogated the effect of HSP90α on pyroptosis and cGAS-STING-ER stress in vitro and in vivo models of HDM. Further data indicated that up-regulation of HSP90α stabilized STING through interaction, which increased localization of STING on the ER. Activation of STING triggered ER stress and leaded to pyroptosis-related airway inflammation. The finding showed the potential role of pyroptosis caused by dysregulation of HSP90α on airway epithelial cells in allergic inflammation, suggested that targeting HSP90α in airway epithelial cells might prove to be a potential additional treatment strategy for asthma.

Corrigendum: Extracellular HSP90α interacts with ER stress to promote fibroblasts activation through PI3K/AKT pathway in pulmonary fibrosis.

[This corrects the article DOI: 10.3389/fphar.2021.708462.].

Optimization design of the portable cylindrical water injection multilayer neutron spectrometer.

The currently widely used multi-sphere neutron spectrometers still have many drawbacks, including complex design and processing, the need for multiple moderating spheres, high costs, large volumes, and complicated measurement procedures. This work proposes the portable cylindrical water injection multilayer neutron spectrometer (CWNS) as a promising alternative based on water pumping injection. The structure of CWNS consists of a central thermal neutron detector and a surrounding 6-layer of coaxial cylindrical water bags with varying diameters. During non-measurement periods, this CWNS is convenient to carry due to the absence of the need to inject moderating water. To optimize the CWNS design, we employed FLUKA simulation software to study and refine various parameters, including the thickness of the water bag, the material composition of the water bag, and the parameters of the supporting column. We finally achieved an optimized design. Specifically, the water bag of the CWNS is constructed using a 0.3 mm thick polyethylene film. The supporting column for the water bag is made of aluminum, providing stability and support to the overall structure. These optimized design parameters determine the specific size and configuration of the CWNS. The CWNS offers the benefits of convenient carrying, simplified processing, cost-effectiveness, and straightforward measurement. It has a promising potential use for the directional neutron dose monitoring.

A Versatile Hydrogel with Antibacterial and Sequential Drug-Releasing Capability for the Programmable Healing of Infectious Keratitis.

Hydrogels have attracted tremendous attention as favorable corneal substitutes for treating severe infectious keratitis (IK). However, current hydrogel-based corneal substitutes were majorly designed to promote the single stage of corneal regeneration, which falls short in meeting the clinical management needs of severe IK including the multiple phases of corneal wound healing. Herein, we introduce a versatile hybrid hydrogel (SQPV) composed of silk fibroin and chitosan, which exhibits spatiotemporal properties for drug release. The SQPV is fabricated by incorporating verteporfin-loaded poly(lactic-co-glycolic)-polyethylene glycol-o-nitrobenzene micelles into a hydrogel network, which is formed from methacrylate silk fibroin and glycidyl methacrylate functionalized quaternized chitosan containing polydeoxyribonucleotide. This double network approach results in a material with exceptional anti-inflammatory, antibacterial, and proliferative stimulation and tissue remodeling regulation capabilities. Furthermore, SQPV showcases mechanical strength and transparency akin to those of native cornea. Extensive in vitro and in vivo studies validate SQPV's ability to effectively eliminate residual bacteria, mitigate inflammation, foster regeneration of corneal epithelium and stroma, prevent corneal scarring, and ultimately expedite wound healing. In summary, the SF/CS-based hybrid hydrogel may represent a promising substitute for comprehensive corneal repair and regeneration in severe IK.

ECM-Like Adhesive Hydrogel for the Regeneration of Large Corneal Stromal Defects.

The repair of large-diameter corneal stroma defects is a major clinical problem. Although some studies have attempted to use hydrogels to repair corneal damage, most of these hydrogels can only be used for focal stromal defects that are ≤3.5 mm in diameter due to poor hydrogel adhesion. Here, a photocurable adhesive hydrogel that mimics the extracellular matrix (ECM) with regard to composition for repairing 6 mm-diameter corneal stromal defects in rabbits is investigated. This ECM-like adhesive can be rapidly cured after light exposure, with high light transmittance and good mechanical properties. More importantly, this hydrogel maintains the viability and adhesion of cornea-derived cells and promotes their migration in vitro in 2D and 3D culture environments. Proteomics analysis confirms that the hydrogel promotes cell proliferation and ECM synthesis. Furthermore, in rabbit corneal stromal defect repair experiments, it is proven by histological and proteomic analysis that this hydrogel can effectively promote corneal stroma repair, reduce scar formation, and increase corneal stromal-neural regeneration at the six months follow-up. This work demonstrates the great application of ECM-like adhesive hydrogels for the regeneration of large-diameter corneal defects.

RNF130 protects against pulmonary fibrosis through suppressing aerobic glycolysis by mediating c-myc ubiquitination.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease,characterized by an excessive accumulation of extracellular matrix (ECM) proteins in response to chronic lung injury. Current evidence suggests that metabolic reprogramming is always accompanied by myofibroblast activation in IPFof whichthe underlying mechanisms remain unclear. Ring finger protein 130 (RNF130), was demonstrated involved in multiple diseases. However, whether RNF130 plays a critical role in the pathogenesis of IPF needs to be clarified. METHODS: We first investigated the expression of RNF130 in pulmonary fibrosis in vivo and in vitro. We then observed the effect and explored the molecular mechanism of RNF130 on the transition of fibroblast to myofibroblast and aerobic glycolysis. Further, we assessed the effects of adeno-associated virus (AAV)-induced RNF130 overexpression in the pulmonary fibrosis model, conducting pulmonary function, assessment of collagen depositionusing the hydroxyproline assay, and biochemical and histopathological analyses. RESULTS: We found that RNF130 was down-regulated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-ß1 (TGF-ß1). Then we demonstrated that RNF130 inhibitedthe transition of fibroblast to myofibroblast by suppressing aerobic glycolysis. Mechanistically, we revealed that RNF130 promotedc-myc ubiquitination and degradation, while c-myc overexpression reverses the inhibitory effects of RNF130. Importantly, pulmonary function, collagen deposition and fibroblast differentiation were significantly alleviated in adeno-associated virus serotype (AAV)6-RNF130 treated mice, which further validated the contribution of RNF130/c-myc signaling axis in pulmonary fibrosis pathological process. CONCLUSIONS: In summary, RNF130 participates in the pathogenesis of pulmonary fibrosis by inhibiting the transition of fibroblast to myofibroblast and aerobic glycolysis through promoting c-myc ubiquitination and degradation. Targeting RNF130-c-myc axismightrepresent a promising strategy to alleviate the progression of IPF.