Tetrahedral framework nucleic acid-based small-molecule inhibitor delivery for ecological prevention of biofilm.

Biofilm formation constitutes the primary cause of various chronic infections, such as wound infections, gastrointestinal inflammation and dental caries. While preliminary achievement of biofilm inhibition is possible, the challenge lies in the difficulty of eliminating the bactericidal effects of current drugs that lead to microbiota imbalance. This study, utilizing in vitro and in vivo models of dental caries, aims to efficiently inhibit biofilm formation without inducing bactericidal effects, even against pathogenic bacteria. The tetrahedral framework nucleic acid (tFNA) was employed as a delivery vector for a small-molecule inhibitor (smI) specifically targeting the activity of glucosyltransferases C (GtfC). It was observed that tFNA loaded smI in a small-groove binding manner, efficiently transferring it into Streptococcus mutans, thereby inhibiting GtfC activity and extracellular polymeric substances formation without compromising bacterial survival. Furthermore, smI-loaded tFNA demonstrated a reduction in the severity of dental caries in vivo without adversely affecting oral microbial diversity and exhibited desirable topical and systemic biosafety. This study emphasizes the concept of 'ecological prevention of biofilm', which is anticipated to advance the optimization of biofilm prevention strategies and the clinical application of DNA nanocarrier-based drug formulations.

ISR inhibition reverses pancreatic ß-cell failure in Wolfram syndrome models.

Pancreatic ß-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of ß cell specific Wfs1 knockout were applied to model ß-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS ß-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted ß-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to ß-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS ß-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed ß-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with ß-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.

Artificial intelligence in liver imaging: methods and applications.

Liver disease is regarded as one of the major health threats to humans. Radiographic assessments hold promise in terms of addressing the current demands for precisely diagnosing and treating liver diseases, and artificial intelligence (AI), which excels at automatically making quantitative assessments of complex medical image characteristics, has made great strides regarding the qualitative interpretation of medical imaging by clinicians. Here, we review the current state of medical-imaging-based AI methodologies and their applications concerning the management of liver diseases. We summarize the representative AI methodologies in liver imaging with focusing on deep learning, and illustrate their promising clinical applications across the spectrum of precise liver disease detection, diagnosis and treatment. We also address the current challenges and future perspectives of AI in liver imaging, with an emphasis on feature interpretability, multimodal data integration and multicenter study. Taken together, it is revealed that AI methodologies, together with the large volume of available medical image data, might impact the future of liver disease care.

Metformin-Loaded Chitosan Hydrogels Suppress Bladder Tumor Growth in an Orthotopic Mouse Model via Intravesical Administration.

Our previous study found that the intravesical perfusion of metformin has excellent inhibitory effects against bladder cancer (BC). However, this administration route allows the drug to be diluted and excreted in urine. Therefore, increasing the adhesion of metformin to the bladder mucosal layer may prolong the retention time and increase the pharmacological activity. It is well known that chitosan (Cs) has a strong adhesion to the bladder mucosal layer. Thus, this study established a novel formulation of metformin to enhance its antitumor activity by extending its retention time. In this research, we prepared Cs freeze-dried powder and investigated the effect of metformin-loaded chitosan hydrogels (MLCH) in vitro and in vivo. The results showed that MLCH had a strong inhibitory effect against proliferation and colony formation in vitro. The reduction in BC weight and the expression of tumor biomarkers in orthotopic mice showed the robust antitumor activity of MLCH via intravesical administration in vivo. The non-toxic profile of MLCH was observed as well, using histological examinations. Mechanistically, MLCH showed stronger functional activation of the AMPKα/mTOR signaling pathway compared with metformin alone. These findings aim to make this novel formulation an efficient candidate for managing BC via intravesical administration.

Charting a high-resolution roadmap for regeneration of pancreatic ß cells by in vivo transdifferentiation from adult acinar cells.

Adult mammals have limited capacity to regenerate functional cells. Promisingly, in vivo transdifferentiation heralds the possibility of regeneration by lineage reprogramming from other fully differentiated cells. However, the process of regeneration by in vivo transdifferentiation in mammals is poorly understood. Using pancreatic ß cell regeneration as a paradigm, we performed a single-cell transcriptomic study of in vivo transdifferentiation from adult mouse acinar cells to induced ß cells. Using unsupervised clustering analysis and lineage trajectory construction, we uncovered that the cell fate remodeling trajectory was linear at the initial stage and the reprogrammed cells either evolved to induced ß cells or toward a "dead-end" state after day 4.Moreover, functional analyses identified both p53 and Dnmt3a that acted as reprogramming barriers during the process of in vivo transdifferentiation. Collectively, we decipher a high-resolution roadmap of regeneration by in vivo transdifferentiation and provide a detailed molecular blueprint to facilitate mammalian regeneration.

Preparation and Properties of a Novel Biodegradable Composite Hydrogel Derived from Gelatin/Chitosan and Polylactic Acid as Slow-Release N Fertilizer.

To improve the efficient use of nitrogen and decrease the environmental pollution of N losses, a novel and biodegradable composite hydrogel was prepared by chemical cross-linking synthesis using gelatin (Gel), chitosan (CS) and polylactic acid (PLA) as raw materials. Urea as the nitrogen source was loaded into this new biodegradable hydrogel using the solution immersion method. The chemical structures of the composite hydrogels were characterized and their properties were analyzed by XRD and XPS. The regulation of urea loading and the swelling behavior of the composite hydrogel under different temperature conditions were investigated; the release behavior and release model of the composite hydrogel in the aqueous phase was explored. The results show that the loading of urea is controllable in aqueous urea solution with different concentrations. In the water phase, it shows a three-stage sustained release behavior, that is, the initial release rate of urea is relatively fast, and the medium release rate of urea gradually slows down, and finally the nutrient release rate tends to be flat. The release behavior in the water phase fits to the Ritger-Peppas model. Within 10 min, 180 min and 900 min, the cumulative nutrient release rate of gelatin/chitosan/PLA-urea (GCPU) composite hydrogel is 20%, 70% and 86%, respectively. Compared with pure urea, The urea diffusion time of GCPU was extended by 1350-times. In addition, the GCPU also has good water absorption and water retention properties, in which average water content can reach as high as 4448%. All of the results in this work showed that GCPU hydrogel had good water absorption and retention and N slow-release properties, which are expected to be widely used in sustainable agriculture and forestry, especially in arid and degraded land.

Nanoscale Treatment of Intervertebral Disc Degeneration: Mesenchymal Stem Cell Exosome Transplantation.

A common surgical disease, intervertebral disc degeneration (IVDD), is increasing at an alarming rate in younger individuals. Repairing damaged intervertebral discs (IVDs) and promoting IVD tissue regeneration at the molecular level are important research goals.Exosomes are extracellular vesicles (EVs) secreted by cells and can be derived from most body fluids. Mesenchymal stem cell-derived exosomes (MSC-exos) have characteristics similar to those of the parental MSCs. These EVs can shuttle various macromolecular substances, such as proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs) and regulate the activity of recipient cells through intercellular communication. Reducing inflammation and apoptosis can significantly promote IVD regeneration to facilitate the repair of the IVD. Compared with MSCs, exosomes are more convenient to store and transport, and the use of exosomes can prevent the risk of rejection with cell transplantation. Furthermore, MSC-exo-mediated treatment may be safer and more effective than MSC transplantation. In this review, we summarize the use of bone marrow mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (AMSCs), nucleus pulposus mesenchymal stem cells (NPMSCs), and stem cells from other sources for tissue engineering and use in IVDD. Here, we aim to describe the role of exosomes in inhibiting IVDD, their potential therapeutic effects, the results of the most recent research, and their clinical application prospects to provide an overview for researchers seeking to explore new treatment strategies and improve the efficacy of IVDD treatment.

Shareholder personal risk and firm risk: An empirical analysis of share pledges and firm debt policies.

The impact of personal risk caused by controlling shareholders' equity pledges on the company's debt policy is an issue worth exploring. Using Chinese A-share listed companies from 2006 to 2020, this paper studies the impact of ultimate owner equity pledges on firm debt size and debt maturity structure and explores the mechanism of ultimate owner personal leverage on firms. The results show that the increase in ultimate owner stock pledges leads to higher financial leverage and a longer debt maturity structure for the company. In addition, the study reveals that the high personal leverage of the ultimate owner of the pledged equity is an influential mechanism driving the transfer of personal risk to the firm. In particular, even if a company's actual debt ratio is higher than its target debt ratio, equity pledges can prompt listed companies to increase their debt ratios and debt maturities, causing them to take on excessive debt risk and transfer the risk to creditors. It follows that the tunneling effect is a driving force of equity pledging and corporate debt policies. These results remain robust after the robustness test and endogenous test. The conclusions of this paper not only emphasize the impact of shareholders' personal risk on the firm but also provide a reference for investors' perception of firm risk.

Evaluating breast ultrasound S-detect image analysis for small focal breast lesions.

Background: S-Detect is a computer-assisted, artificial intelligence-based system of image analysis that has been integrated into the software of ultrasound (US) equipment and has the capacity to independently differentiate between benign and malignant focal breast lesions. Since the revision and upgrade in both the breast imaging-reporting and data system (BI-RADS) US lexicon and the S-Detect software in 2013, evidence that supports improved accuracy and specificity of radiologists' assessment of breast lesions has accumulated. However, such assessment using S-Detect technology to distinguish malignant from breast lesions with a diameter no greater than 2 cm requires further investigation. Methods: The US images of focal breast lesions from 295 patients in our hospital from January 2019 to June 2022 were collected. The BI-RADS data were evaluated by the embedded program and as manually modified prior to the determination of a pathological diagnosis. The receiver operator characteristic (ROC) curves were constructed to compare the diagnostic accuracy between the assessments of the conventional US images, the S-Detect classification, and the combination of the two. Results: There were 326 lesions identified in 295 patients, of which pathological confirmation demonstrated that 239 were benign and 87 were malignant. The sensitivity, specificity, and accuracy of the conventional imaging group were 75.86%, 93.31%, and 88.65%. The sensitivity, specificity, and accuracy of the S-Detect classification group were 87.36%, 88.28%, and 88.04%, respectively. The assessment of the amended combination of S-Detect with US image analysis (Co-Detect group) was improved with a sensitivity, specificity, and accuracy of 90.80%, 94.56%, and 93.56%, respectively. The diagnostic accuracy of the conventional US group, the S-Detect group, and the Co-Detect group using area under curves was 0.85, 0.88 and 0.93, respectively. The Co-Detect group had a better diagnostic efficiency compared with the conventional US group (Z = 3.882, p = 0.0001) and the S-Detect group (Z = 3.861, p = 0.0001). There was no significant difference in distinguishing benign from malignant small breast lesions when comparing conventional US and S-Detect techniques. Conclusions: The addition of S-Detect technology to conventional US imaging provided a novel and feasible method to differentiate benign from malignant small breast nodules.

New Hope for Treating Intervertebral Disc Degeneration: Microsphere-Based Delivery System.

Intervertebral disc (IVD) degeneration (IVDD) has been considered the dominant factor in low back pain (LBP), and its etiological mechanisms are complex and not yet fully elucidated. To date, the treatment of IVDD has mainly focused on relieving clinical symptoms and cannot fundamentally solve the problem. Recently, a novel microsphere-based therapeutic strategy has held promise for IVD regeneration and has yielded encouraging results with in vitro experiments and animal models. With excellent injectability, biocompatibility, and biodegradability, this microsphere carrier allows for targeted delivery and controlled release of drugs, gene regulatory sequences, and other bioactive substances and supports cell implantation and directed differentiation, aiming to improve the disease state of IVD at the source. This review discusses the possible mechanisms of IVDD and the limitations of current therapies, focusing on the application of microsphere delivery systems in IVDD, including targeted delivery of active substances and drugs, cellular therapy, and gene therapy, and attempts to provide a new understanding for the treatment of IVDD.

Aggressive strategies for regenerating intervertebral discs: stimulus-responsive composite hydrogels from single to multiscale delivery systems.

As our research on the physiopathology of intervertebral disc degeneration (IVD degeneration, IVDD) has advanced and tissue engineering has rapidly evolved, cell-, biomolecule- and nucleic acid-based hydrogel grafting strategies have been widely investigated for their ability to overcome the harsh microenvironment of IVDD. However, such single delivery systems suffer from excessive external dimensions, difficult performance control, the need for surgical implantation, and difficulty in eliminating degradation products. Stimulus-responsive composite hydrogels have good biocompatibility and controllable mechanical properties and can undergo solution-gel phase transition under certain conditions. Their combination with ready-to-use particles to form a multiscale delivery system may be a breakthrough for regenerative IVD strategies. In this paper, we focus on summarizing the progress of research on the stimulus response mechanisms of regenerative IVD-related biomaterials and their design as macro-, micro- and nanoparticles. Finally, we discuss multi-scale delivery systems as bioinks for bio-3D printing technology for customizing personalized artificial IVDs, which promises to take IVD regenerative strategies to new heights.

The role of EphA7 in different tumors

Ephrin receptor A7 (EphA7) is a member of the Eph receptor family. It is widely involved in signal transduction between cells, regulates cell proliferation and differentiation, and participates in developing neural tubes and brain. In addition, EphA7 also has a dual role of tumor promoter and tumor suppressor. It can participate in cell proliferation, migration and apoptosis through various mechanisms, and affect tumor differentiation, staging and prognosis. EphA7 may be a potential diagnostic marker and tumor treatment target. This article reviews the effects of EphA7 on a variety of tumor biological processes and pathological characteristics, as well as specific effects and regulatory mechanisms.

A Fullerene-Platinum Complex for Direct Functional Patterning of Single Metal Atom-Embedded Carbon Nanostructures.

The development of patterning materials ("resists") at the nanoscale involves two distinct trends: one is toward high sensitivity and resolution for miniaturization, the other aims at functionalization of the resists to realize bottom-up construction of distinct nanoarchitectures. Patterning of carbon nanostructures, a seemingly ideal application for organic functional resists, has been highly reliant on complicated pattern transfer processes because of a lack of patternable precursors. Herein, we present a fullerene-metal coordination complex as a fabrication material for direct functional patterning of sub-10 nm metal-containing carbon structures. The attachment of one platinum atom per fullerene molecule not only leads to significant improvement of sensitivity and resolution but also enables stable atomic dispersion of the platinum ions within the carbon matrix, which may gain fundamentally new interest in functional patterning of hierarchical carbon nanostructures.

The role of EphA7 in different tumors.

Ephrin receptor A7 (EphA7) is a member of the Eph receptor family. It is widely involved in signal transduction between cells, regulates cell proliferation and differentiation, and participates in developing neural tubes and brain. In addition, EphA7 also has a dual role of tumor promoter and tumor suppressor. It can participate in cell proliferation, migration and apoptosis through various mechanisms, and affect tumor differentiation, staging and prognosis. EphA7 may be a potential diagnostic marker and tumor treatment target. This article reviews the effects of EphA7 on a variety of tumor biological processes and pathological characteristics, as well as specific effects and regulatory mechanisms.

TRIP13 knockdown inhibits the proliferation, migration, invasion, and promotes apoptosis by suppressing PI3K/AKT signaling pathway in U2OS cells.

BACKGROUND: Although osteosarcoma (OS) is the most common malignant bone tumor, the biological mechanism underlying its incidence and improvement remains unclear. This study investigated early diagnosis and treatment objectives using bioinformatics strategies and performed experimental verification. METHODS AND RESULTS: The top 10 OS hub genes-CCNA2, CCNB1, AURKA, TRIP13, RFC4, DLGAP5, NDC80, CDC20, CDK1, and KIF20A-were screened using bioinformatics methods. TRIP13 was chosen for validation after reviewing literature. TRIP13 was shown to be substantially expressed in OS tissues and cells, according to Western blotting (WB) and quantitative real-time polymerase chain reaction data. Subsequently, TRIP13 knockdown enhanced apoptosis and decreased proliferation, migration, and invasion in U2OS cells, as validated by the cell counting kit-8 test, Hoechst 33,258 staining, wound healing assay, and WB. In addition, the levels of p-PI3K/PI3K and p-AKT/AKT in U2OS cells markedly decreased after TRIP13 knockdown. Culturing U2OS cells, in which TRIP13 expression was downregulated, in a medium supplemented with a PI3K/AKT inhibitor further reduced their proliferation, migration, and invasion and increased their apoptosis. CONCLUSIONS: TRIP13 knockdown reduced U2OS cell proliferation, migration, and invasion via a possible mechanism involving the PI3K/AKT signaling pathway.

HIT 2.0: an enhanced platform for Herbal Ingredients' Targets.

Literature-described targets of herbal ingredients have been explored to facilitate the mechanistic study of herbs, as well as the new drug discovery. Though several databases provided similar information, the majority of them are limited to literatures before 2010 and need to be updated urgently. HIT 2.0 was here constructed as the latest curated dataset focusing on Herbal Ingredients' Targets covering PubMed literatures 2000-2020. Currently, HIT 2.0 hosts 10 031 compound-target activity pairs with quality indicators between 2208 targets and 1237 ingredients from more than 1250 reputable herbs. The molecular targets cover those genes/proteins being directly/indirectly activated/inhibited, protein binders, and enzymes substrates or products. Also included are those genes regulated under the treatment of individual ingredient. Crosslinks were made to databases of TTD, DrugBank, KEGG, PDB, UniProt, Pfam, NCBI, TCM-ID and others. More importantly, HIT enables automatic Target-mining and My-target curation from daily released PubMed literatures. Thus, users can retrieve and download the latest abstracts containing potential targets for interested compounds, even for those not yet covered in HIT. Further, users can log into 'My-target' system, to curate personal target-profiling on line based on retrieved abstracts. HIT can be accessible at http://hit2.badd-cao.net.

New Hope for Intervertebral Disc Degeneration: Bone Marrow Mesenchymal Stem Cells and Exosomes Derived from Bone Marrow Mesenchymal Stem Cell Transplantation.

Bone Marrow Mesenchymal Stem Cells (BMSCs), multidirectional cells with self-renewal capacity, can differentiate into many cell types and play essential roles in tissue healing and regenerative medicine. Cell experiments and in vivo research in animal models have shown that BMSCs can repair degenerative discs by promoting cell proliferation and expressing Extracellular Matrix (ECM) components, such as type II collagen and protein-polysaccharides. Delaying or reversing the Intervertebral Disc Degeneration (IDD) process at an etiological level may be an effective strategy. However, despite increasingly in-depth research, some deficiencies in cell transplantation timing and strategy remain, preventing the clinical application of cell transplantation. Exosomes exhibit the characteristics of the mother cells from which they are secreted and can inhibit Nucleus Pulposus Cell (NPC) apoptosis and delay IDD through intercellular communication. Furthermore, the use of exosomes effectively avoids problems associated with cell transplantation, such as immune rejection. This manuscript introduces almost all of the BMSCs and exosomes derived from BMSCs (BMSCs-Exos) described in the IDD literature. Many challenges regarding the use of cell transplantation and therapeutic exosome intervention for IDD remain to be overcome.