Pore-Specific Anisotropic Etching of Zeolitic Imidazolate Frameworks by Carboxylic Acid Vapors.

Anisotropic etching is a powerful way to customize metal-organic frameworks with advanced nanostructures, but it is still in its infancy. Herein, we proposed an unprecedented etching strategy that created anisotropic hollow structures in various zeolitic imidazolate framework (ZIF) nano/single crystals via pore-specific carving. The etching occurred through a newly discovered gas-solid reaction where carboxylic acid vapors bind with ligands in ZIFs at room temperature to form ionic liquid (IL). A series of experiments were conducted to decode the origin of anisotropy and the "hollowing out" effect. We found that large pore openings on {111} facets provide access for the entry of carboxylic acid vapors and the outflow of the IL, resulting in pore-dependent anisotropy features. The unique "etching after adsorption" mechanism and the adsorption capacity of the IL enable acid vapors to hollow out nanocrystals and even single crystals. By altering carboxylic acids and ligands in ZIFs, the etching process can be precisely tuned from the inside out or the outside in. This new method demonstrates broad universality and brings unprecedented morphologies and complexities. It may offer great opportunities for achieving purposeful modification of ZIFs and the rational construction of intricate architectures.

The differentiation of Lgr5+ progenitor cells on nanostructures of self-assembled silica beads.

Supporting cells(SCs) have been demonstrated to be a reliable source for regenerating hair cells(HCs). Previous research has reported that Lgr5+ SCs can regenerate HCs both in vitro and in vivo. However, there is limited knowledge about the impact of the material on Lgr5+ cells. In this study, Lgr5+ cells were isolated from neonatal Lgr5-EGFP-CreERT2 transgenic mice by flow cytometry and then plated on self-assembled silica beads (SB). Lgr5+ cell differentiation was observed by immunofluorescence. We found that in the direct differentiation assay, the SB group generated more hair cells than the control group(*p < 0.05). Especially in the SB group, Lgr5+ progenitors generated significantly more Myo7a+ HCs outside of the colony than in the control group(**p < 0.01). In the sphere differentiation assay, we found that the diameter of spheres in the SB group was significantly larger compared to those of the control group(**p < 0.01). However, the difference in the ratio of myo7a+ cell counts was not obvious(P>0.05). The experiment proved that the self-assembled silica beads could promote the differentiation of Lgr5+ progenitors in vitro. Our findings implicate that nanostructures of self-assembled silica beads can be used as vectors for stem cell research in the inner ear.

Exploring the association between grip strength and adverse pregnancy and perinatal outcomes: A Mendelian randomization study.

Background: Previous observational studies have demonstrated an association between grip strength and detrimental pregnancy and perinatal outcomes. However, the causality of this relationship remains uncertain. Objective: This study aims to investigate if there is a causal relationship between grip strength and adverse pregnancy and perinatal outcomes, providing evidence to support active intervention for adverse pregnancy outcomes. Study design: A two-sample Mendelian randomization method was used to select GWAS data from the UK Biobank and the FinnGen Biobank as data sources. The inverse variance weighting method was used as the main analysis method. The reliability of the results was verified through sensitivity analysis, including Cochran's Q test, MR-egger intercept regression analysis, leave-one-out analysis, and funnel plot. Independent queues are also used to verify the reliability of the results. Results: The study demonstrated a significant positive correlation between genetically predicted hand grip strength and offspring birth weight, specifically left-hand grip strength (ß = 0.193, 95 % CI: 0.099-0.286, p = 0.0001) and right-hand grip strength (ß = 0.310, 95 % CI: 0.235-0.384, p = 3.27E-16). Sensitivity analysis indicated no horizontal multi-effect, and leave-one-out analysis along with the funnel plot showed no abnormalities. The verification queue also yielded similar results. Conclusion: This study revealed a significant association between grip strength-related traits and offspring birth weight, suggesting a potential protective effect. Moreover, a negative predictive trend was observed for other adverse pregnancy outcomes. Modifying grip strength through an active lifestyle and continuous monitoring of pregnant women's grip strength may have implications for improving pregnancy outcomes. However, further research is warranted to investigate these findings more comprehensively.

Causal impact of human blood metabolites and metabolic pathways on serum uric acid and gout: a mendelian randomization study.

Objective: Hyperuricaemia and gout are common metabolic disorders. However, the causal relationships between blood metabolites and serum urate levels, as well as gout, remain unclear. A systematic evaluation of the causal connections between blood metabolites, hyperuricemia, and gout could enhance early screening and prevention of hyperuricemia and gout in clinical settings, providing novel insights and approaches for clinical treatment. Methods: In this study, we employed a bidirectional two-sample Mendelian randomization analysis utilizing data from a genome-wide association study involving 7,286 participants, encompassing 486 blood metabolites. Serum urate and gout data were sourced from the Chronic Kidney Disease Genetics consortium, including 288,649 participants for serum urate and 9,819 African American and 753,994 European individuals for gout. Initially, LDSC methodology was applied to identify blood metabolites with a genetic relationship to serum urate and gout. Subsequently, inverse-variance weighting was employed as the primary analysis method, with a series of sensitivity and pleiotropy analyses conducted to assess the robustness of the results. Results: Following LDSC, 133 blood metabolites exhibited a potential genetic relationship with serum urate and gout. In the primary Mendelian randomization analysis using inverse-variance weighting, 19 blood metabolites were recognized as potentially influencing serum urate levels and gout. Subsequently, the IVW p-values of potential metabolites were corrected using the false discovery rate method. We find leucine (IVW P FDR = 0.00004), N-acetylornithine (IVW P FDR = 0.0295), N1-methyl-3-pyridone-4-carboxamide (IVW P FDR = 0.0295), and succinyl carnitine (IVW P FDR = 0.00004) were identified as significant risk factors for elevated serum urate levels. Additionally, 1-oleoylglycerol (IVW P FDR = 0.0007) may lead to a substantial increase in the risk of gout. Succinyl carnitine exhibited acceptable weak heterogeneity, and the results for other blood metabolites remained robust after sensitivity, heterogeneity, and pleiotropy testing. We conducted an enrichment analysis on potential blood metabolites, followed by a metabolic pathway analysis revealing four pathways associated with serum urate levels. Conclusion: The identified causal relationships between these metabolites and serum urate and gout offer a novel perspective, providing new mechanistic insights into serum urate levels and gout.

Differential distribution of characteristic constituents in peel and pulp of Aurantii Fructus Immaturus (Citrus aurantium L.) using MALDI mass spectrometry imaging.

Aurantii Fructus Immaturus (AFI) was structurally divided into two parts named "peel" and "pulp". The exocarp and mesocarp of materials named "peel". The endocarp separated into multiple compartments and the cystic hair attached to it named "pulp". In order to explore the distribution and content of constituents in AFI, an efficient method to explore the distribution of constituents was developed based on matrix assisted laser desorption/ionization fourier transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI). After simple processing, thirty-two constituents with distinct localization in the mass range of 101-1200 Da were identified by MALDI-FTICR-MSI. In addition, the identified four flavnoids (poncirin, sinensetin, 3,5,6,7,8,3',4'-heptemthoxyflavone, and tangeritin) were analyzed for differences between using LC-MS. Quantitative analysis results supported the quantitative results from MALDI-FT-ICR-MSI. The results implied that different parts had different constituents in AFI, and demonstrated MALDI-MSI have high potential in the direct analysis of constituents.

Ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features for automatic classification of ovarian masses according to O-RADS.

Background: Accurate and rapid discrimination between benign and malignant ovarian masses is crucial for optimal patient management. This study aimed to establish an ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features to automatically classify the ovarian masses into low risk and intermediate-high risk of malignancy lesions according to the Ovarian- Adnexal Reporting and Data System (O-RADS). Methods: The ultrasound images of 1,080 patients with 1,080 ovarian masses were included. The training cohort consisting of 683 patients was collected at the South China Hospital of Shenzhen University, and the test cohort consisting of 397 patients was collected at the Shenzhen University General Hospital. The workflow included image segmentation, feature extraction, feature selection, and model construction. Results: The pre-trained Resnet-101 model achieved the best performance. Among the different mono-modal features and fusion feature models, nomogram achieved the highest level of diagnostic performance (AUC: 0.930, accuracy: 84.9%, sensitivity: 93.5%, specificity: 81.7%, PPV: 65.4%, NPV: 97.1%, precision: 65.4%). The diagnostic indices of the nomogram were higher than those of junior radiologists, and the diagnostic indices of junior radiologists significantly improved with the assistance of the model. The calibration curves showed good agreement between the prediction of nomogram and actual classification of ovarian masses. The decision curve analysis showed that the nomogram was clinically useful. Conclusion: This model exhibited a satisfactory diagnostic performance compared to junior radiologists. It has the potential to improve the level of expertise of junior radiologists and provide a fast and effective method for ovarian cancer screening.

Noncovalently particle-anchored cytokines with prolonged tumor retention safely elicit potent antitumor immunity.

Preclinical studies have shown that immunostimulatory cytokines elicit antitumor immune responses but their clinical use is limited by severe immune-related adverse events upon systemic administration. Here, we report a facile and versatile strategy for noncovalently anchoring potent Fc-fused cytokine molecules to the surface of size-discrete particles decorated with Fc-binding peptide for local administration. Following intratumoral injection, particle-anchored Fc cytokines exhibit size-dependent intratumoral retention. The 1-micrometer particle prolongs intratumoral retention of Fc cytokine for over a week and has minimal systemic exposure, thereby eliciting antitumor immunity while eliminating systemic toxicity caused by circulating cytokines. In addition, the combination of these particle-anchored cytokines with immune checkpoint blockade antibodies safely promotes tumor regression in various syngeneic tumor models and genetically engineered murine tumor models and elicits systemic antitumor immunity against tumor rechallenge. Our formulation strategy renders a safe and tumor-agnostic approach that uncouples cytokines' immunostimulatory properties from their systemic toxicities for potential clinical application.

Ultrasound radiomics-based artificial intelligence model to assist in the differential diagnosis of ovarian endometrioma and ovarian dermoid cyst.

Background: Accurately differentiating between ovarian endometrioma and ovarian dermoid cyst is of clinical significance. However, the ultrasound appearance of these two diseases is variable, occasionally causing confusion and overlap with each other. This study aimed to develop a diagnostic classification model based on ultrasound radiomics to intelligently distinguish and diagnose the two diseases. Methods: We collected ovarian ultrasound images from participants diagnosed as patients with ovarian endometrioma or ovarian dermoid cyst. Feature extraction and selection were performed using the Mann-Whitney U-test, Spearman correlation analysis, and the least absolute shrinkage and selection operator (LASSO) regression. We then input the final features into the machine learning classifiers for model construction. A nomogram was established by combining the radiomic signature and clinical signature. Results: A total of 407 participants with 407 lesions were included and categorized into the ovarian endometriomas group (n = 200) and the dermoid cyst group (n = 207). In the test cohort, Logistic Regression (LR) achieved the highest area under curve (AUC) value (0.981, 95% CI: 0.963-1.000), the highest accuracy (94.8%), and the highest sensitivity (95.5%), while LightGBM achieved the highest specificity (97.1%). A nomogram incorporating both clinical features and radiomic features achieved the highest level of performance (AUC: 0.987, 95% CI: 0.967-1.000, accuracy: 95.1%, sensitivity: 88.0%, specificity: 100.0%, PPV: 100.0%, NPV: 88.0%, precision: 93.6%). No statistical difference in diagnostic performance was observed between the radiomic model and the nomogram (P > 0.05). The diagnostic indexes of radiomic model were comparable to that of senior radiologists and superior to that of junior radiologist. The diagnostic performance of junior radiologists significantly improved with the assistance of the model. Conclusion: This ultrasound radiomics-based model demonstrated superior diagnostic performance compared to those of junior radiologists and comparable diagnostic performance to those of senior radiologists, and it has the potential to enhance the diagnostic performance of junior radiologists.

Directed differentiation of human embryonic stem cells into parathyroid cells and establishment of parathyroid organoids.

Differentiation of human embryonic stem cells (hESCs) into human embryonic stem cells-derived parathyroid-like cells (hESC-PT) has clinical significance in providing new therapies for congenital and acquired parathyroid insufficiency conditions. However, a highly reproducible, well-documented method for parathyroid differentiation remains unavailable. By imitating the natural process of parathyroid embryonic development, we proposed a new hypothesis about the in vitro differentiation of parathyroid-like cells. Transcriptome, differentiation marker protein detection and parathyroid hormone (PTH) secretion assays were performed after the completion of differentiation. To optimize the differentiation protocol and further improve the differentiation rate, we designed glial cells missing transcription factor 2 (GCM2) overexpression lentivirus transfection assays and constructed hESCs-derived parathyroid organoids. The new protocol enabled hESCs to differentiate into hESC-PT. HESC-PT cells expressed PTH, GCM2 and CaSR proteins, low extracellular calcium culture could stimulate hESC-PT cells to secrete PTH. hESC-PT cells overexpressing GCM2 protein secreted PTH earlier than their counterpart hESC-PT cells. Compared with the two-dimensional cell culture environment, hESCs-derived parathyroid organoids secreted more PTH. Both GCM2 lentiviral transfection and three-dimensional cultures could make hESC-PT cells functionally close to human parathyroid cells. Our study demonstrated that hESCs could differentiate into hESC-PT in vitro, which paves the road for applying the technology to treat hypoparathyroidism and introduces new approaches in the field of regenerative medicine.

Advances in Nanoplatforms for Immunotherapy Applications Targeting the Tumor Microenvironment.

Cancer immunotherapy is a treatment method that activates or enhances the autoimmune response of the body to fight tumor growth and metastasis, has fewer toxic side effects and a longer-lasting efficacy than radiotherapy and chemotherapy, and has become an important means for the clinical treatment of cancer. However, clinical results from immunotherapy have shown that most patients lack responsiveness to immunotherapy and cannot benefit from this treatment strategy. The tumor microenvironment (TME) plays a critical role in the response to immunotherapy. The TME typically prevents effective lymphocyte activation, reducing their infiltration, and inhibiting the infiltration of effector T cells. According to the characteristic differences between the TME and normal tissues, various nanoplatforms with TME targeting and regulation properties have been developed for more precise regulation of the TME and have the ability to codeliver a variety of active pharmaceutical ingredients, thereby reducing systemic toxicity and improving the therapeutic effect of antitumor. In addition, the precise structural design of the nanoplatform can integrate specific functional motifs, such as surface-targeted ligands, degradable backbones, and TME stimulus-responsive components, into nanomedicines, thereby reshaping the tumor microenvironment, improving the body's immunosuppressive state, and enhancing the permeability of drugs in tumor tissues, in order to achieve controlled and stimulus-triggered release of load cargo. In this review, the physiological characteristics of the TME and the latest research regarding the application of TME-regulated nanoplatforms in improving antitumor immunotherapy will be described. Furthermore, the existing problems and further applications perspectives of TME-regulated platforms for cancer immunotherapy will also be discussed.

CT-Guided Radiofrequency Ablation Targeting the Herniation Edge of the Cervical Disc for the Treatment of Neck Pain: A Retrospective Study.

INTRODUCTION: Sinuvertebral nerve overactivation is one of the mechanisms of neck pain caused by cervical disc herniation. Radiofrequency ablation (RFA) of sinuvertebral nerves has shown efficacy for the treatment of discogenic low back pain. However, relatively few studies evaluated the efficacy of RFA of sinuvertebral nerves for the treatment of chronic neck pain caused by cervical disc herniation. METHODS: Clinical data were retrospectively collected from 168 patients diagnosed with cervical disc herniated neck pain from January 1, 2019, to September 1, 2022, who were treated with computed tomography (CT)-guided cervical disc RFA of at the Pain Medicine Center of Zhejiang Provincial People's Hospital. A 22-G RFA needle (Inomed, Emmendingen, Germany) was inserted between the carotid artery and trachea to the intervertebral disc under the direction of CT the scanner. Depending on the position of the protruding nucleus pulposus or the rupture of the annulus fibrosus, the needle was inserted into the posterior side of the intervertebral disc until the tip of the needle reached the target position. The numeric rating scale (NRS) score, pain relief and appearance of complications after RFA were evaluated. RESULTS: A total of 168 patients underwent CT-guided RFA for cervical disc herniation. The average duration of pain was 67.07 ± 70.42 months. At 6 months of follow-up, the median preoperative NRS score decreased significantly from preoperative 5.41 ± 1.08 to postoperative 1.341 ± 1.25 at 1 month, 1.4 ± 1.38 at 3 months and 1.72 ± 1.41 at 6 months after RFA (p < 0.01). The numbers of patients with ≥ 50% of their neck pain relieved were 84% (141/168), 87% (147/168), 87% (147/168) and 79% (133/168) at 1 day, 1 month, 3 months and 6 months after RFA, respectively. No serious complications related to treatment or long-term complications were observed. CONCLUSIONS: This study highlights that CT-guided RFA targeting the edge of cervical disc herniation to destroy the sinuvertebral nerves can effectively relieve neck pain, and the computed tomography (CT)-guided RFA treatment strategy has the advantages of having few complications.

Duck Tembusu virus NS3 protein induces apoptosis by activating the PERK/PKR pathway and mitochondrial pathway.

IMPORTANCE: Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that replicates well in mosquito, bird, and mammalian cells. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in the serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and poses a threat to mammalian health. Thus, understanding the pathogenic mechanism of DTMUV is crucial for identifying potential antiviral targets. In this study, we discovered that NS3 can induce the mitochondria-mediated apoptotic pathway through the PERK/PKR pathway; it can also interact with voltage-dependent anion channel 2 to induce apoptosis. Our findings provide a theoretical basis for understanding the pathogenic mechanism of DTMUV infection and identifying potential antiviral targets and may also serve as a reference for exploring the pathogenesis of other flaviviruses.

NS5 hijacks TRAF3 to inhibit type I interferon signaling during duck Tembusu virus infection.

The tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) is a key signaling molecule in the retinoic acid-inducible gene I (RIG-I) signaling pathway and plays an important role in host innate immune regulation. The function of TRAF3 has been extensively studied in mammals, however, the role of TRAF3 in ducks remains unclear. In order to reveal the function of duck TRAF3 (duTRAF3) in the innate immune response induced by virus infection, the TRAF3 homologue of mallard (Anas platyrhynchos) has been cloned and the function of duTRAF3 is investigated in this study. We sequenced duTRAF3 and found that the open reading frame (ORF) region of duTRAF3 is 1704 bp long and encodes 567 amino acids (aa), which has a similar functional domain to the mammalian gene. Analysis of tissue distribution of duTRAF3 in 7-day-old ducks showed that the expression of duTRAF3 was highest in harderian gland, followed by heart and lung. Subsequently, duck Tembusu virus (DTMUV) has been shown to enhance duTRAF3 expression, and overexpression of duTRAF3 inhibits DTMUV replication in a dose-dependent manner. In addition, duTRAF3 activates the transcriptional activity of IFN-α and its downstream interferon-stimulating genes (ISGs) induced after DTMUV infection. In this process, DTMUV non-structural (NS) protein 5 resists this innate immune process by interacting with TRAF3 and inhibiting TRAF3 expression. These data support the conclusion that duTRAF3 is an antiviral protein that plays a key role in the defense against DTMUV invasion. These results lay a theoretical foundation for developing new anti-DTMUV strategies.

Physical Activity, Sedentary Behavior, and Osteoarthritis: A Two-Sample Mendelian Randomization Analysis.

Background: Sedentary behavior and physical activity are still ambiguous in their effects on osteoarthritis. We aimed to evaluate the effects of physical activity and sedentary behavior on osteoarthritis to provide a reference for the prevention of osteoarthritis. Methods: This study was conducted in Changchun, China in 2022. We used two-sample Mendelian randomization with the SNP as an instrumental variable to investigate the effect of physical activity and sedentary behavior on osteoarthritis. In addition, a two-step Mendelian randomization method was used to test whether mediating factors (BMI, smoking, Apolipoprotein B) were involved in mediating the effects of exposure factors on osteoarthritis. Results: TV watching was causally related to knee osteoarthritis and spine osteoarthritis, and they were positively correlated (knee osteoarthritis: OR=1.162,95 %CI: 1.027-1.315, P=0.017; spine osteoarthritis: OR=1.208,95 %CI: 1.033-1.413, P=0.018). BMI played a mediating role in the process of TV watching with knee osteoarthritis and spine osteoarthritis. ((The proportion of BMI mediating effect: knee osteoarthritis: 47.1% (95% CI: 36.7%~63.2%); spine osteoarthritis: 29.5% (95% CI: 19.3%~40.8%)). The proportion of Smoking mediating effect in the process of TV watching with spine osteoarthritis was 16.1% (95% CI: 3.7% ~ 31.6%). Conclusion: TV watching is a potential risk factor for osteoarthritis and plays a role through modifiable factors such as BMI and smoking, therefore, interventions on these factors have the potential to reduce the burden of osteoarthritis caused by longer TV watching times.

No evidence of a causal relationship between ankylosing spondylitis and cardiovascular disease: a two-sample Mendelian randomization study.

Objective: Observational studies have suggested an increased risk of cardiovascular disease in individuals with ankylosing spondylitis. However, these studies are prone to confounding factors and reverse causality. To address these limitations, we conducted a Mendelian randomization study to assess the causal relationship between AS and CVD. Methods: The study population comprises 9,069 individuals with ankylosing spondylitis and 509,093 individuals with either of six common cardiovascular diseases and a related indicator. Causal analysis using summary effect estimates and inverse variance weighting were employed as the main methods. Results: The CAUSE analysis showed no evidence of a causal relationship between AS and CVD. The odds ratios for total CVD, heart failure, myocardial infarction, valvular heart disease, ischemic heart disease, and venous thromboembolism, Arterial stiffness index, were as follows: OR, 1.01; 95% confidence interval, 0.96-1.05; P = 0.91; OR, 1.03; 95% CI, 0.99-1.08; P = 0.50; OR, 0.94; 95% CI, 0.86-1.03; P = 0.53; OR, 0.99; 95% CI, 0.94-1.04; P = 0.99; OR, 0.98; 95% CI, 0.91-1.04; P = 0.94; OR, 0.98; 95% CI, 0.91-1.04; P = 0.99; ß, -0.0019; 95% CI, 0.97-1.01; P = 0.99. The IVW and weighted median methods also yielded consistent results, and no heterogeneity or pleiotropy was found. Likewise, a reverse Mendelian randomization analysis did not uncover a heritable causal relationship between AS and CVD. Conclusion: This Mendelian randomization study does not support a causal relationship between AS and CVD. Further research is needed to confirm this association.

Effects of blood pressure and antihypertensive drugs on osteoarthritis: a mendelian randomized study.

BACKGROUND: Previous studies have suggested that antihypertensive drugs may play a role in the treatment of osteoarthritis, but these studies may be limited by confounding factors and lead to biased results. Therefore, we conducted a Mendelian randomization study to investigate the effects of blood pressure and antihypertensive drugs on osteoarthritis. METHODS: We used published large-scale genome-wide association data and applied univariate and multivariate Mendelian randomization methods. The main analysis model was inverse variance weighting, and the reliability of the results was tested using MR-Egger intercept analysis, Cochran's Q test, and leave-one-out analysis. We comprehensively evaluated the relationship between systolic blood pressure, diastolic blood pressure, 12 antihypertensive drugs, and osteoarthritis. We also conducted verification in the independent queue of UK Biobank and built a simple linear regression model to obtain an independent comparison. RESULTS: We found no evidence that systolic and diastolic blood pressure significantly affected osteoarthritis. However, among antihypertensive drugs, we observed a significant positive correlation between potassium-preserving diuretics and aldosterone antagonists and all osteoarthritis (OR: 0.560, 95% CI 0.406-0.772, P = 0.0004). Sensitivity analysis showed no horizontal pleiotropy or heterogeneity, and the leave-one-out analysis demonstrated the reliability of the results. This result was replicated with nominally statistical significance in the validation cohort and exhibited significant correlation in the linear regression analysis. CONCLUSIONS: Our study suggested that controlling the protein targets of potassium-sparing diuretics and aldosterone antagonists may have beneficial results for osteoarthritis. These findings provide valuable medication strategies for the control of hypertension in patients with osteoarthritis.

Recent advances of CREKA peptide-based nanoplatforms in biomedical applications.

Nanomedicine technology is a rapidly developing field of research and application that uses nanoparticles as a platform to facilitate the diagnosis and treatment of diseases. Nanoparticles loaded with drugs and imaging contrast agents have already been used in clinically, but they are essentially passive delivery carriers. To make nanoparticles smarter, an important function is the ability to actively locate target tissues. It enables nanoparticles to accumulate in target tissues at higher concentrations, thereby improving therapeutic efficacy and reducing side effects. Among the different ligands, the CREKA peptide (Cys-Arg-Glu-Lys-Ala) is a desirable targeting ligand and has a good targeting ability for overexpressed fibrin in different models, such as cancers, myocardial ischemia-reperfusion, and atherosclerosis. In this review, the characteristic of the CREKA peptide and the latest reports regarding the application of CREKA-based nanoplatforms in different biological tissues are described. In addition, the existing problems and future application perspectives of CREKA-based nanoplatforms are also addressed.

The Amyloid-Beta Clearance: From Molecular Targets to Glial and Neural Cells.

The deposition of amyloid-beta (Aß) plaques in the brain is one of the primary pathological characteristics of Alzheimer's disease (AD). It can take place 20-30 years before the onset of clinical symptoms. The imbalance between the production and the clearance of Aß is one of the major causes of AD. Enhancing Aß clearance at an early stage is an attractive preventive and therapeutic strategy of AD. Direct inhibition of Aß production and aggregation using small molecules, peptides, and monoclonal antibody drugs has not yielded satisfactory efficacy in clinical trials for decades. Novel approaches are required to understand and combat Aß deposition. Neurological dysfunction is a complex process that integrates the functions of different types of cells in the brain. The role of non-neurons in AD has not been fully elucidated. An in-depth understanding of the interactions between neurons and non-neurons can contribute to the elucidation of Aß formation and the identification of effective drug targets. AD patient-derived pluripotent stem cells (PSCs) contain complete disease background information and have the potential to differentiate into various types of neurons and non-neurons in vitro, which may bring new insight into the treatment of AD. Here, we systematically review the latest studies on Aß clearance and clarify the roles of cell interactions among microglia, astroglia and neurons in response to Aß plaques, which will be beneficial to explore methods for reconstructing AD disease models using inducible PSCs (iPSCs) through cell differentiation techniques and validating the applications of models in understanding the formation of Aß plaques. This review may provide the most promising directions of finding the clues for preventing and delaying the development of AD.

Pyroptosis in development, inflammation and disease.

In the early 2000s, caspase-1, an important molecule that has been shown to be involved in the regulation of inflammation, cell survival and diseases, was given a new function: regulating a new mode of cell death that was later defined as pyroptosis. Since then, the inflammasome, the inflammatory caspases (caspase-4/5/11) and their substrate gasdermins (gasdermin A, B, C, D, E and DFNB59) has also been reported to be involved in the pyroptotic pathway, and this pathway is closely related to the development of various diseases. In addition, important apoptotic effectors caspase-3/8 and granzymes have also been reported to b involved in the induction of pyroptosis. In our article, we summarize findings that help define the roles of inflammasomes, inflammatory caspases, gasdermins, and other mediators of pyroptosis, and how they determine cell fate and regulate disease progression.

Irisin promotes the proliferation and tenogenic differentiation of rat tendon-derived stem/progenitor cells via activating YAP/TAZ.

Tendinopathy is a common tendon disorder characterized by pain, swelling, and dysfunction. Current evidence has demonstrated that the depletion of stem cell pool and non-tenogenic differentiation of tendon-derived stem/progenitor cells (TSPCs) might account for the pathogenesis of tendinopathy. FNDC5/Irisin, as a novel exercise-induced myokine, is proved to be involved in the exercise-induced protective effects on musculoskeletal disorders. However, whether irisin can affect TSPCs fate is still unknown. To ascertain the roles of irisin on the proliferation and tenogenic differentiation of TSPCs, rat TSPCs were isolated and incubated with irisin. Cell viability, phenotypic changes, and related signaling pathways were evaluated by CCK-8 assay, colony formation assay, real-time PCR, Western blot, immunofluorescence, and proteasome activity assay. We found that irisin treatment increased the proliferative and colony-forming abilities, and promoted the tenogenic differentiation of TSPCs by upregulating the expression of YAP/TAZ. In conclusion, our work showed for the first time that irisin promotes the proliferation and tenogenic differentiation of rat TSPCs in vitro by activating YAP/TAZ, and the process was associated with a ubiquitin-proteasome proteolytic pathway. In conclusion, irisin and agents targeting YAP/TAZ may be promising therapeutic options for tendinopathy.