Mechanical deformation and death of circulating tumor cells in the bloodstream.

The circulation of tumor cells through the bloodstream is a significant step in tumor metastasis. To better understand the metastatic process, circulating tumor cell (CTC) survival in the circulation must be explored. While immune interactions with CTCs in recent decades have been examined, research has yet to sufficiently explain some CTC behaviors in blood flow. Studies related to CTC mechanical responses in the bloodstream have recently been conducted to further study conditions under which CTCs might die. While experimental methods can assess the mechanical properties and death of CTCs, increasingly sophisticated computational models are being built to simulate the blood flow and CTC mechanical deformation under fluid shear stresses (FSS) in the bloodstream.Several factors contribute to the mechanical deformation and death of CTCs as they circulate. While FSS can damage CTC structure, diverse interactions between CTCs and blood components may either promote or hinder the next metastatic step-extravasation at a remote site. Overall understanding of how these factors influence the deformation and death of CTCs could serve as a basis for future experiments and simulations, enabling researchers to predict CTC death more accurately. Ultimately, these efforts can lead to improved metastasis-specific therapeutics and diagnostics specific in the future.

Novel High-Performance Glyoxylate Derivative-Based Photoinitiators for Free Radical Photopolymerization and 3D Printing with Visible LED.

Investigations concerning the glyoxylate moiety as a photocleavable functional group for visible light photoinitiators, particularly in the initiation of free radical photopolymerization remain limited. This study introduces nine innovative carbazole-based ethyl glyoxylate derivatives (CEGs), which are synthesized and found to exhibit excellent photoinitiation abilities as monocomponent photoinitiating systems. Notably, these structures demonstrate robust absorption in the near-UV/visible range, surpassing the commercial photoinitiators. Moreover, the newly developed glyoxylate derivatives show higher acrylate function conversions compared to a benchmark photoinitiator (MBF) in free radical photopolymerization. Elucidation of the photoinitiation mechanism of CEGs is achieved through a comprehensive analysis involving the decarboxylation reaction and electron spin resonance spin trapping. Furthermore, their practical utility is confirmed during direct laser writing and 3D printing processes, enabling the successful fabrication of 3D printed objects. This study introduces pioneering concepts and effective strategies in the molecular design of novel photoinitiators, showcasing their potential for highly advantageous applications in 3D printing.

Planar thermal Hall effect of topological bosons in the Kitaev magnet α-RuCl3.

The honeycomb magnet α-RuCl3 has attracted considerable interest because it is proximate to the Kitaev Hamiltonian whose excitations are Majoranas and vortices. The thermal Hall conductivity κxy of Majorana fermions is predicted to be half-quantized. Half-quantization of κxy/T (T, temperature) was recently reported, but this observation has proven difficult to reproduce. Here, we report detailed measurements of κxy on α-RuCl3 with the magnetic field B ∥ a (zigzag axis). In our experiment, κxy/T is observed to be strongly temperature dependent between 0.5 and 10 K. We show that its temperature profile matches the distinct form expected for topological bosonic modes in a Chern-insulator-like model. Our analysis yields magnon band energies in agreement with spectroscopic experiments. At high B, the spin excitations evolve into magnon-like modes with a Chern number of ~1. The bosonic character is incompatible with half-quantization of κxy/T.

Effects of charge asymmetry on the liquid-liquid phase separation of polyampholytes and their condensate properties.

Liquid-liquid phase separation (LLPS) is the mechanism underlying the formation of bio-molecular condensates which are important compartments regulating intra- and extra-cellular functions. Electrostatic interactions are some of the important driving forces of the LLPS behaviors of biomolecules. However, the understanding of the electrostatic interactions is still limited, especially in the mixtures of biomolecules with different charge patterns. Here, we focus on the electrostatic interactions in mixtures of charge-asymmetric and charge-symmetric polyampholytes and their roles in the phase separation behaviors. We build charge-asymmetric and charge-symmetric model proteins consisting of both glutamic acid (E, negatively charged) and lysine (K, positively charged), i.e. polyampholytes of E35K15 (charge asymmetric) and E25K25 (charge symmetric). Pure E25K25 can undergo LLPS. To investigate the effects of charge-asymmetric polyampholytes on the mixtures of E25K25/E35K15, we perform coarse-grained simulations to determine their phase separation. The charge-asymmetric polyampholyte E35K15 is resistant to the LLPS of the mixtures of E25K25/E35K15. The condensate density decreases with the molar fraction of E35K15 increasing to 0.4, and no LLPS occurs at the molar fraction of 0.5 and above. This can be attributed to the electrostatic repulsion between the negatively charged E35K15 polymers. We further investigate the effects of charge asymmetry on the conformations and properties of the condensates. The E35K15 polymers in the condensates exhibit a more collapsed state as the molar fraction of E35K15 increases. However, the conformation of E25K25 polymers changes slightly across different condensates. The surface tensions of condensates decline with the increase of the molar fraction of E35K15 polymers, while the diffusivity of polymers in the condensed phases is enhanced. This work elucidates the role of charge-asymmetric polyampholytes in determining the LLPS behaviours of binary mixtures of charge-symmetric and charge-asymmetric proteins as well as the properties of condensed phases.

Self-delivery photothermal-boosted-nanobike multi-overcoming immune escape by photothermal/chemical/immune synergistic therapy against HCC.

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have shown encouraging clinical benefits for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). Nevertheless, therapeutic efficacy and wide clinical applicability remain a challenge due to "cold" tumors' immunological characteristics. Tumor immunosuppressive microenvironment (TIME) continuously natural force for immune escape by extracellular matrix (ECM) infiltration, tumor angiogenesis, and tumor cell proliferation. Herein, we proposed a novel concept by multi-overcoming immune escape to maximize the ICIs combined with antiangiogenic therapy efficacy against HCC. A self-delivery photothermal-boosted-NanoBike (BPSP) composed of black phosphorus (BP) tandem-augmented anti-PD-L1 mAb plus sorafenib (SF) is meticulously constructed as a triple combination therapy strategy. The simplicity of BPSP's composition, with no additional ingredients added, makes it easy to prepare and presents promising marketing opportunities. (1) NIR-II-activated BPSP performs photothermal therapy (PTT) and remodels ECM by depleting collagen I, promoting deep penetration of therapeutics and immune cells. (2) PTT promotes SF release and SF exerts anti-vascular effects and down-regulates PD-L1 via RAS/RAF/ERK pathway inhibition, enhancing the efficacy of anti-PD-L1 mAb in overcoming immune evasion. (3) Anti-PD-L1 mAb block PD1/PD-L1 recognition and PTT-induced ICD initiates effector T cells and increases response rates of PD-L1 mAb. Highly-encapsulated BPSP converted 'cold' tumors into 'hot' ones, improved CTL/Treg ratio, and cured orthotopic HCC tumors in mice. Thus, multi-overcoming immune escape offers new possibilities for advancing immunotherapies, and photothermal/chemical/immune synergistic therapy shows promise in the clinical development of HCC.

SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes.

Sprouty-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain containing 2 (SPRED2) is an inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and has been shown to promote autophagy in several cancers. Here, we aimed to determine whether SPRED2 plays a role in autophagy in hepatocellular carcinoma (HCC) cells. The Cancer Genome Atlas (TCGA) Liver Cancer Database showed a negative association between the level of SPRED2 and p62, a ubiquitin-binding scaffold protein that accumulates when autophagy is inhibited. Immunohistochemically, accumulation of p62 was detected in human HCC tissues with low SPRED2 expression. Overexpression of SPRED2 in HCC cells increased the number of autophagosomes and autophagic vacuoles containing damaged mitochondria, decreased p62 levels, and increased levels of light-chain-3 (LC3)-II, an autophagy marker. In contrast, SPRED2 deficiency increased p62 levels and decreased LC3-II levels. SPRED2 expression levels were negatively correlated with translocase of outer mitochondrial membrane 20 (TOM20) expression levels, suggesting its role in mitophagy. Mechanistically, SPRED2 overexpression reduced ERK activation followed by the mechanistic or mammalian target of rapamycin complex 1 (mTORC1)-mediated signaling pathway, and SPRED2 deficiency showed the opposite pattern. Finally, hepatic autophagy was impaired in the liver of SPRED2-deficient mice with hepatic lipid droplet accumulation in response to starvation. These results indicate that SPRED2 is a critical regulator of autophagy not only in HCC cells, but also in hepatocytes, and thus the manipulation of this process may provide new insights into liver pathology.

P2Y12 Inhibitor vs Aspirin Monotherapy Following Dual Antiplatelet Therapy after Percutaneous Coronary Intervention: An Updated Meta-Analysis.

Background: With the publication of a large number of clinical studies on antiplatelet therapy in recent years, it is still controversial which antiplatelet monotherapy should be continued after a period of dual antiplatelet therapy (DAPT) in the post percutaneous coronary intervention (post-PCI) population. We conducted a meta-analysis to investigate the efficacy and safety of P2Y 12 inhibitors versus aspirin in the post-PCI population after completing DAPT. Methods: We searched studies in electronic databases from January 1, 2015 to November 20, 2022. We conducted a meta-analysis to estimate the effect of P2Y 12 inhibitor monotherapy on clinical end-points in post-PCI patients after a period of DAPT, using trial-level data with consistent end-point definitions. The primary outcome was major adverse cardiovascular events (MACE). Odd ratio (OR) was pooled with 95% confidence interval (CI) for dichotomous data. This study is registered with INPLASY 2022120011. Results: We included five studies that included 24,460 patients. The patients who received a P2Y 12 inhibitor showed a lower risk of MACE than patients who received aspirin (OR 0.70 [95% CI 0.60-0.80], I 2 = 0%, p < 0.00001) monotherapy. Subgroup analysis of MACE based on patient characteristics showed consistent results with the main analysis. The risk of major bleeding was similar in patients who received a P2Y 12 inhibitor and those who received aspirin (OR 0.86 [95% CI 0.53-1.39], I 2 = 57%, p = 0.54). The risk of major bleeding was borderline increased in patients who received ticagrelor versus aspirin (OR 1.81 [95% CI 0.99-3.31], p = 0.05). Conclusions: In the post-PCI population, P2Y 12 inhibitor monotherapy may be superior to aspirin for MACE, repeat revascularization, and stroke without increasing the risk of major bleeding.

MMP-Responsive Nanoparticle-Loaded, Injectable, Adhesive, Self-Healing Hydrogel Wound Dressing Based on Dynamic Covalent Bonds.

Developing a multifunctional hydrogel wound dressing with good injectability, self-healing, tissue adhesion, biocompatibility, and fast skin wound healing efficiency remains challenging. In this work, an injectable adhesive dopamine-functionalized oxidized hyaluronic acid/carboxymethyl chitosan/collagen (AHADA/CCS/Col) hydrogel was constructed. The Schiff dynamic bond between AHADA and CCS, the N-Ag-N bond between CCS and Ag ions, and the S-Ag-S dynamic bond between sulfhydryl-modified collagen (ColSH) and Ag ions allowed the hydrogel to be both injectable and self-healing. Moreover, the aldehyde groups and catechol groups presented in the hydrogel could generate force with several groups on the tissue interface; therefore, the hydrogel also had good tissue adhesion. In vitro experiments proved that this hydrogel exhibited good biocompatibility and could promote cell proliferation. Additionally, curcumin (Cur)-loaded gelatin nanoparticles (Cur@Gel NPs) were prepared, which could respond to matrix metalloproteinases (MMPs) and controllably release Cur to hasten wound healing efficiency. Animal experiment results showed that this AHADA/CCS/Col hydrogel loaded with Cur@Gel NPs promoted wound repairing better, indicating its potential as a wound dressing.

Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding.

Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form. This form, however, lacks a C-terminal fragment and possesses reduced ß3-integrin binding. Here, we present a crystal structure of a full-length talin head in complex with the ß3-integrin tail. The structure reveals a compact FERM-like conformation and a tightly associated N-P-L-Y motif of ß3-integrin. A critical C-terminal poly-lysine motif mediates FERM interdomain contacts and assures the tight association with the ß3-integrin cytoplasmic segment. Removal of the poly-lysine motif or disrupting the FERM-folded configuration of the talin head significantly impairs integrin activation and clustering. Therefore, structural characterization of the FERM-folded active talin head provides fundamental understanding of the regulatory mechanism of integrin function.

Dark-Channel Soft-Constrained and Object-Perception-Enhanced Deep Dehazing Networks Used for Road Inspection Images.

Haze seriously affects the visual quality of road inspection images and contaminates the discrimination of key road objects, which thus hinders the execution of road inspection work. The basic assumptions of the classical dark-channel prior are not suitable for road images containing light-colored lane lines and vehicles, while typical deep dehazing networks lack physical model interpretability, and they focus on global dehazing effects, neglecting the preservation of object features. For this reason, this paper proposes a Dark-Channel Soft-Constrained and Object-Perception-Enhanced Deep Dehazing Network (DCSC-OPE-Net) for the information recovery of road inspection images. The network is divided into two modules: a dark-channel soft-constrained dehazing module and a near-view object-perception-enhanced module. Unlike the traditional dark-channel algorithms that impose strong constraints on dark pixels, a dark-channel soft-constrained loss function is constructed to ensure that the features of light-colored vehicles and lane lines are effectively maintained. To avoid resolution loss due to patch-based dark-channel processing for image dehazing, a resolution enhancement module is used to strengthen the contrast of the dehazed image. To autonomously perceive and enhance key road features to support road inspection, edge enhancement loss combined with a transmission map is embedded into the network to autonomously discover near-view objects and enhance their key features. The experiments utilize public datasets and real road inspection datasets to validate the performance of the proposed DCSC-OPE-Net compared with typical networks using dehazing evaluation metrics and road object recognition metrics. The experimental results demonstrate that the proposed DCSC-OPE-Net can obtain the best dehazing performance, with an NIQE score of 4.5 and a BRISQUE score of 18.67, and obtain the best road object recognition results (i.e., 83.67%) among the comparison methods.

Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes by Inhibiting Inflammation and Ferroptosis through Activating AMPK Pathway.

Diabetic cardiomyopathy (DCM) is a myocardial disease independent of other cardiovascular diseases, such as coronary heart disease, hypertension, etc. Lipotoxicity is closely related to DCM. In this study, we investigated the mechanism of lipid metabolism disturbance in DCM in HL-1 cells. Through bioinformatics and Western blotting analysis, we found that canagliflozin (CAN) significantly inhibited the expression of inflammatory factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Ferroptosis is mediated by lipid peroxidation. We demonstrated the presence of ferroptosis in cardiomyocytes by detecting intracellular Fe2+ content and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH), and mitochondrial membrane potential (MMP). CAN could significantly regulate the indicators of ferroptosis. By using specific inhibitors celecoxib (coxib), S-methylisothiourea sulfate (SMT), Ferrostatin-1 (Fer-1), and Compound C, we further found that CAN regulated inflammation and ferroptosis through AMP-activated protein (AMPK), and inflammation interacted with ferroptosis. Our study indicated that CAN attenuated lipotoxicity in cardiomyocytes by regulating inflammation and ferroptosis through activating the AMPK pathway. This study provides a new direction of myocardial lipotoxicity and some new information for the treatment of DCM.

SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells.

The downregulation of SPRED2, a negative regulator of the ERK1/2 pathway, was previously detected in human cancers; however, the biological consequence remains unknown. Here, we investigated the effects of SPRED2 loss on hepatocellular carcinoma (HCC) cell function. Human HCC cell lines, expressing various levels of SPRED2 and SPRED2 knockdown, increased ERK1/2 activation. SPRED2-knockout (KO)-HepG2 cells displayed an elongated spindle shape with increased cell migration/invasion and cadherin switching, with features of epithelial-mesenchymal transition (EMT). SPRED2-KO cells demonstrated a higher ability to form spheres and colonies, expressed higher levels of stemness markers and were more resistant to cisplatin. Interestingly, SPRED2-KO cells also expressed higher levels of the stem cell surface markers CD44 and CD90. When CD44+CD90+ and CD44-CD90- populations from WT cells were analyzed, a lower level of SPRED2 and higher levels of stem cell markers were detected in CD44+CD90+ cells. Further, endogenous SPRED2 expression decreased when WT cells were cultured in 3D, but was restored in 2D culture. Finally, the levels of SPRED2 in clinical HCC tissues were significantly lower than those in adjacent non-HCC tissues and were negatively associated with progression-free survival. Thus, the downregulation of SPRED2 in HCC promotes EMT and stemness through the activation of the ERK1/2 pathway, and leads to more malignant phenotypes.

Antibacterial Activity and Mechanism of Canagliflozin against Methicillin-Resistant Staphylococcus aureus.

Diabetic foot infection (DFI) is a common complication in diabetes patients, with foot infections being the leading cause of amputations. Staphylococcus aureus is frequently found in diabetic foot infections, of which methicillin-resistant Staphylococcus aureus (MRSA) has become a major clinical and epidemiological challenge. Since MRSA strains are resistant to most ß-lactam antibiotics, and also partially resistant to other antibiotics, treatment is difficult and costly. The emergence of drug-resistant bacteria often arises from overuse or misuse of antibiotics. Clinically, canagliflozin is commonly used for the treatment of type 2 diabetes. On this basis, we investigated the antibacterial activity and mechanism of canagliflozin against MRSA, with the aim to discover novel functions of canagliflozin and provide new insights for the treatment of MRSA. Using the microbroth dilution method to determine the half maximal inhibitory concentration of drugs, we found that canagliflozin not only can inhibit the growth of methicillin-sensitive Staphylococcus aureus (MSSA) but also exhibits antibacterial activity against MRSA. The IC50 values, at approximately 56.01 µM and 57.60 µM, were almost the same. At 12 h, canagliflozin showed a significant antibacterial effect against MRSA at and above 30 µM. In addition, its combined use with penicillin achieved better antibacterial effects, which were increased by about three times. Additive antibacterial activity (FICI = 0.69) was found between penicillin and canagliflozin, which was better than that of doxycycline and canagliflozin (FICI = 0.95). Canagliflozin also affected bacterial metabolic markers, such as glucose, ATP, and lactic acid. The results of crystal violet staining indicate that canagliflozin disrupted the formation of bacterial biofilm. Our electron microscopy results showed that canagliflozin distorted the bacterial cell wall. The results of RT-PCR suggest that canagliflozin down-regulated the expressions of biofilm-related gene (clfA, cna, agrC, mgrA, hld) and methicillin-resistance gene (mecA), which was related to MRSA. Molecular docking also indicated that canagliflozin affected some interesting targets of MRSA, such as the sarA, crtM and fnbA proteins. In conclusion, canagliflozin exhibits antibacterial activity against MRSA by affecting bacterial metabolism, inhibiting its biofilm formation, distorting the bacterial cell wall, and altering the gene expression of biofilm formation and its virulence. Our study reveals the antibacterial activity of canagliflozin against MRSA, providing a new reference for treating diabetic foot infections.

Photodynamic therapy (PDT) for oral leukoplakia: a systematic review and meta-analysis of single-arm studies examining efficacy and subgroup analyses.

OBJECTIVE: This study aims to evaluate the efficacy of photodynamic therapy (PDT) in the treatment of oral leukoplakia and explore the subgroup factors that may influence its effectiveness. METHODS: A systematic search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science databases to identify relevant studies. Meta-analysis was performed using Stata15.0 software. Cochran's Q test and I2 statistics were used to evaluate heterogeneity, egger's test was used to evaluate publication bias. RESULTS: The analysis of 17 studies included in this study suggests that PDT may be effective in achieving complete response (CR) [ES = 0.50, 95%CI: (0.33,0.66)], partial response (PR) [ES = 0.42, 95%CI: (0.27,0.56)], no response (NR) [ES = 0.19, 95%CI: (0.11,0.27)]in patients with oral leukoplakia. The recurrence rate was also evaluated [ES = 0.13, 95%CI: (0.08,0.18)]. Subgroup analysis showed that various factors such as light source, wavelength, medium, duration of application, clinical and pathological diagnosis classification influenced efficacy of PDT. The lesion areas of the leukoplakia after treatment were reduced by 1.97cm2 compared with those before treatment. CONCLUSION: Our findings show that PDT is a viable treatment for oral leukoplakia. However, the effectiveness of the therapy may depend on several factors, as suggested by our subgroup analyses. (Registration no. CRD42023399848 in Prospero, 26/02/2023).

Enhanced Li+ Diffusion and Lattice oxygen Stability by the High Entropy Effect in Disordered-Rocksalt Cathodes.

Cation-disordered Rocksalt oxides (DRXs) are a promising new class of cathode materials for Li-ion batteries due to their natural abundance, low cost and great electrochemical performance. High entropy strategy in Mn-based DRXs appears to be an effective strategy for improving the rate capability, but it suffers from challenges including capacity degradation. The present paper reports a new group of high entropy DRXs (HE DRX) based on Ni2+ -Nb5+ pair; the structural and chemical evolution upon cycling of DRXs with an increasing transition metal (TM) species are systematically investigated. An explanation is proposed for how the crystal field stability energy determines that HE DRX could exist in single Rocksalt solid solution structures. We further reveal that the charge compensation mechanism in HE DRX is the result of various TM synergistic effect. More importantly, through various in situ and ex situ techniques and theoretical calculation, the effective integration of more TM cation species within the HE DRX framework promotes better Li+ diffusion and improves lattice oxygen stability, consequently increasing capacity upon cycling.

Understanding topological defects in fluidized dry active nematics.

Dense assemblies of self-propelling rods (SPRs) may exhibit fascinating collective behaviors and anomalous physical properties that are far away from equilibrium. Using large-scale Brownian dynamics simulations, we investigate the dynamics of disclination defects in 2D fluidized swarming motions of dense dry SPRs (i.e., without hydrodynamic effects) that form notable local positional topological structures that are reminiscent of smectic order. We find the deformations of smectic-like rod layers can create unique polar structures that lead to slow translations and rotations of ±1/2-order defects, which are fundamentally different from the fast streaming defect motions observed in wet active matter. We measure and characterize the statistical properties of topological defects and reveal their connections with the coherent structures. Furthermore, we construct a bottom-up active-liquid-crystal model to analyze the instability of polar lanes, which effectively leads to defect formation between interlocked polar lanes and serves as the origin of the large-scale swarming motions.

CircRNA hsa_circ_0014130 function as a miR-132-3p sponge for playing oncogenic roles in bladder cancer via upregulating KCNJ12 expression.

The modern categories of endogenous non-coding RNAs, namely circular RNAs (circRNAs), involved within the carcinogenesis and progression of various human cancers. The fundamental aim of the current investigation was the evaluation of the hsa_circ_0014130 expressions, their biological functions, and potential regulatory network in bladder cancer. The level of expression for hsa_circ_0014130 was evaluated by qRT-PCR, and its relationships to clinicopathological features and survival outcomes of cases experiencing cancer of the bladder were scrutinized. The impact of hsa_circ_0014130 expressions on biological attitudes of bladder cancer cells in vitro was investigated. The interactions between hsa_circ_0014130 and microRNA (miRNA) sponge, miRNA, and its direct targets were determined by RNA pull-down as well as luciferase reporter gene assay. The correlations of their expression were determined by Pearson's correlation analysis. Rescue experiments were carried out to identify the biological roles of the regulation network. The expressions of hsa_circ_0014130 were markedly ameliorated in bladder cancer samples and linked with aggressive characteristics and unfavorable survival. Ectopic expression of hsa_circ_0014130 clearly enhanced the differentiation, proliferative, migratory, invasive potential of the cell in bladder cancer, and the development of tumor xenograft in vivo, while malignant biological behaviors were inhibited by hsa_circ_0014130 knockdown. The expression of hsa_circ_0014130 was tied to miR-132-3p in a negative manner with the cells and tissues of bladder cancer. hsa_circ_0014130 function as a competitive endogenous RNA for miR-132-3p to play oncogenic roles in bladder cancer cells. On the other hand, KCNJ12 was a straightforward target of miR-132-3p at the downstream, and the expressions of KCNJ12 were inversely related to that of miR-132-3p. Furthermore, a significantly positive correlation was found between hsa_circ_0014130 and KCNJ12 mRNA expression. More importantly, the oncogenic impact of hsa_circ_0014130 on bladder cancer cells was partly suppressed by ectopic expression of miR-132-3p or KCNJ12 knockdown. The underlined data revealed that hsa_circ_0014130 exerted its biological roles by regulating miR-132-3p/KCNJ12 expression. Further research revealed hsa_circ_0014130/miR-132-3p/KCNJ12 axis has participated in the Epithelial-mesenchymal transition (EMT) progress and GSK3ß/AKT signaling pathway. hsa_circ_0014130 works as a sponge of miR-132-3p to advance the oncogenesis and metastasis of bladder cancer by regulation of the KCNJ12 expression. These achievements might ameliorate the comprehension of tumor pathogenesis and provide novel therapeutic targets for cancer of the bladder.

In Situ Forming Cellulose Nanofibril-Reinforced Hyaluronic Acid Hydrogel for Cartilage Regeneration.

Hyaluronic acid (HA) based hydrogels are one of most functional natural biomaterials in the field of cartilage tissue engineering (CTE). Even with the promising advantages of HA hydrogels, the complicated mechanical properties of the native cartilage have not been realized, and fabricating HA hydrogels with excellent mechanical properties to make them practical in CTE still remains a current challenge. Here, a strategy that integrates hydrogels and nanomaterials is shown to form a HA hydrogel with sufficient mechanical loading for cartilage tissue production and recombination. Cellulose nanofibrils (CNFs) are promising nanomaterial candidates as they possess high mechanical strength and excellent biocompatibility. In this study, we developed methacrylate-functionalized CNFs that are able to photo-crosslink with methacrylated HA to fabricate HA/CNF nanocomposite hydrogels. The present composite hydrogels with a compressive modulus of 0.46 ± 0.05 MPa showed adequate compressive strength (0.198 ± 0.009 MPa) and restorability, which can be expected to employ as a stress-bearing tissue such as articular cartilage. Besides, this nanocomposite hydrogel could provide a good microenvironment for bone marrow mesenchymal stem cell proliferation, as well as chondrogenic differentiation, and exhibit prominent repair effect in the full-thickness cartilage defect model of SD rats. These results suggest that the HA/CNF nanocomposite hydrogel creates a new possibility for fabricating a scaffold in CTE.

Immune response induced by oral administration with a Saccharomyces cerevisiae-based SARS-CoV-2 vaccine in mice.

BACKGROUND: The global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the need to develop safe and effective vaccines with a top priority. Multiple vaccine candidates are under development, and several vaccines are currently available. Efforts need to be undertaken to counter the threat of the global COVID-19 pandemic. RESULTS: We generated a Saccharomyces cerevisiae (S. cerevisiae)-based SARS-CoV-2 vaccine, EBY100/pYD1-RBD, in which the full-length receptor binding domain (RBD) of the spike protein of SARS-CoV-2 was expressed on the surface of yeast. Mice vaccinated orally with unadjuvanted EBY100/pYD1-RBD could produce significant humoral and mucosal responses as well as robust cellular immune responses. Notably, EBY100/pYD1-RBD elicited a mixed Th1/Th2-type cellular immune response with a Th1-biased immune response in a mouse model. CONCLUSIONS: Our findings highlight the importance of the RBD as a key target to design and develop vaccines against SARS-CoV-2 and provide evidence of oral administration of a S. cerevisiae-based SARS-CoV-2 vaccine eliciting significant immune responses. Most importantly, the S. cerevisiae surface display system can serve as a universal technology platform and be applied to develop other oral viral or bacterial vaccines.

Immune evaluation of a Saccharomyces cerevisiae-based oral vaccine against Helicobacter pylori in mice.

BACKGROUND: Helicobacter pylori (H. pylori) is a common human pathogenic bacterium that is associated with gastric diseases. The current leading clinical therapy is combination antibiotics, but this treatment has safety issues, especially the induction of drug resistance. Therefore, developing a safe and effective vaccine against H. pylori is one of the best alternatives. OBJECTIVE: To develop Saccharomyces cerevisiae (S. cerevisiae)-based oral vaccines and then demonstrate the feasibility of this platform for preventing H. pylori infection in the absence of a mucosal adjuvant. MATERIALS AND METHODS: Saccharomyces cerevisiae (S. cerevisiae)-based oral vaccines, including EBY100/pYD1-UreB and EBY100/pYD1-VacA, were generated and analyzed by Western blot, Immunofluorescence analysis, flow cytometric assay, and indirect enzyme-link immunosorbent assay (ELISA). Further, antibody responses induced by oral administration of EBY100/pYD1-UreB, EBY100/pYD1-VacA, or EBY100/pYD1-UreB + EBY100/pYD1-VacA were measured in a mouse model. Lastly, the vaccinated mice were infected with H. pylori SS1, and colonization in the stomach were evaluated. RESULTS: Saccharomyces cerevisiae-based H. pylori oral vaccines were successfully constructed. Mice orally administered with EBY100/pYD1-UreB, EBY100/pYD1-VacA, or EBY100/pYD1-UreB + EBY100/pYD1-VacA exhibited a significant humoral immune response as well as a mucosal immune response. Importantly, S. cerevisiae-based oral vaccines could effectively reduce bacterial loads with statistical significance after H. pylori infection. CONCLUSIONS: Our study shows that S. cerevisiae-based platforms can serve as an alternative approach for the future development of promising bacterial oral vaccine candidates.