Retinal nerve fiber layer defects and chronic kidney disease: the Kailuan Eye Study.

AIM: To investigate whether retinal nerve fiber layer defects (RNFLDs) is a potential risk factor for chronic kidney disease (CKD) in Chinese adults. METHODS: The Kailuan Eye Study was a population-based study that included 14 440 participants. All participants underwent detailed assessments, RNFLDs were diagnosed using color fundus photographs. RESULTS: Overall, 12 507 participants [8533 males (68.23%)] had complete systemic examination data and at least one evaluable fundus photograph. RNFLDs were found in 621 participants [5.0%; 95% confidence interval (CI): 4.6%-5.34%], and 70 cases of multiple RNFLDs were found (11.27%). After adjusting multiple factors, RNFLDs was significantly associated with CKD severity, the ORs of CKD stage 3, stage 4 and stage 5 were 1.698, 4.167, and 9.512, respectively. Multiple RNFLDs were also associated with CKD severity after adjusting multiple factors, the ORs of CKD stage 3 and stage 5 were 4.465 and 11.833 respectively. Furthermore, 2294 participants had CKD (18.34%, 95%CI: 17.68%-18.99%). After adjusting for other factors, CKD presence was significantly correlated with the presence of RNFLDs. CONCLUSION: The strongest risk factors for RNFLDs are CKD and hypertension. Conversely, RNFLDs can be an ocular feature in patients with CKD. Fundoscopy can help detect systemic diseases, and assessment for RNFLDs should be considered in CKD patients.

Revealing Different Pathways for Influenza A Virus To Reach Microtubules after Endocytosis by Quantum Dot-Based Single-Virus Tracking.

Actin- and microtubule (MT)-based transport systems are essential for intracellular transport. During influenza A virus (IAV) infection, MTs provide long tracks for virus trafficking toward the nucleus. However, the role of the actin cytoskeleton in IAV entry and especially the transit process is still ambiguous. Here, by using quantum dot-based single-virus tracking, it was revealed that the actin cytoskeleton was crucial for the virus entry via clathrin-mediated endocytosis (CME). After entry via CME, the virus reached MTs through three different pathways: the virus (1) was driven by myosin VI to move along actin filaments to reach MTs (AF); (2) was propelled by actin tails assembled by an Arp2/3-dependent mechanism to reach MTs (AT); and (3) directly reached MTs without experiencing actin-related movement (NA). Therefore, the NA pathway was the main one and the fastest for the virus to reach MTs. The AT pathway was activated only when plenty of viruses entered the cell. The viruses transported by the AF and AT pathways shared similar moving velocities, durations, and displacements. This study comprehensively visualized the role of the actin cytoskeleton in IAV entry and transport, revealing different pathways for IAV to reach MTs after entry. The results are of great significance for globally understanding IAV infection and the cellular endocytic transport pathway.

Inhalable Polymeric Microparticles for Phage and Photothermal Synergistic Therapy of Methicillin-Resistant Staphylococcus aureus Pneumonia.

Acute methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a common and serious lung infection with high morbidity and mortality rates. Due to the increasing antibiotic resistance, toxicity, and pathogenicity of MRSA, there is an urgent need to explore effective antibacterial strategies. In this study, we developed a dry powder inhalable formulation which is composed of porous microspheres prepared from poly(lactic-co-glycolic acid) (PLGA), internally loaded with indocyanine green (ICG)-modified, heat-resistant phages that we screened for their high efficacy against MRSA. This formulation can deliver therapeutic doses of ICG-modified active phages to the deep lung tissue infection sites, avoiding rapid clearance by alveolar macrophages. Combined with the synergistic treatment of phage therapy and photothermal therapy, the formulation demonstrates potent bactericidal effects in acute MRSA pneumonia. With its long-term stability at room temperature and inhalable characteristics, this formulation has the potential to be a promising drug for the clinical treatment of MRSA pneumonia.

Exploring the Link Between Autophagy-Lysosomal Dysfunction and Early Heterotopic Ossification in Tendons.

Heterotopic ossification (HO), the pathological formation of bone within soft tissues such as tendon and muscle, is a notable complication resulting from severe injury. While soft tissue injury is necessary for HO development, the specific molecular pathology responsible for trauma-induced HO remains a mystery. The previous study detected abnormal autophagy function in the early stages of tendon HO. Nevertheless, it remains to be determined whether autophagy governs the process of HO generation. Here, trauma-induced tendon HO model is used to investigate the relationship between autophagy and tendon calcification. In the early stages of tenotomy, it is observed that autophagic flux is significantly impaired and that blocking autophagic flux promoted the development of more rampant calcification. Moreover, Gt(ROSA)26sor transgenic mouse model experiments disclosed lysosomal acid dysfunction as chief reason behind impaired autophagic flux. Stimulating V-ATPase activity reinstated both lysosomal acid functioning and autophagic flux, thereby reversing tendon HO. This present study demonstrates that autophagy-lysosomal dysfunction triggers HO in the stages of tendon injury, with potential therapeutic targeting implications for HO.

Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

Bacteria-mediated resistance of neutrophil extracellular traps to enzymatic degradation drives the formation of dental calculi.

Dental calculi can cause gingival bleeding and periodontitis, yet the mechanism underlying the formation of such mineral build-ups, and in particular the role of the local microenvironment, are unclear. Here we show that the formation of dental calculi involves bacteria in local mature biofilms converting the DNA in neutrophil extracellular traps (NETs) from being degradable by the enzyme DNase I to being degradation resistant, promoting the nucleation and growth of apatite. DNase I inhibited NET-induced mineralization in vitro and ex vivo, yet plasma DNases were ineffective at inhibiting ectopic mineralization in the oral cavity in rodents. The topical application of the DNA-intercalating agent chloroquine in rodents fed with a dental calculogenic diet reverted NET DNA to its degradable form, inhibiting the formation of calculi. Our findings may motivate therapeutic strategies for the reduction of the prevalence of the deposition of bacteria-driven calculi in the oral cavity.

Biomimetic Self-Maturation Mineralization System for Enamel Repair.

Enamel repair is crucial for restoring tooth function and halting dental caries. However, contemporary research often overlooks the retention of organic residues within the repair layer, which hinders the growth of dense crystals and compromises the properties of the repaired enamel. During the maturation of natural enamel, the organic matrix undergoes enzymatic processing to facilitate further crystal growth, resulting in a highly mineralized tissue. Inspired by this process, a biomimetic self-maturation mineralization system is developed, comprising ribonucleic acid-stabilized amorphous calcium phosphate (RNA-ACP) and ribonuclease (RNase). The RNA-ACP induces initial mineralization in the form of epitaxial crystal growth, while the RNase present in saliva automatically triggers a biomimetic self-maturation process. The mechanistic study further indicates that RNA degradation prompts conformational rearrangement of the RNA-ACP, effectively excluding the organic matter introduced earlier. This exclusion process promotes lateral crystal growth, resulting in the generation of denser enamel-like apatite crystals that are devoid of organic residues. This strategy of eliminating organic residues from enamel crystals enhances the mechanical and physiochemical properties of the repaired enamel. The present study introduces a conceptual biomimetic mineralization strategy for effective enamel repair in clinical practice and offers potential insights into the mechanisms of biomineral formation.

Genome-wide identification and analysis of the evolution and expression pattern of the SBP gene family in two Chimonanthus species.

BACKGROUND: Chimonanthus praecox and Chimonanthus salicifolius are closely related species that diverged approximately six million years ago. While both C. praecox and C. salicifolius could withstand brief periods of low temperatures of - 15 °C. Their flowering times are different, C. praecox blooms in early spring, whereas C. salicifolius blooms in autumn. The SBP-box (SQUAMOSA promoter-binding protein) is a plant-specific gene family that plays a crucial vital role in regulating plant flowering. Although extensively studied in various plants, the SBP gene family remains uncharacterized in Calycanthaceae. METHODS AND RESULTS: We conducted genome-wide identification of SBP genes in both C. praecox and C. salicifolius and comprehensively characterized the chromosomal localization, gene structure, conserved motifs, and domains of the identified SBP genes. In total, 15 and 18 SBP genes were identified in C. praecox and C. salicifolius, respectively. According to phylogenetic analysis, the SBP genes from Arabidopsis, C. praecox, and C. salicifolius were clustered into eight groups. Analysis of the gene structure and conserved protein motifs showed that SBP proteins of the same subfamily have similar motif structures. The expression patterns of SBP genes were analyzed using transcriptome data. The results revealed that more than half of the genes exhibited lower expression levels in leaves than in flowers, suggesting their potential involvement in the flower development process and may be linked to the winter and autumn flowering of C. praecox and C. salicifolius. CONCLUSION: Thirty-three SBPs were identified in C. praecox and C. salicifolius. The evolutionary characteristics and expression patterns were examined in this study. These results provide valuable information to elucidate the evolutionary relationships of the SBP family and help determine the functional characteristics of the SBP genes in subsequent studies.

Effect of Extracellular Ribonucleic Acids on Neurovascularization in Osteoarthritis.

Osteoarthritis is a degenerative disease characterized by abnormal neurovascularization at the osteochondral junctions, the regulatory mechanisms of which remain poorly understood. In the present study, a murine osteoarthritic model with augmented neurovascularization at the osteochondral junction is used to examine this under-evaluated facet of degenerative joint dysfunction. Increased extracellular RNA (exRNA) content is identified in neurovascularized osteoarthritic joints. It is found that the amount of exRNA is positively correlated with the extent of neurovascularization and the expression of vascular endothelial growth factor (VEGF). In vitro binding assay and molecular docking demonstrate that synthetic RNAs bind to VEGF via electrostatic interactions. The RNA-VEGF complex promotes the migration and function of endothelial progenitor cells and trigeminal ganglion cells. The use of VEGF and VEGFR2 inhibitors significantly inhibits the amplification of the RNA-VEGF complex. Disruption of the RNA-VEGF complex by RNase and polyethyleneimine reduces its in vitro activities, as well as prevents excessive neurovascularization and osteochondral deterioration in vivo. The results of the present study suggest that exRNAs may be potential targets for regulating nerve and blood vessel ingrowth under physiological and pathological joint conditions.