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Interstitial lung disease (ILD) is a group of diffuse parenchymal infiltrating diseases of different etiologies. The neutrophil-to-lymphocyte ratio (NLR) can reflect ILD’s existence, progression, and prognosis and is currently regarded as a promising biological marker. This meta-analysis assessed elevated NLR levels in ILD for their predictive value. From inception to July 27, 2022, the Scopus, Cochrane Library, Web of Science, Embase, and PubMed databases were checked thoroughly. We used the weighted mean difference (WMD) and 95% confidence interval (CI) to compare blood NLR values between groups. We examined the relationship between poor prognoses and elevated NLR concentrations in ILD patients using odds ratios (ORs) and 95% CI. After initially including 443 studies, 24 were ultimately analyzed. Fifteen studies(ILD:n = 2,912, Non-ILD: n = 2,868) revealed that the NLR values in the ILD group were relatively high (WMD = 0.61, 95% CI 0.43–0.79, p = 0.001). Eight articles (with poor prognoses: n = 407, without poor prognoses: n = 340) indicated that ILD patients with poor prognoses had higher NLR values (WMD = 1.33, 95% CI 0.32–2.33, p = 0.01). This distinction was especially noticeable in patients with the connective tissue disease (CTD)associated with ILD subgroup (WMD = 3.53, 95% CI 1.54–5.51, p = 0.0005). The pooled OR for increased NLR levels forecasting poor prognoses of ILD was 1.09 (95% CI 1.03–1.15, p = 0.0008). Increasing blood NLR values have clinical significance and application value for detecting ILD and predicting its poor prognosis, especially in CTD patients.

Objective To evaluate the clinical efficacy of a novel ophthalmic viscosurgical device-free method using an anterior chamber maintainer for intraocular collamer lens implantation in eyes with myopia. Methods Forty patients underwent bilateral intraocular collamer lens implantation, with one eye receiving the traditional implantation method using an ophthalmic viscosurgical device and the other eye undergoing the anterior chamber maintainer method. Preoperative and postoperative parameters, including uncorrected distance visual acuity, best-corrected distance visual acuity, spherical equivalent, intraocular pressure, aberrations, subjective visual quality, corneal endothelial cell density, operation time, and complications, were compared between and within the two groups. Results In the traditional group, 10% of eyes had intraocular pressure >22 mmHg at 2 h postoperatively, compared with 0% in the anterior chamber maintainer group (P < 0.001). The anterior chamber maintainer group showed better uncorrected and best-corrected distance visual acuity, spherical equivalent, total and low-order aberrations, and defocus at 1 day postoperatively (all P < 0.05), as well as shorter operation time (2.85 ± 0.30 vs. 4.37 ± 0.66 min, P < 0.001). No complications were observed except early intraocular pressure elevation in the traditional group. Conclusion The anterior chamber maintainer intraocular collamer lens implantation method provides faster visual recovery, a shorter operation time, and more stable intraocular pressure. It offers a convenient alternative to the traditional approach, avoiding ophthalmic viscosurgical device-related complications without introducing new ones.

Vancomycin-resistant enterococci (VRE), consisting of pathogenic Enterococcus faecalis and E. faecium, is a leading cause of hospital-acquired infections (HAIs). We recently repurposed the FDA-approved human carbonic anhydrase (CA) inhibitor acetazolamide (AZM) against VRE agent with the likely mechanism of action for the molecules being inhibition of one, or both, of the bacterial CA isoforms expressed in VRE. To elucidate how inhibitor binding to the enzymes relates to MIC, we further characterised the inhibition constants (K i ) against the E. faecium α-CA (Efα-CA) and γ-CA (Efγ-CA), as well as against human CA I (hCAI) and human CA II (hCAII) to assess selectivity. We have also utilised homology modelling and molecular dynamics (MD) simulations to gain a better understanding of the potential interactions the molecules are making with the targets. In this paper, we elaborate on the SAR for the AZM analogs as it pertains to MIC and K i for each CA.

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk.

Systemic sclerosis (SSc) is a chronic systemic disease characterized by immune dysregulation and fibrosis for which there is no effective treatment. Animal models are crucial for advancing SSc research. Tree shrews are genetically, anatomically, and immunologically closer to humans than rodents. Thus, the tree shrew model provides a unique opportunity for translational research in SSc. In this study, a SSc tree shrew model was constructed by subcutaneous injection of different doses of bleomycin (BLM) for 21 days. We assessed the degree of inflammation and fibrosis in the skin and internal organs, and antibodies in serum. Furthermore, RNA sequencing and a series of bioinformatics analyses were performed to analyze the transcriptome changes, hub genes and immune infiltration in the skin tissues of BLM induced SSc tree shrew models. Multiple sequence alignment was utilized to analyze the conservation of selected target genes across multiple species. Subcutaneous injection of BLM successfully induced a SSc model in tree shrew. This model exhibited inflammation and fibrosis in skin and lung, and some developed esophageal fibrosis and secrum autoantibodies including antinuclear antibodies and anti-scleroderma-70 antibody. Using RNA sequencing, we compiled skin transcriptome profiles in SSc tree shrew models. 90 differentially expressed genes (DEGs) were identified, which were mainly enriched in the PPAR signaling pathway, tyrosine metabolic pathway, p53 signaling pathway, ECM receptor interaction and glutathione metabolism, all of which are closely associated with SSc. Immune infiltration analysis identified 20 different types of immune cells infiltrating the skin of the BLM-induced SSc tree shrew models and correlations between those immune cells. By constructing a protein-protein interaction (PPI) network, we identified 10 hub genes that were significantly highly expressed in the skin of the SSc models compared to controls. Furthermore, these genes were confirmed to be highly conserved in tree shrews, humans and mice. This study for the first time comfirmed that tree shrew model of SSc can be used as a novel and promising experimental animal model to study the pathogenesis and translational research in SSc.

Aortic aneurysm and dissection (AAD) represent a highly lethal cardiovascular condition. Ferroptosis has recently been implicated in AAD development and progression. However, ferroptosis-related genes (FRGs) have not been systematically identified and verified in AAD. Seven human AAD datasets downloaded from Gene Expression Omnibus were analyzed, and 113 potential AAD-related FRGs were identified. Function enrichment analyses revealed that the FRGs were mainly associated with responses to chemical stress and cytokine signaling in the immune system. Protein-protein interaction network analyses identified 8 hub FRGs including . All these FRGs were significantly increased in patients with aortic aneurysm. Additionally, immune cell infiltration analyses revealed these FRGs were strongly correlated with the higher CD4 Tem and macrophages fraction in AAD patients. Particularly, increased expression of PTGS2 in AAD patients was further validated using our newly collected clinical aortic specimens. Importantly, we found that PTGS2 knockdown could reduce the expression of MMP9 and MMP2 but increase GPX4 expression in macrophages. Conversely, while PTGS2 overexpression upregulated MMP9 and MMP2 expression but downregulated GPX4 expression, the regulatory effects of PTGS2 on these genes were largely blunted by ferroptosis inhibitors. Functionally, administration of celecoxib, a PTGS2-specific inhibitor, into mice significantly reduced β-aminopropionitrile-induced AAD development and progression. Through an integrative bioinformatics analysis, we have identified multiple key AAD-related FRGs including PTGS2. Functional studies also suggest a functional role of PTGS2 in ferroptosis and AAD development, offering novel insights into pathogenesis of human AAD.

In this study, we designed and developed a new drug delivery system of multifunctional composite microcapsules for oral administration of insulin. Firstly, in order to enhance the encapsulation efficiency, insulin was complexed with functional sodium deoxycholate to form insulin-sodium deoxycholate complex using hydrophobic ion pairing method. Then the complex was encapsulated into poly(lactide-co-glycolide) (PLGA) nanoparticles by emulsion solvent diffusion method. The PLGA nanoparticles have a mean size of 168 nm and a zeta potential of −29.2 mV. The encapsulation efficiency was increased to 94.2% for the complex. In order to deliver insulin to specific gastrointestinal regions and reduce the burst release of insulin from PLGA nanoparticles, hence enhancing the bioavailability of insulin, enteric targeting multifunctional composite microcapsules were further prepared by encapsulating PLGA nanoparticles into pH-sensitive hydroxypropyl methyl cellulose phthalate (HP55) using organic spray-drying method. A pH-dependent insulin release profile was observed for this drug delivery system in vitro. All these strategies help to enhance the encapsulation efficiency, control the drug release, and protect insulin from degradation. In diabetic fasted rats, administration of the composite microcapsules produced a great enhancement in the relative bioavailability, which illustrated that this formulation was an effective candidate for oral insulin delivery.

Background/Aims: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, and is the most common type of lymphoma in adults. Although significant progress in treatment has been made using chemotherapy combinations, there exist a large amount of relapse or refractory cases. Thus, effective clinical biomarkers for DLBCL are urgently needed. Our study aims to explore the predictive significance of using the immune response to tumor burden ratio [defined as the lymphocyte to monocyte ratio (LMR)/lactate dehydrogenase (LDH) levels] in 184 DLBCL patients and the potential mechanism underlying the use of the LMR to tumor burden ratio in predicting patient survival. Methods: The correlation between serum LDH levels and tumor levels assessed by PET-CT was determined using Spearman’s correlation analysis. Clinical data from 184 DLBCL patients was assessed using receiver operating characteristic curve analysis and survival analysis. The potential correlation between tumor burden and lymphocytes or monocytes was analyzed by immunohistochemical staining, flow cytometry, and ELISA analysis of patient samples. In addition, we performed in vitro studies to further determine the effects of tumor burden on the anti-tumor activity of T lymphocytes. Results: We observed that serum LDH was an excellent surrogate marker of tumor burden in DLBCL patients, and that the ratio of LMR to LDH was an independent prognostic biomarker capable of predicting survival in DLBCL patients. Further analysis showed that a high tumor burden was correlated with decreased Ki67 expression in T cells, either in the solid tumor tissue or in the circulating blood. In addition, based on an in vitro co-culture study, a higher tumor burden led to the suppression of the anti-tumor response of T cells. Furthermore, we found that a higher tumor burden was correlated with the differentiation of monocytes to tumor associated macrophages in the tumor micro-environment. Both results demonstrate the importance of considering both the immune system and tumor burden for prognostic analysis. Conclusion: Our study has identified a novel clinical biomarker, namely, the immune response to tumor burden ratio, that can be used to distinguish survival outcomes in DLBCL patients, and demonstrated the potential mechanism underlying the use of this biomarker, that incorporates both the immune system and tumor burden, for use in future clinical applications.

Cyclin Y-like 1 (Ccnyl1) is a newly-identified member of the cyclin family and is highly similar in protein sequences to Cyclin Y (Ccny). However, the function of Ccnyl1 is poorly characterized in any organism. Here we found that Ccnyl1 was most abundantly expressed in the testis of mice and was about seven times higher than the level of Ccny. Male Ccnyl1-/- mice were infertile, whereas both male and female Ccny-/- mice displayed normal fertility. These results suggest that Ccnyl1, but not Ccny, is indispensable for male fertility. Spermatozoa obtained from Ccnyl1-/- mice displayed significantly impaired motility, and represented a thinned annulus region and/or a bent head. We found that the protein, but not the mRNA, level of cyclin-dependent kinase 16 (CDK16) was decreased in the testis of Ccnyl1-/- mice. Further study demonstrated that CCNYL1 interacted with CDK16 and this interaction mutually increased the stability of these two proteins. Moreover, the interaction increased the kinase activity of CDK16. In addition, we observed an alteration of phosphorylation levels of CDK16 in the presence of CCNYL1. We identified the phosphorylation sites of CDK16 by mass spectrometry and revealed that several phosphorylation modifications on the N-terminal region of CDK16 were indispensable for the CCNYL1 binding and the modulation of CDK16 kinase activity. Our results therefore reveal a previously unrecognized role of CCNYL1 in regulating spermatogenesis through the interaction and modulation of CDK16.

Introduction: Bacterial keratitis refers to a prevalent sight-threatening ophthalmologic infection. Owing to the challenge of antimicrobial resistance in treating bacterial keratitis, novel therapeutic strategies are needed. Resolvin D1 (RvD1), an endogenous lipid mediator, exhibits anti-inflammatory and immune-regulatory effects. The present study was aimed at investigating whether RvD1 alleviates lipopolysaccharide-induced inflammation to protect corneal fibroblasts and explore its potential mechanisms. Methods: In this study, Raw264.7 cells were polarized towards M1 or M2 macrophages by the addition of lipopolysaccharides LPS or interleukin (IL)-4, respectively, and were treated with or without RvD1. Flow cytometry and Western blot were used to determine the expression of M1 and M2-related markers. EdU assay and trans-well assay were performed to detect the proliferation and migration ability of corneal fibroblasts. Bioinformatics analysis (GO and KEGG) of RNA-seq was applied to explore the RvD1-related signaling pathways. siRNA-c-Fos was further used to confirm the role of Fos expression in RvD1-mediated macrophage polarization. Flow cytometry and Western blotting analysis were performed to demonstrate that RvD1 alleviated LPS-induced inflammation by suppressing M1 macrophage polarization, facilitating M2 macrophage polarization, and increasing corneal fibroblast proliferation. Bioinformatics analysis identified PI3K-AKT, IL-17, and MAPK signaling pathways as potential targets of RvD1 in corneal inflammation. Results: Enrichment analysis indicated that the RvD1 target gene showed a strong relationship to the regulation of macrophage polarization. RvD1 highly upregulated M2 macrophages by promoting c-Fos expression and enhanced the proliferation and migration of mouse corneal fibroblasts through modulating c-Fos expression. Conclusion: Our findings reveal that RvD1 conferred protective effects against LPS-induced inflammation by enhancing M2 macrophage polarization through the promotion of c-Fos expression. Thus, RvD1 may be a potential therapeutic compound for enhancing corneal fibroblast proliferation and migration while attenuating inflammation.