Genome editing of FTR42 improves zebrafish survival against virus infection by enhancing IFN immunity.

The development of CRISPR-Cas9 technology introduces an efficient tool for precise engineering of fish genomes. With a short reproduction cycle, zebrafish infection mode can be referenced as antiviral breeding researches in aquaculture fish. Previously we identified a crucian carp-specific gene ftrca1 as an inhibitor of interferon response in vitro. Here, we demonstrate that genome editing of zebrafish ftr42, a homolog of ftrca1, generates a zebrafish mutant (ftr42lof/lof) with an improved resistance to SVCV infection. Zebrafish ftr42 acts as a virus-induced E3 ligase and downregulates IFN antiviral response by facilitating TBK1 protein degradation and also IRF7 mRNA decay. Genome editing results in loss of function of zebrafish ftr42, which enables zebrafish to have enhanced interferon response, thus improving zebrafish survival against virus infection. Our results suggest that fine-tuning fish IFN innate immunity through genome editing of negative regulators can genetically improve viral resistance in fish.

Inverted U-shaped associations between serum uric acid and fasting - plasma glucose level in non-diabetic, pre-diabetic, and diabetic adults: A population-based study in China.

OBJECTIVE: This study was designed to examine the correlation between serum uric acid (SUA) and fasting plasma glucose (FPG) levels across non-diabetic, pre-diabetic, and diabetic adults from Northwest China. MATERIALS AND METHODS: This study utilized data from a cross-sectional survey conducted in Ningxia Hui Autonomous Region, which investigated the prevalence and risk factors of cardiovascular disease. All subjects underwent tests for SUA and FPG levels. Generalized additive models and two-piecewise linear regression models were applied to explore the relationships between SUA and FPG level. The triglyceride-glucose (TyG) index was examined as a measure of insulin resistance, with an analysis of its mediating effects on the association between SUA and FPG level. RESULTS: A total of 10,217 individuals aged 18 and over were included. Generalized additive models verified the inverted U-shaped association between SUA and FPG levels, and the inflection points of FPG levels in the curves were 6.5 mmol/L in males and 8.8 mmol/L in females. The TyG index is an intermediate variable in the relationship between SUA levels and elevated FPG levels, with mediating effects of 12.82% (P < 0.001) for males and 34.02% (P < 0.001) for females. CONCLUSIONS: An inverted U-shaped association between FPG and SUA levels was observed in both genders. The threshold of FPG level was lower in males than in females. The relationship between these variables seems to be partially mediated by serum insulin levels.

Reconfigurable moiré nanolaser arrays with phase synchronization.

Miniaturized lasers play a central role in the infrastructure of modern information society. The breakthrough in laser miniaturization beyond the wavelength scale has opened up new opportunities for a wide range of applications1-4, as well as for investigating light-matter interactions in extreme-optical-field localization and lasing-mode engineering5-19. An ultimate objective of microscale laser research is to develop reconfigurable coherent nanolaser arrays that can simultaneously enhance information capacity and functionality. However, the absence of a suitable physical mechanism for reconfiguring nanolaser cavities hinders the demonstration of nanolasers in either a single cavity or a fixed array. Here we propose and demonstrate moiré nanolaser arrays based on optical flatbands in twisted photonic graphene lattices, in which coherent nanolasing is realized from a single nanocavity to reconfigurable arrays of nanocavities. We observe synchronized nanolaser arrays exhibiting high spatial and spectral coherence, across a range of distinct patterns, including P, K and U shapes and the Chinese characters '' and '' ('China' in Chinese). Moreover, we obtain nanolaser arrays that emit with spatially varying relative phases, allowing us to manipulate emission directions. Our work lays the foundation for the development of reconfigurable active devices that have potential applications in communication, LiDAR (light detection and ranging), optical computing and imaging.

Prevalence of hyperuricaemia among adults from Ningxia Hui Autonomous Region, China: a cross-sectional study.

OBJECTIVE: This study aimed to estimate the prevalence of hyperuricaemia (HUA) and investigate its risk factors in the general adult population of Ningxia Hui Autonomous Region (NHAR), China. DESIGN: Cross-sectional study. SETTING: Survey of cardiovascular disorders and their related risk factors in NHAR, China. PARTICIPANTS: 10 803 permanent residents aged 18 and older. MAIN OUTCOME MEASURES: HUA was defined as serum uric acid levels >420 µmol/L for men and >360 µmol/L for women. RESULTS: The overall prevalence of HUA in NHAR adults was 19.81% (95% CI 19.06 to 20.57), with prevalence values of 24.91% (95% CI 23.70 to 26.14) in men and 15.58% (95% CI 14.66 to 16.53, p<0.001) in women. The prevalence of HUA was higher in urban residents than in rural residents (23.26% vs 17.02%, p<0.001). HUA prevalence was relatively high in individuals younger than 30 years for both men and women, then decreased with age, and began to increase at the age of 40 for women and 60 for men. Higher level of education, being overweight or obese, alcohol consumption, hypertension, diabetes, higher triglycerides, higher total cholesterol and poorer renal function were associated with an increased risk of HUA. CONCLUSIONS: HUA prevalence is high among adults in NHAR. Young adults under 30 years and women over 50 years were identified as populations at high risk for HUA. Further attention ought to be placed to promoting healthy diets and implementing early interventions to manage dyslipidaemia, obesity and blood glucose level, as well as advocating for moderation of alcohol consumption.

Identification of novel therapeutic target and prognostic biomarker in matrix metalloproteinase gene family in pancreatic cancer.

Matrix metalloproteinases (MMPs) play an essential role in various physiological events. Recent studies have revealed its carcinogenic effect in malignancies. However, the different expression patterns, prognostic value, and immunological value of MMPs in pancreatic ductal adenocarcinoma (PDAC) are yet to be comprehensively explored. We utilized Gene Expression Profiling Interactive Analysis (GEPIA) and Gene Expression Omnibus databases to explore the abnormal expression of MMPs in PDAC. Then, Kaplan-Meier survival curve and Cox regression analysis were performed to assess the prognostic value of MMPs. Association between MMPs expression and clinicopathological features was analyzed through UALCAN website. Functional annotations and GSEA analysis were performed to excavate the possible signaling pathways involving prognostic-related MMP. TIMER and TISCH database were used to performed immune infiltration analysis. The expression of prognostic-related MMP in pancreatic cancer cell lines and normal pancreatic cells was detected by Real time quantitative PCR. We observed that 10 MMP genes were consistently up-regulated in GEPIA and GSE62452 dataset. Among them, five highly expressed MMPs (MMP1, MMP3, MMP11, MMP14, MMP28) were closely related to poor clinical outcomes of PDAC patients. Cox regression analysis indicated MMP28 was a risk factor influencing the overall survival of patients. In the clinicopathological analysis, up-regulated MMP28 was significantly associated with higher tumor grade and the mutation status of TP53. GSEA analysis demonstrated that high expression of MMP28 was involved in "interferon_alpha_response" and "P53_pathway". Immune infiltration analysis showed that there was no correlation between MMP28 expression and immune cell infiltration. Single-cell sequencing analysis showed MMP28 has strong correlations with malignant cells and stromal cells infiltration in the tumor microenvironment. And MMP28 was highly expressed in various pancreatic cancer cell lines. In conclusion, MMP28 may represent a potential prognosis biomarker and novel therapeutic molecular targets for PDAC.

Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway.

INTRODUCTION: Hexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI). Nevertheless, the impact of Hexarelin on acute kidney injury (AKI) and its underlying mechanism remains unclear. In this study, we investigated the therapeutic potential of Hexarelin in I/R-induced AKI and elucidated its molecular mechanisms. METHODS: We assessed the protective effects of Hexarelin through both in vivo and in vitro experiments. In the I/R-induced AKI model, rats were pretreated with Hexarelin at 100 µg/kg/d for 7 days before being sacrificed 24 h post-IRI. Subsequently, kidney function, histology, and apoptosis were assessed. In vitro, hypoxia/reoxygenation (H/R)-induced HK-2 cell model was used to investigate the impact of Hexarelin on apoptosis in HK-2 cells. Then, we employed molecular docking using a pharmmapper server and autodock software to identify potential target proteins of Hexarelin. RESULTS: In this study, rats subjected to I/R developed severe kidney injury characterized by tubular necrosis, tubular dilatation, increased serum creatinine levels, and cell apoptosis. However, pretreatment with Hexarelin exhibited a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis. This was achieved through the downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and the upregulation of the anti-apoptotic protein Bcl-2. Consistent with the in vivo results, Hexarelin also reduced cell apoptosis in post-H/R HK-2 cells. Furthermore, our analysis using GSEA confirmed the essential role of the apoptosis pathway in I/R-induced AKI. Molecular docking revealed a strong binding affinity between Hexarelin and MDM2, suggesting the potential mechanism of Hexarelin's anti-apoptosis effect at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein that of p53. To validate these findings, we evaluated the relative expression of MDM2 and p53 in I/R-induced AKI with or without Hexarelin pre-administration and observed a significant suppression of MDM2 and p53 by Hexarelin in both in vivo and in vitro experiments. CONCLUSION: Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI.

Hospitalized patients received furosemide undergoing acute kidney injury: the risk and prediction tool.

PURPOSE: Furosemide, a frequently prescribed diuretic for managing congestive heart failure and edema, remains a topic of debate regarding its potential risk of inducing acute kidney injury (AKI) in patients. Consequently, this study aims to examine the occurrence of hospital-acquired AKI (HA-AKI) in hospitalized patients who are administered furosemide and to investigate potential risk factors associated with this outcome. METHODS: This study encompassed a cohort of 22374 hospitalized patients who either received furosemide treatment or not from June 1, 2012, to December 31, 2017. Propensity score matching was employed to establish comparability between the two groups regarding covariates. Subsequently, a nomogram was constructed to predict the probability of AKI occurrence among patients who underwent furosemide treatment. RESULTS: The regression analysis identified the single-day total dose of furosemide as the most significant factor for AKI, followed by ICU administration, estimated glomerular filtration rate, antibiotic, statin, NSAIDs, ß-blockers, proton pump inhibitor, chronic kidney disease, and 7 other indicators. Subgroup analysis revealed a synergistic effect of furosemide with surgical operation, previous treatment with ß-blockers, ACEI/ARB and antibiotics, leading to an increased risk of AKI when used in combination. Subsequently, a visually represented prognostic nomogram was developed to predict AKI occurrence in furosemide users. The predictive accuracy of the nomogram was assessed through calibration analyses, demonstrating an excellent agreement between the nomogram predictions and the actual likelihood of AKI, with a probability of 77.40%. CONCLUSIONS: Careful consideration of factors such as dosage, concurrent medication use, and renal function of the patient is necessary for clinical practice when using furosemide. Our practical prognostic model for HA-AKI associated with furosemide use can be utilized to assist clinicians in making informed decisions about patient care and treatment.

Land Use Influencing the Distribution of Pesticides in Surface Water: The Case of the Ma River and Its Tributaries in Thanh Hoa Province, Vietnam.

Pesticide residues are regularly found in surface water, which could be dangerous for freshwater ecosystems and biodiversity. Pesticides may enter waters through a variety of pathways, but runoff from irrigation or precipitation has the highest quantities. Previous studies analyzing the pesticides pollution or ecological risks of pesticides focused on few regions (e.g., European and United States), whereas analysis of pesticide pollution in Southeast Asia and especially in Vietnam is limited. This study presents an investigation of banned pesticides used across the range of land use in catchments of the Ma river and its tributaries in Thanh Hoa province, Vietnam. Applying principal component analysis (PCA), we investigated the relationship between specific pesticides and land use. Besides, cluster analysis (CA), the method of aggregating monitoring locations, was applied in this study to find spatial pattern of pesticides pollution. Due to their persistence and remobilization during floods and runoff, all ten banned pesticides-eight insecticides (aldrin/dieldrin, BHC, chlordane, endrin, heptachlor, lindane, malathion, and parathion) and two herbicides (paraquat, and 2,4D)-still remain in surface water and are not presumably influenced by the fraction of land use area in the catchments. Clustering results revealed that banned pesticides still occur in some areas. Site TH08 close to Le Mon industrial zone and TH18 in Thanh Hoa city have higher concentrations of banned pesticides than other sites due to their highly toxic and long-time existence in the environment. Overall, our study provides approach to investigate pesticides in surface water for a province in Vietnam that may be used for future ecotoxicological studies to enhance risk assessment for stream ecosystems.

Association between serum uric acid levels and clinical outcomes in patients with acute kidney injury.

BACKGROUND: The effects of serum uric acid (SUA) on clinical outcomes in patients with acute kidney injury (AKI) are unclear. The aim of this study was to investigate the association of SUA levels with clinical outcomes of AKI patients. METHODS: The data of AKI patients hospitalized in the Affiliated Hospital of Qingdao University were retrospectively reviewed. Multivariable logistic regression was utilized to assess the association between SUA levels and the clinical outcomes of AKI patients. Receiver operating characteristic (ROC) analysis was applied to assess the predictive ability of SUA levels for in-hospital mortality in patients with AKI. RESULTS: A total of 4,646 AKI patients were eligible for study inclusion. In multivariable analysis, after adjustment for various confounding factors in the fully adjusted model, a higher SUA level was found to be associated with increased in-hospital mortality of AKI patients with an odds ratio (OR) of 1.72 (95% CI, 1.21-2.33, p = 0.005) for the SUA level >5.1-6.9 mg/dl group and 2.75 (95% CI, 1.78-4.26, p < 0.001) for the SUA level >6.9 mg/dl group compared with the reference group (SUA ≤3.6 mg/dl). In the ROC analysis, the area under the curve (AUC) of SUA was 0.65 with a sensitivity of 51% and a specificity of 73%. CONCLUSIONS: An elevated SUA level is associated with an increased risk of in-hospital mortality in patients with AKI, and it appears to be an independent prognostic marker for these patients.

Mesenchymal stem cells protect against sepsis-associated acute kidney injury by inducing Gal-9/Tim-3 to remodel immune homeostasis.

OBJECTIVE: The present study investigated the specific mechanism by which mesenchymal stem cells (MSCs) protect against sepsis-associated acute kidney injury (SA-AKI). METHODS: Male C57BL/6 mice underwent cecal ligation and puncture surgery to induce sepsis and then received either normal IgG or MSCs (1 × 106 cells, intravenously) plus Gal-9 or soluble Tim-3 3 h after surgery. RESULTS: After cecal ligation and puncture surgery, the mice injected with Gal-9 or MSCs plus Gal-9 had a higher survival rate than the mice in the IgG treatment group. Treatment with MSCs plus Gal-9 decreased serum creatinine and blood urea nitrogen levels, improved tubular function recovery, reduced IL-17 and RORγt levels and induced IL-10 and FOXP3 expression. Additionally, the Th17/Treg cell balance was altered. However, when soluble Tim-3 was used to block the Gal-9/Tim-3 pathway, the septic mice developed kidney injury and exhibited increased mortality. Treatment with MSCs plus soluble Tim-3 blunted the therapeutic effect of MSCs, inhibited the induction of Tregs, and suppressed the inhibition of differentiation into Th17 cells. CONCLUSION: Treatment with MSCs significantly reversed the Th1/Th2 balance. Thus, the Gal-9/Tim-3 pathway may be an important mechanism of MSC-mediated protection against SA-AKI.

Dynamic multivariate analysis for pollution assessment and river habitat conservation in the Vietnamese La Buong watershed.

Analysis of temporal patterns of high-dimensional time-series water quality data is essential for pollution management worldwide. This study has applied dynamic factor analysis (DFA) and cluster analysis (CA) to analyze time-series water quality data monitored at the five stations installed along the La Buong river in Southern Vietnam. Application of the DFA identified two types of temporal patterns, one of the run-off driven parameters (total suspended solid (TSS), turbidity, and iron) and the other of diffuse source pollution. The association of the variables like BOD5 and COD at most stations to the run-off-driven parameters revealed their sharing of drivers. On the contrary, separating variables like phosphate (PO43) at the three upstream stations from the run-off patterns suggested their local point-source origin. The DFA-derived factors were later used in the time-point CA to explore the seasonality of water quality parameters and their pollution intensities compared to regulatory levels. The result suggested intensification in wet season of Fe, TSS, BOD5, and COD concentrations at most sites, which are unobservable in run-off detached parameters like reactive nitrogen, phosphate (PO43-), and E. coli. These findings generated robust insights to support water quality management for river habitat conservation.

Topological polarization singular lasing with highly efficient radiation channel.

Bound states in the continuum (BICs) in photonic crystals describe the originally leaky Bloch modes that can become bounded when their radiation fields carry topological polarization singularities. However, topological polarization singularities do not carry energy to far field, which limits radiation efficiencies of BICs for light emitting applications. Here, we demonstrate a topological polarization singular laser which has a topological polarization singular channel in the second Brillouin zone and a paired linearly polarized radiation channel in the first Brillouin zone. The presence of the singular channel enables the lasing mode with a higher quality factor than other modes for single mode lasing. In the meanwhile, the presence of the radiation channel secures the lasing mode with high radiation efficiency. The demonstrated topological polarization singular laser operates at room temperature with an external quantum efficiency exceeding 24%. Our work presents a new paradigm in eigenmode engineering for mode selection, exotic field manipulation and lasing.

Madelung's Disease: Analysis of Clinical Characteristics, Fatty Mass Distribution, Comorbidities and Treatment of 54 Patients in China.

Purpose: Madelung's disease (MD) is a rare disease characterized by the deposition of unencapsulated fat masses on the face, neck, chest, back and other areas of patients. The aim of the study was to analyze the clinical characteristics, comorbidities and treatment of MD in Chinese populations. Patients and Methods: We retrospectively reviewed the medical records of 54 patients who were diagnosed with MD at the Affiliated Hospital of Qingdao University and Qingdao Municipal Hospital from January 2005 to February 2021 and collected the subjects' demographic information, clinical indicators, location of fat deposits, treatment, complications and prognostic data. Results: Among 54 MD patients in the study, only 1 (1.85%) was female, and the subjects had an average age of 56.65 ± 7.93 years. More than 70% of patients had a history of long-term smoking or/and alcohol abuse. In our study, type I accounted for approximately 61.11% of cases according to Donhauser's classification, and almost all patients had neck fat deposition. MD patients often have multiple comorbidities across several systems, such as the endocrine, digestive, circulatory, urinary, and neurological systems. Among these, endocrine system diseases were the most common comorbidities in our study, accounting for 81.48%. Notably, up to 20.37% of cases were complicated with cancer, especially digestive system tumors. More than 70% of the patients received surgical treatment, and nearly 40% experienced postoperative recurrence. Conclusion: Considering that MD patients often have comorbidities of multiple systems and that a small number of cases are even complicated by cancer, we recommend that clinicians comprehensively assess a patient's condition and complications, advocate that patients quit consuming alcohol and smoking as soon as possible, establish healthy dietary and living habits, and formulate individualized and comprehensive diagnosis and treatment plans.

Association Between Visceral Adiposity Index and Insulin Resistance: A Cross-Sectional Study Based on US Adults.

Background: Visceral obesity index (VAI) is an empirical mathematical model used to evaluate the distribution and function of fat. Some studies have shown that VAI may be associated with the development of insulin resistance. In view of the differences in insulin resistance among different ethnic groups, this study attempts to analyze the special relationship between VAI and insulin resistance in American adults. Methods: We conducted a cross-sectional study through NHANES database. A total of 27309 patients over the age of 18 from the United States took part in the survey. It was divided into two groups: the IR-positive group and the IR-negative group. The association of VAI with IR was evaluated by logistic regression analyses mainly, including univariate analysis, multivariate regression analysis, curve fitting analysis and subgroup analysis. Results: The results showed that in the full-adjusted model, there is a strong positive association between VAI level and insulin resistance (OR: 1.28 (1.2~1.37), P<0.001) and there is a threshold effect. Conclusions: This study suggests that higher VAI levels are associated with insulin resistance. VAI index may be used as a predictor of insulin resistance.

Exploration and validation of metastasis-associated genes for skin cutaneous melanoma.

Skin cutaneous melanoma is a malignant and highly metastatic skin tumor, and its morbidity and mortality are still rising worldwide. However, the molecular mechanisms that promote melanoma metastasis are unclear. Two datasets (GSE15605 and GSE46517) were retrieved to identify the differentially expressed genes (DEGs), including 23 normal skin tissues (N), 77 primary melanoma tissues (T) and 85 metastatic melanoma tissues (M). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to explore the functions of the DEGs. We constructed protein-protein interaction network using the STRING database and Cytoscape software. Using the cytoHubba plugin of Cytoscape, we identified the most significant hub genes by five analytical methods (Degree, Bottleneck, MCC, MNC, and EPC). Hub gene expression was validated using the UALCAN website. Clinical relevance was investigated using The Cancer Genome Atlas resources. Finally, we explored the association between metastasis-associated genes and immune infiltrates through the Tumor Immune Estimation Resource (TIMER) database and performed drug-gene interaction analysis using the Drug-Gene Interaction database. A total of 294 specific genes were related to melanoma metastasis and were mainly involved in the positive regulation of locomotion, mitotic cell cycle process, and epithelial cell differentiation. Four hub genes (CDK1, FOXM1, KIF11, and RFC4) were identified from the cytoHubba plugin of Cytoscape. CDK1 was significantly upregulated in metastatic melanoma compared with primary melanoma, and high CDK1 expression was positively correlated with worse overall survival. Immune infiltration analysis revealed that CDK1 expression negatively correlated with macrophage infiltration (Rho = - 0.164, P = 2.02e-03) and positively correlated with neutrophil cells (Rho = 0.269, P = 2.72e-07) in SKCM metastasis. In addition, we identified that CDK1 had a close interaction with 10 antitumor drugs. CDK1 was identified as a hub gene involved in the progression of melanoma metastasis and may be regarded as a therapeutic target for melanoma patients to improve prognosis and prevent metastasis in the future.

[Scutellarin alleviates lipopolysaccharide-induced renal injury via mediating cysteine-rich protein 61-connective tissue growth factor-nephroblastoma overexpressed gene 1 expression to inhibit nuclear factor-κB signaling pathway].

OBJECTIVE: To explore the protective effect and mechanism of scutellarin (Scu) on sepsis associated-acute kidney injury (SA-AKI). METHODS: (1) In vivo experiment: 36 male C57BL/6 mice were divided into normal saline (NS) control group, lipopolysaccharide (LPS) induced SA-AKI model group (LPS group), 20 mg/kg Scu control group (Scu 20 control group), and 5, 10, 20 mg/kg Scu pretreatment groups by random number table with 6 mice in each group. The SA-AKI model was reproduced by intraperitoneal injection of 10 mg/kg LPS. The NS control group was injected with NS intraperitoneally. The Scu pretreatment groups were intraperitoneally injected with different doses of Scu every day before LPS injection for 1 week. Scu 20 control group was injected with 20 mg/kg Scu for 1 week. After 24 hours of LPS treatment, mice in each group were sacrificed, kidney tissues were collected, and kidney injury was detected by hematoxylin-eosin (HE) staining. Western blotting was used to detect the protein expression levels of nuclear factor-κB (NF-κB) signaling pathway related molecules, apoptosis-related proteins and cysteine-rich protein 61-connective tissue growth factor-nephroblastoma overexpressed gene 1 (CCN1). (2) In vitro experiment: human renal tubular epithelial cell line HK-2 was cultured in vitro and used for experiment when the cells fused to 80%. In the cells without LPS treatment and after 100 g/L LPS treatment, pcDNA3.1-CCN1 and small interfering RNA (siRNA) CCN1 sequence were transfected to overexpress and inhibit CCN1 expression, respectively, to observe whether CCN1 was involved in NF-κB signaling pathway activation and apoptosis. In addition, 100g/L LPS and 20 µmol/L Scu were added into HK-2 cells transfected with and without CCN1 siRNA to investigate the mechanism of protective effect of Scu on LPS-induced HK-2 cells injury. RESULTS: (1) The results of in vivo experiment: the renal function of SA-AKI mice induced by LPS was significantly decreased, and had kidney histological damage and severely damaged renal tubules. Scu could alleviate renal function and histological damage in a dose-dependent manner. Western blotting results showed Scu could reduce the protein expression of NF-κB signaling pathway related molecules and CCN1 in the renal tissue, and had a significant alleviating effect on apoptosis, indicating that CCN1 was involved in NF-κB signaling pathway activation and apoptosis. (2) The results of in vitro experiment: in HK-2 cells not treated with LPS, CCN1 overexpression had no effect on apoptosis related protein and pro-inflammatory factors of NF-κB signaling pathway. In HK-2 cells treated with LPS, overexpression of CCN1 significantly inhibited the mRNA expressions of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), with significant differences as compared with cells stimulated only by LPS [IL-1ß mRNA (2-ΔΔCT): 3.20±0.57 vs. 4.88±0.69, TNF-α mRNA (2-ΔΔCT): 2.99±0.44 vs. 5.00±0.81, MCP-1 mRNA (2-ΔΔCT): 2.81±0.50 vs. 5.41±0.75, all P < 0.05], and the apoptosis-related protein was significantly down-regulated. However, when siRNA was used to inhibit the expression of CCN1, the mRNA expressions of pro-inflammatory factors were significantly increased as compared with cells stimulated only by LPS [IL-1ß mRNA (2-ΔΔCT): 6.01±1.13 vs. 4.88±0.69, TNF-α mRNA (2-ΔΔCT): 5.15±0.86 vs. 5.00±0.81, all P < 0.05], and apoptosis-related protein was significantly up-regulated. In the LPS-induced HK-2 cells, the mRNA expressions of pro-inflammatory factors were significantly down-regulated after Scu treatment as compared with cells stimulated only by LPS [IL-1ß mRNA(2-ΔΔCT): 2.55±0.50 vs. 6.15±1.04, TNF-α mRNA (2-ΔΔCT): 2.58±0.40 vs. 3.95±0.52, MCP-1 mRNA (2-ΔΔCT): 2.64±0.44 vs. 6.21±0.96, all P < 0.05], and apoptosis-related protein was also significantly reduced. When the expression of CCN1 was inhibited by siRNA, the protective effect of Scu on cells was weakened, which showed that the mRNA expressions of pro-inflammatory factors in cells was significantly up-regulated compared with the cells without inhibition of CCN1 expression [IL-1ß mRNA (2-ΔΔCT): 5.34±0.76 vs. 2.55±0.50, TNF-α mRNA (2-ΔΔCT): 3.66±0.54 vs. 2.58±0.40, MCP-1 mRNA (2-ΔΔCT): 5.15±0.79 vs. 2.64±0.44, all P < 0.05], and the expression of apoptosis related protein was also significantly up-regulated. CONCLUSIONS: Scu could protect the renal function in SA-AKI mice, and the protective effect is associated with NF-κB signaling pathway and CCN1. Thus, Scu could alleviate LPS-induced kidney injury by regulating the NF-κB signaling pathway.

Tilianin Reduces Apoptosis via the ERK/EGR1/BCL2L1 Pathway in Ischemia/Reperfusion-Induced Acute Kidney Injury Mice.

Background: Acute kidney injury (AKI) is a common syndrome impacting about 13.3 million patients per year. Tilianin has been reported to alleviate myocardial ischemia/reperfusion (I/R) injury, while its effect on AKI is unknown; thus, this study aimed to explore if tilianin protects I/R-induced AKI and the underlying mechanisms. Methods: The microarray dataset GSE52004 was downloaded from GEO DataSets (Gene Expression Omnibus). Differential expression analysis and gene-set enrichment analysis (GSEA) were performed by R software to identify apoptosis pathway-related genes. Then, RcisTarget was applied to identify the transcription factor (TF) related to apoptosis. The STRING database was used to construct a protein-protein interaction (PPI) network. Cytoscape software visualized PPI networks, and hub TFs were selected via cytoHubba. AutoDock was used for molecular docking of tilianin and hub gene-encoded proteins. The expression levels of hub genes were assayed and visualized by quantitative real-time PCR, Western blotting, and immunohistochemistry by establishing I/R-induced AKI mouse models. Results: Bioinformatics analysis showed that 34 genes, including FOS, ATF4, and Gadd45g, were involved in the apoptosis pathway. In total, seven hub TFs might play important roles in tilianin-regulating apoptosis pathways. In in vivo, tilianin improved kidney function and reduced the number of TUNEL-positive renal tubular epithelial cells (RTECs) after I/R-induced AKI. Tilianin reduced the activation of the ERK pathway and then downregulated the expression of EGR1. This further ameliorated the expression of anti-apoptotic genes such as BCL2L1 and BCL2, reduced pro-apoptotic genes such as BAD, BAX, and caspase-3, and reduced the release of cytochrome c. Conclusion: Tilianin reduced apoptosis after I/R-induced AKI by the ERK/EGR1/BCL2L1 pathway. Our findings provided novel insights for the first time into the protective effect and underlying molecular mechanisms of tilianin on I/R-induced AKI.

The identification of liver metastasis- and prognosis-associated genes in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an often fatal malignancy with an extremely low survival rate. Liver metastasis, which causes high mortality, is the most common recurring metastasis for PDAC. However, the mechanisms underlying this liver metastasis and associated candidate biomarkers are unknown. METHODS: We performed mRNA profiling comparisons in 8 primary tumors (T) and 12 liver metastases (M) samples using the Gene Expression Omnibus (GEO) database. After determining differentially expressed genes (DEG), gene ontology (GO), pathway enrichment and protein-protein interaction (PPI) network analyses were performed to determine DEG functions. Then, Cytoscape was used to screen out significant hub genes, after which their clinical relevance was investigated using The Cancer Genome Atlas (TCGA) resources. Furthermore, prognosis-associated gene expression was validated using Oncomine and TCGA database. Lastly, associations between prognosis-associated genes, immune cells and immunological checkpoint genes were evaluated using the Tumor Immune Estimation Resource (TIMER). RESULTS: In total, 102 genes were related to liver metastasis and predominantly involved in cell migration, motility, and adhesion. Using Cytoscape, this number was narrowed down to 16 hub genes. Elevated mRNA expression levels for two of these genes, SPARC (P = 0.019) and TPM1 (P = 0.037) were significantly correlated with poor disease prognosis. For the remaining 14, expression was not related to overall patient survival. SPARC had higher expression in patients with metastatic PDAC than those with non-metastatic PDAC in TCGA dataset. SPARC and TPM1 levels were also positively correlated with the immune infiltration of specific cell types. Additionally, both genes exhibited strong co-expression associations with immune checkpoint genes. CONCLUSIONS: Combined, we suggest SPARC has high potential as biomarker to predict liver metastasis during PDAC. Additionally, both SPARC and TPM1 appeared to recruit and regulate immune-infiltrating cells during these pathophysiological processes.

Associations between early thiamine administration and clinical outcomes in critically ill patients with acute kidney injury.

The effects of early thiamine use on clinical outcomes in critically ill patients with acute kidney injury (AKI) are unclear. The purpose of this study was to investigate the associations between early thiamine administration and clinical outcomes in critically ill patients with AKI. The data of critically ill patients with AKI within 48 h after ICU admission were extracted from the Medical Information Mart for Intensive Care III (MIMIC III) database. PSM was used to match patients early receiving thiamine treatment to those not early receiving thiamine treatment. The association between early thiamine use and in-hospital mortality due to AKI was determined using a logistic regression model. A total of 15 066 AKI patients were eligible for study inclusion. After propensity score matching (PSM), 734 pairs of patients who did and did not receive thiamine treatment in the early stage were established. Early thiamine use was associated with lower in-hospital mortality (OR 0·65; 95 % CI 0·49, 0·87; P < 0·001) and 90-d mortality (OR 0·58; 95 % CI 0·45, 0·74; P < 0·001), and it was also associated with the recovery of renal function (OR 1·26; 95 % CI 1·17, 1·36; P < 0·001). In the subgroup analysis, early thiamine administration was associated with lower in-hospital mortality in patients with stages 1 to 2 AKI. Early thiamine use was associated with improved short-term survival in critically ill patients with AKI. It was possible beneficial role in patients with stages 1 to 2 AKI according to the Kidney Disease: Improving Global Outcomes criteria.

Magic-angle lasers in nanostructured moiré superlattice.

Conventional laser cavities require discontinuity of material property or disorder to localize a light field for feedback. Recently, an emerging class of materials, twisted van der Waals materials, have been explored for applications in electronics and photonics. Here we propose and develop magic-angle lasers, where the localization is realized in periodic twisted photonic graphene superlattices. We reveal that the confinement mechanism of magic-angle lasers does not rely on a full bandgap but on the mode coupling between two twisted layers of photonic graphene lattice. Without any fine-tuning in structure parameters, a simple twist can result in nanocavities with strong field confinement and a high quality factor. Furthermore, the emissions of magic-angle lasers allow direct imaging of the wavefunctions of magic-angle states. Our work provides a robust platform to construct high-quality nanocavities for nanolasers, nano light-emitting diodes, nonlinear optics and cavity quantum electrodynamics at the nanoscale.