A novel biomarker GATM suppresses proliferation and malignancy of cholangiocarcinoma cells by modulating the JNK/c-Jun signalling pathways.

Background: Cholangiocarcinoma (CCA) is the second most common primary malignancy of the liver and is associated with poor prognosis. Despite the emerging role of glycine amidinotransferase (GATM) in cancer development, its function in CCA remains elusive. This study investigated the biological significance and molecular mechanisms of GATM in CCA. Method: GATM expression was measured using immunohistochemistry and western blotting. Cell proliferation, migration, and invasion were assessed through CCK-8, EdU, clone formation, wound healing, and Transwell assays. Rescue experiments were performed to determine whether the JNK/c-Jun pathway is involved in GATM-mediated CCA development. Immunoprecipitation and mass spectrometry were performed to screen for proteins that interact with GATM. The role of GATM in vivo was investigated according to the xenograft experiment. Result: GATM expression was downregulated in CCA tissues and cells (p < 0.05) and had a significant suppressive effect on CCA cell proliferation, migration, and invasion in vitro as well as on tumour growth in vivo (p < 0.05); conversely, GATM knockdown promoted these phenotypes (p < 0.05). Notably, GATM inhibited the JNK/c-Jun pathway, and JNK activation abrogated GATM's antitumor effects (p < 0.05). Isocitrate dehydrogenase 1 (IDH1) interacts with GATM, and IDH1 knockdown significantly attenuated GATM protein degradation. Overexpression of IDH1 restored the biological function of CCA by reversing the inhibition of JNK/c-Jun pathway phosphorylation by GATM (p < 0.05). Conclusion: GATM acts as a tumour suppressor in CCA by regulating the phosphorylation of the JNK/c-Jun pathway. IDH1 interacted with GATM to regulate CCA progression.

Modulation of m6A RNA modification by DAP3 in cancer cells.

N6-methyladenosine (m6A) RNA methylation is a prevalent RNA modification that significantly impacts RNA metabolism and cancer development. Maintaining the global m6A levels in cancer cells relies on RNA accessibility to methyltransferases and the availability of the methyl donor S-adenosylmethionine (SAM). Here, we reveal that death associated protein 3 (DAP3) plays a crucial role in preserving m6A levels through two distinct mechanisms. First, although DAP3 is not a component of the m6A writer complex, it directly binds to m6A target regions, thereby facilitating METTL3 binding. Second, DAP3 promotes MAT2A's last intron splicing, increasing MAT2A protein, cellular SAM, and m6A levels. Silencing DAP3 hinders tumorigenesis, which can be rescued by MAT2A overexpression. This evidence suggests DAP3's role in tumorigenesis, partly through m6A regulation. Our findings unveil DAP3's complex role as an RNA-binding protein and tumor promoter, impacting RNA processing, splicing, and m6A modification in cancer transcriptomes.

Establishment and validation of a prognostic model based on common laboratory indicators for SARS-CoV-2 infection in Chinese population.

BACKGROUND: At the beginning of December 2022, the Chinese government made major adjustments to the epidemic prevention and control measures. The epidemic infection data and laboratory makers for infected patients based on this period may help with the management and prognostication of COVID-19 patients. METHODS: The COVID-19 patients hospitalized during December 2022 were enrolled. Logistic regression analysis was used to screen significant factors associated with mortality in patients with COVID-19. Candidate variables were screened by LASSO and stepwise logistic regression methods and were used to construct logistic regression as the prognostic model. The performance of the models was evaluated by discrimination, calibration, and net benefit. RESULTS: 888 patients were eligible, consisting of 715 survivors and 173 all-cause deaths. Factors significantly associated with mortality in COVID-19 patients were: lactate dehydrogenase (LDH), albumin (ALB), procalcitonin (PCT), age, smoking history, malignancy history, high density lipoprotein cholesterol (HDL-C), lactate, vaccine status and urea. 335 of the 888 eligible patients were defined as ICU cases. Seven predictors, including neutrophil to lymphocyte ratio, D-dimer, PCT, C-reactive protein, ALB, bicarbonate, and LDH, were finally selected to establish the prognostic model and generate a nomogram. The area under the curve of the receiver operating curve in the training and validation cohorts were respectively 0.842 and 0.853. In terms of calibration, predicted probabilities and observed proportions displayed high agreements. Decision curve analysis showed high clinical net benefit in the risk threshold of 0.10-0.85. A cutoff value of 81.220 was determined to predict the outcome of COVID-19 patients via this nomogram. CONCLUSIONS: The laboratory model established in this study showed high discrimination, calibration, and net benefit. It may be used for early identification of severe patients with COVID-19.

Machine learning-based model to predict composite thromboembolic events among Chinese elderly patients with atrial fibrillation.

OBJECTIVE: Accurate prediction of survival prognosis is helpful to guide clinical decision-making. The aim of this study was to develop a model using machine learning techniques to predict the occurrence of composite thromboembolic events (CTEs) in elderly patients with atrial fibrillation(AF). These events encompass newly diagnosed cerebral ischemia events, cardiovascular events, pulmonary embolism, and lower extremity arterial embolism. METHODS: This retrospective study included 6,079 elderly hospitalized patients (≥ 75 years old) with AF admitted to the People's Liberation Army General Hospital in China from January 2010 to June 2022. Random forest imputation was used for handling missing data. In the descriptive statistics section, patients were divided into two groups based on the occurrence of CTEs, and differences between the two groups were analyzed using chi-square tests for categorical variables and rank-sum tests for continuous variables. In the machine learning section, the patients were randomly divided into a training dataset (n = 4,225) and a validation dataset (n = 1,824) in a 7:3 ratio. Four machine learning models (logistic regression, decision tree, random forest, XGBoost) were trained on the training dataset and validated on the validation dataset. RESULTS: The incidence of composite thromboembolic events was 19.53%. The Least Absolute Shrinkage and Selection Operator (LASSO) method, using 5-fold cross-validation, was applied to the training dataset and identified a total of 18 features that exhibited a significant association with the occurrence of CTEs. The random forest model outperformed other models in terms of area under the curve (ACC: 0.9144, SEN: 0.7725, SPE: 0.9489, AUC: 0.927, 95% CI: 0.9105-0.9443). The random forest model also showed good clinical validity based on the clinical decision curve. The Shapley Additive exPlanations (SHAP) showed that the top five features associated with the model were history of ischemic stroke, high triglyceride (TG), high total cholesterol (TC), high plasma D-dimer, age. CONCLUSIONS: This study proposes an accurate model to stratify patients with a high risk of CTEs. The random forest model has good performance. History of ischemic stroke, age, high TG, high TC and high plasma D-Dimer may be correlated with CTEs.

Spurious dyslipidemia due to paraprotein in a patient with Waldenström macroglobulinemia.

INTRODUCTION: Serum lipid profiles play a crucial role in diagnosing and evaluating cardiovascular diseases. However, the presence of paraprotein can lead to inaccurate dyslipidemia results on automated analyzers. CASE REPORT: A 65-year-old woman whose combined concentrations of HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) consistently surpassed her total serum cholesterol levels over a period of three months presented with unusual lipid component detection. Further analysis revealed the presence of a monoclonal paraprotein, identified as an IgMλ band, with a concentration of 28.0 g/L. The patient was subsequently diagnosed with Waldenström macroglobulinemia. The use of abnormal reaction kinetic curves and the ß quantification method, along with an alternative method that did not suffer from interference, revealed that the monoclonal paraprotein interfered with the measurements of HDL-C, LDL-C, apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB) when using the Roche detection system. This interference led to spurious elevated HDL-C concentrations and falsely decreased apoA-I and apoB concentrations, while the LDL-C results were minimally affected. Although diluting the sample normalized the HDL-C and LDL-C measurements, the interference with the apoA-I and apoB assays persisted. No other common biochemical tests were interfered with this paraprotein. CONCLUSION: Caution is advised when using a homogenous method for direct measurement of HDL-C and LDL-C in patients with monoclonal paraprotein. Techniques to recognize and eliminate this interference are available. However, immunoturbidimetric detection of apoA-I and apoB levels is also susceptible to this interference, which is not readily removable.

Induction of antiherbivore defense responses in poplars using a methyl jasmonate and mesoporous silica nanoparticle complex.

BACKGROUND: Poplar in China has long been plagued by the fall webworm Hyphantria cunea. Enhancing plant immunity using chemical elicitors is an environmentally friendly approach to pest control. The phytohormone methyl jasmonate (MeJA) can stimulate the chemical defenses of poplars against herbivores but has been shown to have limited efficacy in practice. Here, we studied the effects of a MeJA and mesoporous silica nanoparticle (MSN) complex (MeJA@MSN) regarding the induction of poplar resistance to H. cunea, which may provide strategies for the effective use of MeJA. RESULTS: The silicon-based phytohormone complex (MeJA@MSNs) exhibited excellent biological and physiochemical properties, such as excellent biocompatibility and plant tissue transportability. The changes in metabolites in poplar leaves induced by MeJA, MSNs, and MeJA@MSNs were investigated by metabolic analysis. MeJA@MSNs led to highly potent induced resistance along with elevated salicylaldehyde content, which increased with the dose administered. The salicylaldehyde metabolite showed a strong antifeedant effect on H. cunea larvae at a dosage of 1 µg, with the 50% lethal dose being 20.4 µg/mg. Furthermore, transcriptional analysis showed that MeJA@MSNs upregulated key genes in biosynthetic pathways more than MeJA and MSNs. CONCLUSION: Our results show that MeJA and MSNs interact positively in poplar, leading to salicylaldehyde accumulation and increased induced resistance to H. cunea, providing new insights into the underlying resistance mechanisms induced by MeJA@MSNs. © 2024 Society of Chemical Industry.

Exploring the ED50 and ED95 of Remimazolam for Laryngeal Mask Airway Insertion During General Anesthesia in Pediatric Strabismus Correction Surgery.

AIM: Remimazolam, known for its rapid onset, quick metabolism, and short recovery time from sedation, offers significant advantages in clinical anesthesia. Previous studies have primarily investigated its application in adult surgical anesthesia, with less focus on its utilization in pediatric patients. Therefore, we aimed to explore the 50% effective dose (ED50) and 95% effective dose (ED95) of remimazolam for laryngeal mask airway (LMA) insertion during general anesthesia in pediatric strabismus correction surgery and investigate its dose-response relationship, thereby providing valuable reference data for safer and more rational clinical use of remimazolam. METHODS: This study included 32 patients aged 3-12 years undergoing strabismus correction surgery at Ningbo Aier Guangming Eye Hospital in 2024. The dosage of remimazolam was determined according to the Dixon 'up-and-down' sequential method: the starting induction dose was 0.2 mg/kg, with a step dose of 0.05 mg/kg. In cases of positive anesthetic effect, the subsequent patient received a reduced step dose, while in cases of negative anesthetic effect, the next subject received an increased step dose. The trial was terminated upon observing seven "positive-negative" crossover points. Furthermore, the ED50 and ED95, along with their 95% confidence intervals (95% CI) were calculated using the Probit regression analysis. Additionally, vital signs of the patients, such as peripheral oxygen (SpO2), heart rate, and blood pressure, along with the incidence of adverse events, were monitored. RESULTS: The ED50 of remimazolam for LMA insertion in pediatric strabismus correction surgery was 0.300 mg/kg (95% CI 0.276-0.323 mg/kg), and the ED95 was 0.369 mg/kg (95% CI 0.324-0.414 mg/kg). Throughout the surgery, SpO2, heart rate, and blood pressure remained stable without any significant fluctuations. CONCLUSIONS: The ED50 and ED95 of remimazolam for LMA insertion in pediatric strabismus correction surgery are 0.300 mg/kg and 0.369 mg/kg, respectively. This study demonstrates that remimazolam is both safe and effective for LMA insertion during general anesthesia in pediatric strabismus correction surgery.

Macrophage-derived exosomes promote telomere fragility and senescence in tubular epithelial cells by delivering miR-155.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence. METHODS: Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155-/- mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization. RESULTS: Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16INK4A expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16INK4A/p21expression and senescence-associated ß-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs. CONCLUSIONS: Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.

Targeting CD73 limits tumor progression and enhances anti-tumor activity of anti-PD-1 therapy in intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Patients with intrahepatic cholangiocarcinoma (iCCA) respond poorly to immune checkpoint blockades (ICBs). In this study, we aimed to dissect the potential mechanisms underlying poor response to ICBs and explore a rational ICB-based combination therapy in iCCA. METHODS: scRNA-seq dataset GSE151530 was analyzed to investigate the differentially expressed genes in malignant cells following ICBs therapy. RNA-seq analysis and western blot assays were performed to examine the upstream and downstream signaling pathways of CD73. Subcutaneous tumor xenograft models were utilized to investigate the impact of CD73 on iCCA growth. Plasmid AKT/NICD-induced spontaneous murine iCCAs were used to explore the therapeutic efficacy of CD73 enzymatic inhibitor AB680 combined with PD-1 blockade. Time-of-flight mass cytometry (CyTOF) was conducted to identify the tumor-infiltrating immune cell populations and their functional changes in murine iCCAs treated with AB680 in combination with PD-1 antibody. RESULTS: scRNA-seq analysis identified elevated CD73 expression in malignant cells in response to ICBs therapy. Mechanistically, ICBs therapy upregulated CD73 expression in malignant cells via TNF-α/NF-κB signaling pathway. In vivo studies revealed that CD73 inhibition suppressed the growth of subcutaneous tumors, and achieved synergistic depression effects with gemcitabine and cisplatin (GC). Adenosine produced by CD73 activates AKT/GSK3ß/ß-catenin signaling axis in iCCA cells. CD73 inhibitor AB680 potentiates anti-tumor efficacy of PD-1 antibody in murine iCCAs. CyTOF analysis showed that AB680 combined with anti-PD-1 therapy promoted the infiltration of CD8+ T, CD4+ T cells, and NK cells in murine iCCAs, while simultaneously decreased the proportions of macrophages and neutrophils. Moreover, AB680 combined with anti-PD-1 significantly upregulated the expression of Granzyme B, Tbet and co-stimulatory molecule ICOS in infiltrating CD8+ T cells. CONCLUSIONS: CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response.

Evaluating anemia in HIV-infected patients using chest CT.

Objective: The aim of this study was to investigate the role of the Hounsfield unit value of chest CT non-contrast enhanced scan in evaluating the severity of anemia in HIV-infected patients. Methods: Patients with HIV infection combined with anemia admitted to the Kunming Third People's Hospital were retrospectively collected and divided into mild anemia, moderate anemia, and severe anemia groups by peripheral hemoglobin (HB) content and calculated the ratio of ventricular septum density (VSD) to left ventricular density (LVD) and VSD to right ventricular density (RVD); then, the above patients were divided into the critical value group and the non-critical value group according to HB and compared the differences of LVD, RVD, VSD/LVD, and VSD/RVD in the two groups of patients. Results: A total of 126 patients were included, with a mean age of 47.9 ± 11.1 years; 43 cases were in the mild anemia group, 59 cases were in the moderate anemia group, and 24 cases were in the severe anemia group; the differences in LVD, RVD, VSD/LVD, and VSD/RVD were significant in the three groups; VSD/LVD was an independent predictor for the diagnosis of anemia critical value in the non-critical value group vs critical value group by multifactorial binary logistic regression analysis, and the ROC was plotted using VSD/LVD with an area under the curve of 0.731. Conclusions: The measurement of cardiac cavity density and ventricular septal density under CT plain film scan has a high accuracy in evaluating the severity of anemia in patients with HIV infection and can quickly determine the severity of HIV infection in the early stage and treat it as soon as possible.

Causal relevance of different blood pressure traits on risk of cardiovascular diseases: GWAS and Mendelian randomisation in 100,000 Chinese adults.

Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk.

Probing the structural evolution on the surface of cardiolipin vesicles with an amphiphilic second harmonic generation and fluorescence probe.

Investigating the influence of the ambient chemical environment on molecular behaviors in liposomes is crucial for understanding and manipulating cellular vitality as well as the capabilities of lipid drug carriers in various environments. Here, we designed and synthesized a second harmonic generation (SHG) and fluorescence probe molecule called Pyr-Py+-N+ (PPN), which possesses membrane-targeting capability. We employed PPN to investigate the response of lipid vesicles composed of cardiolipin to the presence of exogenous salt. The kinetic behaviors, including the adsorption and embedding of PPN on the surface of small unilamellar vesicles (SUVs) composed of cardiolipin, were analyzed. The response of the SUVs to the addition of NaCl was also monitored. A rapid decrease in vesicle size can be evidenced through the rapid drop in SHG emission originating from PPN located on the vesicle surface.

Peripheral blood eosinophils: an important reference for radiologists to distinguish between pulmonary paragonimiasis and tuberculous pleurisy in children.

OBJECTIVE: In this study, we examined the value of chest CT signs combined with peripheral blood eosinophil percentage in differentiating between pulmonary paragonimiasis and tuberculous pleurisy in children. METHODS: Patients with pulmonary paragonimiasis and tuberculous pleurisy were retrospectively enrolled from January 2019 to April 2023 at the Kunming Third People's Hospital and Lincang People's Hospital. There were 69 patients with pulmonary paragonimiasis (paragonimiasis group) and 89 patients with tuberculous pleurisy (tuberculosis group). Clinical symptoms, chest CT imaging findings, and laboratory test results were analyzed. Using binary logistic regression, an imaging model of CT signs and a combined model of CT signs and eosinophils were developed to calculate and compare the differential diagnostic performance of the two models. RESULTS: CT signs were used to establish the imaging model, and the receiver operating characteristic (ROC) curve was plotted. The area under the curve (AUC) was 0.856 (95% CI: 0.799-0.913), the sensitivity was 66.7%, and the specificity was 88.9%. The combined model was established using the CT signs and eosinophil percentage, and the ROC was plotted. The AUC curve was 0.950 (95% CI: 0.919-0.980), the sensitivity was 89.9%, and the specificity was 90.1%. The differential diagnostic efficiency of the combined model was higher than that of the imaging model, and the difference in AUC was statistically significant. CONCLUSION: The combined model has a higher differential diagnosis efficiency than the imaging model in the differentiation of pulmonary paragonimiasis and tuberculous pleurisy in children. The presence of a tunnel sign on chest CT, the absence of pulmonary nodules, and an elevated percentage of peripheral blood eosinophils are indicative of pulmonary paragonimiasis in children.

Temperature-Modulated Evolution of Surface Structures Induces Significant Enhancement of Two-Photon Fluorescent Emission from a Dye Molecule.

Fluorescence is an essential property of molecules and materials that plays a pivotal role across various areas such as lighting, sensing, imaging, and other applications. For instance, temperature-sensitive fluorescence emission is widely utilized for chemo-/biosensing but usually decreases the intensity upon the increase in temperature. In this study, we observed a temperature-induced enhancement of up to ∼150 times in two-photon fluorescence (TPF) emission from a dye molecule, 4-(4-diethylaminostyry)-1-methylpyridinium iodide (D289), as it interacted with binary complex vesicles composed of two commonly applied surfactants: sodium dodecyl sulfate (SDS) and cetyltrimethylammonium bromide (CTAB). By employing second harmonic generation (SHG) and TPF techniques, we clearly revealed the temperature-dependent kinetic behavior of D289 on the surface of the vesicles and utilized it to interpret the origin of the significant TPF enhancement. Additionally, we also demonstrated a similar heating-induced enhancement of the TPF emission from D289 on the membrane of phospholipid vesicles, indicating the potential application of TPF in temperature sensing in the biology systems. The embedding of D289 in the tightly packed alkane chains was identified as the key factor in enhancing the TPF emission from D289. This finding may provide valuable information for synthesizing fluorescence materials with a high optical yield.

Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.

ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.

Enhancing hepatocellular carcinoma management: prognostic value of integrated CCL17, CCR4, CD73, and HHLA2 expression analysis.

PURPOSE: Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC. METHODS: 873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software. RESULTS: The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE. CONCLUSION: This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.

Evaluating spray drift from Uncrewed Aerial Spray Systems: A machine learning and variance-based sensitivity analysis of environmental and spray system parameters.

Uncrewed Aerial Spray Systems (UASS), commonly called drones, have become an important application technique for plant protection products in Asia and worldwide. As such, environmental variables and spray system parameters influencing spray drift deserve detailed investigations. This study presents the data analysis of 114 UASS drift trials conducted between December 2021 and December 2022 in China. Study design was based on the ISO 22866:2005 protocol for spray drift trials and considered different UASS platforms, nozzles, and release heights, and specifically continuously measured weather conditions. The relative importance of the environmental variables and spray system parameters was evaluated by a random forest (RF) feature importance analysis, a Sobol sensitivity analysis and partial dependence plots. This approach was preferred to linear ranking techniques such as ANOVA (analysis of variance) due to the non-linearity of the system. In addition, partial dependence plots are proposed to visualize the relationship between specific input parameters within the system. Drift deposition curves calculated from the 114 trials show good agreement with previous UASS trials reported in the literature. As reported in previous studies, spray drift following UASS applications is lower than for manned aerial vehicles, greater than for ground spray applications, and similar to drift observed from orchard air blast applications. In addition, 9 trials were conducted on corn fields in order to evaluate the potential effect of crop cover on spray drift. Spray drift was observed to be reduced over the cropped soil, suggesting that plant cover might possibly reduce spray drift. These findings could help supporting drift mitigation policies, stewardship advice and product labelling around the world.

Emerging biosensor probes for glycated hemoglobin (HbA1c) detection.

Glycated hemoglobin (HbA1c), originating from the non-enzymatic glycosylation of ßVal1 residues in hemoglobin (Hb), is an essential biomarker indicating average blood glucose levels over a period of 2 to 3 months without external environmental disturbances, thereby serving as the gold standard in the management of diabetes instead of blood glucose testing. The emergence of HbA1c biosensors presents affordable, readily available options for glycemic monitoring, offering significant benefits to small-scale laboratories and clinics. Utilizing nanomaterials coupled with high-specificity probes as integral components for recognition, labeling, and signal transduction, these sensors demonstrate exceptional sensitivity and selectivity in HbA1c detection. This review mainly focuses on the emerging probes and strategies integral to HbA1c sensor development. We discussed the advantages and limitations of various probes in sensor construction as well as recent advances in diverse sensing strategies for HbA1c measurement and their potential clinical applications, highlighting the critical gaps in current technologies and future needs in this evolving field.

HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.

Symmetry-Reduction Enhanced Polarization-Sensitive Photoresponse Based on One-Dimensional van der Waals Materials.

Designing high-performance polarization-sensitive photodetectors is essential for photonic device applications. Anisotropic one-dimensional (1D) van der Waals (vdW) materials have provided a promising platform to that end. Despite significant advances in 1D vdW photonic devices, their performance is still far from delivering practical potential. Herein, we propose the design of high-performance polarization-sensitive photodetectors using unique 1D vdW materials. By leveraging the chemical vapor transport technique, we successfully fabricate high-quality 1D vdW Nb2Pd1-xSe5 (x = 0.29) nanowires. The 1D vdW Nb2Pd1-xSe5 photodetector exhibits a high mobility of ∼56 cm2/(V s) and superior photoresponse performance, including a high responsivity of 1A/W and an ultrafast response time of ∼8 µs under 638 nm illumination. Moreover, the 1D vdW Nb2Pd1-xSe5 photodetector demonstrates excellent polarization-sensitive photoresponse with a degree of linear polarization (DOLP) up to 0.85 and can be modulated by adjusting the gate voltage, laser power density, and wavelength. Those exceptional performance are believed to be relevant to the symmetry-reduction induced by the partial occupation of Pd sites. This study offers feasible approaches to enhance the anisotropy of 1D vdW materials and the modulation of their polarization-sensitive photoresponse, which may provide deep insights into the physical origin of anisotropic properties of 1D vdW materials.