Purine metabolism in lung adenocarcinoma: A single-cell analysis revealing prognostic and immunotherapeutic insights.

Lung adenocarcinoma (LUAD) is a prevalent subtype of lung cancer, yet the contribution of purine metabolism (PM) to its pathogenesis remains poorly elucidated. PM, a critical component of intracellular nucleotide synthesis and energy metabolism, is hypothesized to exert a significant influence on LUAD development. Herein, we employed single-cell analysis to investigate the role of PM within the tumour microenvironment (TME) of LUAD. PM scoring (PMS) across distinct cell types was determined using AUCell, UCell, singscore and AddModuleScore algorithms. Subsequently, we explored communication networks among cells within high- and low-PMS groups, establishing a robust PM-associated signature (PAS) utilizing a comprehensive dataset comprising LUAD samples from TCGA and five GEO datasets. Our findings revealed that the high-PMS group exhibited intensified cell interactions, while the PAS, constructed using PM-related genes, demonstrated precise prognostic predictive capability. Notably, analysis across the TCGA dataset and five GEO datasets indicated that low-PAS patients exhibited a superior prognosis. Furthermore, the low-PAS group displayed increased immune cell infiltration and elevated CD8A expression, coupled with reduced PD-L1 expression. Moreover, data from eight publicly available immunotherapy cohorts suggested enhanced immunotherapy outcomes in the low-PAS group. These results underscore a close association between PAS and tumour immunity, offering predictive insights into genomic alterations, chemotherapy drug sensitivity and immunotherapy responses in LUAD. The newly established PAS holds promise as a valuable tool for selecting LUAD populations likely to benefit from future clinical stratification efforts.

Clinical prognostication and immunotherapy response prediction in esophageal squamous cell carcinoma using the DNA damage repair-associated signature.

BACKGROUND: The relationship between DNA damage repair (DDR) and cancer is intricately intertwined; however, its specific role in esophageal squamous cell carcinoma (ESCC) remains enigmatic. METHODS: Employing single-cell analysis, we delineated the functionality of DDR-related genes within the tumor microenvironment (TME). A diverse array of scoring mechanisms, including AUCell, UCell, singscore, ssgsea, and AddModuleScore, were harnessed to scrutinize the activity of DDR-related genes across different cell types. Differential pathway alterations between high-and low-DDR activity cell clusters were compared. Furthermore, leveraging multiple RNA-seq datasets, we constructed a robust DDR-associated signature (DAS), and through integrative multiomics analysis, we explored differences in prognosis, pathways, mutational landscapes, and immunotherapy predictions among distinct DAS groups. RESULTS: Notably, high-DDR activity cell subpopulations exhibited markedly enhanced cellular communication. The DAS demonstrated uniformity across multiple datasets. The low-DAS group exhibited improved prognoses, accompanied by heightened immune infiltration and elevated immune checkpoint expression. SubMap analysis of multiple immunotherapy datasets suggested that low-DAS group may experience enhanced immunotherapy responses. The "oncopredict" R package analyzed and screened sensitive drugs for different DAS groups. CONCLUSION: Through the integration of single-cell and bulk RNA-seq data, we have developed a DAS associated with prognosis and immunotherapy response. This signature holds promise for the future stratification and personalized treatment of ESCC patients in clinical settings.

Manipulating the Rectifying Contact between Ultrafine Ru Nanoclusters and N-Doped Carbon Nanofibers for High-Efficiency pH-Universal Electrocatalytic Hydrogen Evolution.

The rational design of ingenious strategies to boost the intrinsic activity and stability of ruthenium (Ru) is of great importance for the substantial progression of water electrolysis technology. Based on Mott-Schottky effect, electronic regulation within a metal/semiconductor hybrid electrocatalyst represents a versatile strategy to boost the electrochemical performance. Herein, a typical Mott-Schottky hydrogen evolution reaction (HER) electrocatalyst composed of uniform ultrafine Ru nanoclusters in situ anchored on N-doped carbon nanofibers (abbreviated as Ru@N-CNFs hereafter) through a feasible and scalable "phenolic resin-bridged" strategy is reported. Both spectroscopy analyses and density functional theory calculations manifest that such rectifying contact can induce the spontaneous electron transfer from Ru to N-doped carbon nanofibers to generate a built-in electric field, thus enormously promoting the charge transfer efficiency and HER intrinsic activity. Moreover, the seamless immobilization of Ru nanoclusters on the substrate can prevent the active sites from unfavorable migration, coarsening, and detachment, rendering the excellent structural stability. Consequently, the well-designed Ru@N-CNFs afford prominent pH-universal HER performances with small overpotentials of 16 and 17 mV at 10 mA cm-2 and low Tafel slopes of 31.8 and 28.5 mV dec-1 in acidic and alkaline electrolytes, respectively, which are superior to the state-of-the-art commercial Pt/C and Ru/C benchmarks.

Interfacial Engineering of CoN/Co3 O4 Heterostructured Hollow Nanoparticles Embedded in N-Doped Carbon Nanowires as a Bifunctional Oxygen Electrocatalyst for Rechargeable Liquid and Flexible all-Solid-State Zn-Air Batteries.

The design of economical, efficient, and robust bifunctional oxygen electrocatalysts is greatly imperative for the large-scale commercialization of rechargeable Zn-air battery (ZAB) technology. Herein, the neoteric design of an advanced bifunctional electrocatalyst composed of CoN/Co3 O4 heterojunction hollow nanoparticles in situ encapsulated in porous N-doped carbon nanowires (denoted as CoN/Co3 O4 HNPs@NCNWs hereafter) is reported. The simultaneous implementation of interfacial engineering, nanoscale hollowing design, and carbon-support hybridization renders the synthesized CoN/Co3 O4 HNPs@NCNWs with modified electronic structure, improved electric conductivity, enriched active sites, and shortened electron/reactant transport pathways. Density functional theory computations further demonstrate that the construction of a CoN/Co3 O4 heterojunction can optimize the reaction pathways and reduce the overall reaction barriers. Thanks to the composition and architectural superiorities, the CoN/Co3 O4 HNPs@NCNWs exhibit distinguished oxygen reduction reaction and oxygen evolution reaction performance with a low reversible overpotential of 0.725 V and outstanding stability in KOH medium. More encouragingly, the homemade rechargeable liquid and flexible all-solid-state ZABs utilizing CoN/Co3 O4 HNPs@NCNWs as the air-cathode deliver higher peak power densities, larger specific capacities, and robust cycling stability, exceeding the commercial Pt/C + RuO2 benchmark counterparts. The concept of heterostructure-induced electronic modification herein may shed light on the rational design of advanced electrocatalysts for sustainable energy applications.

Development and validation of a potential biomarker to improve the assessment of liver fibrosis progression in patients with chronic hepatitis B.

We aimed to develop and validate a novel combined score to improve the assessment of liver fibrosis progression in patients with chronic hepatitis B (CHB). In this study, a total of 331 CHB patients from three cohorts who underwent liver biopsy were enrolled, and the Scheuer system was used for liver fibrosis classification. The combined score was derived by principal component analysis of key differentially expressed genes. For significant liver fibrosis (≥S2), the areas under the receiver operating characteristics curves (AUROCs) of the combined score were 0.838, 0.842, and 0.881 in the three cohorts, respectively. And for advanced liver fibrosis (≥S3), the AUROCs were 0.794, 0.801, and 0.901, respectively. Compared with the results of AUROCs for aspartate aminotransferase≥to≥platelet ratio (APRI) and fibrosis index based on four factors (FIB-4) in the validation cohorts, better clinical diagnostic value for assessing the progression of liver fibrosis was found in the combined score. Additionally, univariate ordered logistic regression analysis indicated that the combined score could serve as a more superior and stable risk factor than APRI and FIB-4 in the assessment of liver fibrosis. For CHB patients with normal alanine aminotransferase (ALT), our results further emphasized the diagnostic value of the combined score for significant fibrosis (≥S2) and advanced fibrosis (≥S3). Moreover, it was found that patients with the high combined score, who were associated with the advanced fibrosis stage, had higher levels of drug sensitivity and immune checkpoint expression. In conclusion, the novel combined score could serve as a potential biomarker and contribute to improving the assessment of fibrosis stage in CHB patients.

Serum ribonucleotide reductase M2 is a potential biomarker for diagnosing and monitoring liver fibrosis in chronic hepatitis B patients.

It is known that ribonucleotide reductase M2 (RRM2) could be induced by hepatitis B virus (HBV) via DNA damage response. However, whether RRM2 is a potential biomarker for diagnosing and monitoring liver fibrosis in chronic hepatitis B (CHB) patients is still unclear. In this study, CHB patients from GSE84044 (a transcriptome data from GEO data set) were downloaded and RRM2 was selected as a hub gene. Interestingly, a positive correlation was found between serum RRM2 and liver fibrosis stage. The similar results were found in CHB patients with normal alanine aminotransferase (ALT). Notably, RRM2 could effectively differentiate preliminary fibrosis from advanced fibrosis in CHB patients with/without normal ALT. In addition, RRM2 had a better performance in diagnosing liver fibrosis than two commonly used noninvasive methods (aspartate aminotransferase-to-platelet ratio index and fibrosis index based on the four factors), two classic fibrotic biomarkers (hyaluronic acid and type IV collagen) as well as Mac-2 binding protein glycosylation isomer, a known serum fibrosis marker. Moreover, CHB patients with high RRM2, who were associated with advanced fibrosis, had higher expressions of immune checkpoints. Overall, serum RRM2 may be a promising biomarker for diagnosing and monitoring liver fibrosis in CHB patients.

Template-assisted Fabrication of O-doped CoP Microflowers with Optimal Electronic Modulation for Electrochemical Hydrogen Evolution.

Exploring efficient, affordable and stable electrocatalyst toward hydrogen evolution reaction (HER) is of great scientific significance for the practical implementation of the water splitting. The heteroatom doping represents a serviceable strategy to further elevate the catalytic performance for a transition metal-based electrocatalyst because of the electronic regulation effect. Herein, a reliable self-sacrificial template-engaged approach is proposed to synthesize O-doped CoP (denoted as O-CoP) microflowers, which simultaneously considers the regualtion of electronic configuration via anion doping and sufficient exposure of active sites via nanostructure engineering. The suitable O incorporation content in CoP matrix could tremendously modify the electronic configuration, accelerate the charge transfer, promote the exposure of active sites, strengthen the electrical conductivity, and adjust the adsorption state of H*. Consequently, the optimized O-CoP microflowers with optimal O concentration display a remarkable HER property with a small overpotential of 125 mV to afford a current density of 10 mA cm-2 , a low Tafel slope of 68 mV dec-1 and long-term durability for 32 h under alkaline electrolyte, manifesting a considerable potential application for hydrogen production at large scale. The integration of anion incorporation and architecture engineering in this work will bring in a depth insight for the design of low-cost and effective electrocatalysts in energy conversion and storage systems.

Effect of liver steatosis on liver stiffness measurement in chronic hepatitis B patients with normal serum alanine aminotransferase levels: A multicentre cohort study.

Liver steatosis is becoming increasingly common in patients with chronic hepatitis B (CHB), and its effect on liver stiffness measurement (LSM), as assessed by transient elastography, remains controversial. Seven hundred and fifty-five patients with CHB and normal serum alanine aminotransferase levels, who underwent vibration-controlled transient elastography and liver biopsy, were included in the study. We examined whether the histological degree of liver steatosis affects the accuracy of transient elastography-assessed LSM in these patients. Among the 755 CHB patients included in the study, 286 (37.9%) had liver steatosis, of whom 156 had grade S1, 74 had grade S2, and 56 had grade S3 on histology. Presence of liver steatosis was independently associated with greater body mass index (BMI, adjusted-odds ratio [OR] = 5.786, 95% CI: 3.998-8.373, p = 0.018), and higher serum total cholesterol (adjusted-OR = 7.944, 95% CI: 4.731-13.339, p < 0.001) and triglyceride levels (adjusted-OR = 2.777, 95% CI: 2.050-3.761, p < 0.001). There was no significant association between liver steatosis and fibrosis stage (OR = 1.016, 95% CI: 0.905-1.140, p = 0.790). Age (B-coefficient = 0.020, 95% CI: 0.001-0.040, p = 0.044), BMI (B-coefficient = 0.060, 95% CI: 0.011-0.127, p = 0.019), serum gamma-glutamyl-transpeptidase (GGT, B-coefficient = 0.015, 95% CI: 0.001-0.029, p = 0.032), positivity for HBeAg (B-coefficient = -0.816, 95% CI: -1.568 to -0.064, p = 0.034), as well as liver fibrosis stage (B-coefficient = 2.796, 95% CI: 2.501-3.090, p < 0.001), and inflammation activity grade (B-coefficient = 0.648, 95% CI: 0.162-1.135, p = 0.009) were all independently associated with higher LSM, while no significant association was found between degree of liver steatosis and LSM. Among patients with the same histological fibrosis stage, LSM values did not show any significant difference among patients with absent, mild, moderate or severe steatosis. We conclude that liver steatosis has no significant effect on transient elastography-measured LSM in CHB patients with normal serum alanine aminotransferase levels.

One-Step Template/Solvent-Free Pyrolysis for In Situ Immobilization of CoP Nanoparticles onto N and P Co-Doped Carbon Porous Nanosheets towards High-efficiency Electrocatalytic Hydrogen Evolution.

The search for economical, active and stable electrocatalysts towards the hydrogen evolution reaction (HER) is highly imperative for the progression of water electrolysis technology and related sustainable energy conversion technologies. The delicate optimization of chemical composition and architectural configuration is paramount to design high-efficiency non-precious metal HER electrocatalysts. Herein, we report a one-step scalable template/solvent-free pyrolysis approach for in situ immobilizing uniform CoP nanoparticles onto N and P co-doped carbon porous nanosheets (denoted as CoP@N,P-CNSs hereafter). The simultaneous consideration of architectural design and nanocarbon hybridization renders the formed CoP@N,P-CNSs with plentiful well-dispersed anchored active sites, shortened pathway for mass diffusion, enhanced electric conductivity, and reinforced mechanical stability. As a consequence, the optimized CoP@N,P-CNSs exhibit an overpotential of 115 mV to afford a current density of 10 mA cm-2 , small Tafel slope of 74.2 mV dec-1 , high Faradaic efficiency of nearly 100 %, and superb long-term durability in an alkaline medium. Given the fabrication feasibility, mass production potential and outstanding HER performance, the CoP@N,P-CNSs may hold great promise for large-scale electrochemical water splitting. More importantly, the explored one-step template/solvent-free pyrolysis methodology offers a feasible and versatile route to fabricate carbon nanosheet-based nanocomposites for diverse energy conversation-related applications.

ASK1 Enhances Angiotensin II-Induced Liver Fibrosis In Vitro by Mediating Endoplasmic Reticulum Stress-Dependent Exosomes.

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) has been reported to induce fibrotic signaling in the setting of oxidative stress. However, the role of ASK1 and its mechanism of action in angiotensin II- (Ang II-) induced liver fibrosis remain largely unknown. METHODS: Human hepatic LX-2 stellate cells were treated with Ang II alone or cotreated with Ang II plus an ASK1 inhibitor (GS-4997) or siRNA-targeting ASK1. Immunofluorescent staining, real-time PCR, and western blotting were used to determine the expressionof α-SMA, Col I, and Col III expression. Cell viability was assessed by the CCK-8 assay. The concentrations of IL-1ß, IL-18, and TNF-α in conditioned medium were determined by ELISA. The levels of intracellular ROS in LX-2 cells were analyzed using a ROS assay kit. Exosome size was determined by electron microscopy. RESULTS: Ang II markedly increased the expression of extracellular matrix (ECM) proteins (α-SMA, Col I, and Col III) and proinflammatory cytokines (IL-1ß, IL-18, and TNF-α). Ang II also increased the expression of endoplasmic reticulum stress (ERS) markers (GRP78, p-PERK, and CHOP) and p-ASK1. Results also showed that pretreatment with GS-4997 or siRNA could abolish all the abovementioned effects on LX-2 cells. Furthermore, we found that exosome release caused by ASK1-mediated ERS was involved in the activation of LX-2 cells by Ang II. The activation of LX-2 cells could be blocked by treating the exosomes with annexin. CONCLUSIONS: In summary, we found that ASK1 mediates Ang II-activated ERS in HSCs and the subsequent activation of HSCs, suggesting a promising strategy for treating liver fibrosis.

Base-pair ambiguity and the kinetics of RNA folding.

BACKGROUND: A pairings of nucleotide sequences. Given this forbidding free-energy landscape, mechanisms have evolved that contribute to a directed and efficient folding process, including catalytic proteins and error-detecting chaperones. Among structural RNA molecules we make a distinction between "bound" molecules, which are active as part of ribonucleoprotein (RNP) complexes, and "unbound," with physiological functions performed without necessarily being bound in RNP complexes. We hypothesized that unbound molecules, lacking the partnering structure of a protein, would be more vulnerable than bound molecules to kinetic traps that compete with native stem structures. We defined an "ambiguity index"-a normalized function of the primary and secondary structure of an individual molecule that measures the number of kinetic traps available to nucleotide sequences that are paired in the native structure, presuming that unbound molecules would have lower indexes. The ambiguity index depends on the purported secondary structure, and was computed under both the comparative ("gold standard") and an equilibrium-based prediction which approximates the minimum free energy (MFE) structure. Arguing that kinetically accessible metastable structures might be more biologically relevant than thermodynamic equilibrium structures, we also hypothesized that MFE-derived ambiguities would be less effective in separating bound and unbound molecules. RESULTS: We have introduced an intuitive and easily computed function of primary and secondary structures that measures the availability of complementary sequences that could disrupt the formation of native stems on a given molecule-an ambiguity index. Using comparative secondary structures, the ambiguity index is systematically smaller among unbound than bound molecules, as expected. Furthermore, the effect is lost when the presumably more accurate comparative structure is replaced instead by the MFE structure. CONCLUSIONS: A statistical analysis of the relationship between the primary and secondary structures of non-coding RNA molecules suggests that stem-disrupting kinetic traps are substantially less prevalent in molecules not participating in RNP complexes. In that this distinction is apparent under the comparative but not the MFE secondary structure, the results highlight a possible deficiency in structure predictions when based upon assumptions of thermodynamic equilibrium.

TRAIL Enhances Shikonin Induced Apoptosis through ROS/JNK Signaling in Cholangiocarcinoma Cells.

BACKGROUND/AIMS: Cholangiocarcinoma (CCA), arising from varying locations within the biliary tree, is the second most common primary liver malignancy worldwide. Shikonin, an active compound extracted from the Chinese herb Zicao, holds anti-bacterial, anti-inflammatory, and anti-tumor activities. However, the effect of shikonin on human cholangiocarcinoma and detailed mechanisms of TRAIL enhancement remains to be elucidated. The purpose of the study was to investigate the protective functions of TRAIL enhancement for shikonin induced apoptosis in cholangiocarcinoma cells. METHODS: We use MTT assay, apoptosis assay, caspase activity assay, flow cytometry assay, real time PCR and Western blot to observe the effects of TRAIL on shikonin induced cholangiocarcinoma cells apoptosis and its mechanism. RESULTS: Shikonin inhibited cell viability and induced apoptosis of CCA cells, effects enhanced by TRAIL treatment via activation of caspase-3, -8, -9. Furhermore, TRAIL enhanced anti-proliferation of shikonin and shikonin induced apoptosis through induction of ROS mediated JNK activation, while AKT activation had an effect on shikonin anti-proliferation activity, but not in the TRAIL enhanced counterparts. Finally, shikonin upregulated DR5 expression, an effect essential for TRAIL-enhanced activities of shikonin in RBE cells. CONCLUSIONS: Our results revealed that shikonin could inhibit cells viability and induce apoptosis of CCA cells, effects enhanced by TRAIL treatment via ROS mediated JNK signalling pathways, involving up-regulation of DR5 expression. Our results provide further insight into the mechanism underlying the anti-tumor effects of shikonin by TRAIL enhanced in CCA and a new therapeutic strategy to CCA treatment.

Serum lincRNA-p21 as a potential biomarker of liver fibrosis in chronic hepatitis B patients.

Serum long non-coding RNAs (lncRNAs) are emerging as promising biomarkers for various human diseases. The aim of this study was to investigate the feasibility of using serum long intergenic non-coding RNA-p21 (lincRNA-p21) as a biomarker for chronic hepatitis B patients. Serum lincRNA-p21 levels were quantified using real-time PCR in 417 CHB patients and 363 healthy controls. The promoter methylation level of lincRNA-p21 was detected using bisulphite-sequencing analysis in primary hepatic stellate cells (HSCs). Sera from hepatitis B-infected patients contained lower levels of lincRNA-p21 than sera from healthy controls. Serum lincRNA-p21 levels negatively correlated with stages of liver fibrosis in infected patients. Receiver operating characteristic (ROC) curve analyses suggested that serum lincRNA-p21 had a significant diagnostic value for liver fibrosis in these patients. It yielded an area under the curve of ROC of 0.854 with 100% sensitivity and 70% specificity in discriminating liver fibrosis from healthy controls. There was additionally a negative correlation between serum lincRNA-p21 level and the markers of liver fibrosis including α-SMA and Col1A1. However, there was no correlation of serum lincRNA-p21 level with the markers of viral replication, liver inflammatory activity, and liver function. Notably, during primary HSCs culture, loss of lincRNA-p21 expression was associated with promoter methylation. Serum lincRNA-p21 could serve as a potential biomarker of liver fibrosis in CHB patients. Down-regulation of lincRNA-p21 in liver fibrosis may be associated with promoter methylation.

Age and severity matched comparison of gender differences in the prevalence of periodic limb movements during sleep in patients with obstructive sleep apnea.

PURPOSE: The aim of this study was to investigate gender differences of periodic limb movements during sleep (PLMS) in patients with obstructive sleep apnea (OSA). METHODS: This was a case-control study recruiting 364 patients with OSA (182 men, 182 women) matched for age and apnea-hypopnea index (AHI). All participants underwent overnight polysomnography (PSG), followed by the multiple sleep latency test (MSLT) and the Epworth Sleepiness Scale (ESS). RESULTS: Women with OSA had a significantly higher prevalence of PLMS than men (24.2 vs. 15.9 %, p < 0.05). Women with OSA showed an increased prevalence of PLMS compared to men in the younger group aged ≤55 years (23.0 vs. 10.6 %, p < 0.05), but not in the older groups >55 years (25.3 vs. 21.6 %, p > 0.05). Binary linear regression analysis in OSA patients confirmed that women were more likely to have PLMS than men (OR 1.71, 95 % CI 1.00-2.92), particularly in patients with age ≤55 years old (OR 2.48, 95 % CI 1.06-5.79), after adjusting for age, BMI, AHI, and habits of smoking and drinking. CONCLUSIONS: The results demonstrate that, for patients with OSA, young women had significantly increased prevalence of PLMS compared to young men, but there was no difference in prevalence of PLMS between the men and women in the older age group.

Serum miR-181b Is Correlated with Hepatitis B Virus Replication and Disease Progression in Chronic Hepatitis B Patients.

BACKGROUND: Previously, we reported that microRNA-181b (miR-181b) activates hepatic stellate cells partly through the phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/Akt pathway. AIMS: The main objective of this study was to ascertain whether serum miR-181b expression is correlated with that of liver hepatitis B virus (HBV) DNA and disease progression in chronic hepatitis B (CHB) patients. METHODS: Serum miR-181b and liver HBV DNA levels were quantified in 64 CHB patients with real-time PCR. Liver fibrosis and necroinflammation were graded according to the Ishak scoring system. RESULTS: Serum miR-181b levels were evaluated in the CHB group, compared with healthy controls. Expression in patients with HBsAg (+) was higher than that in patients with HBsAg (-). Notably, serum miR-181b and liver HBV DNA levels were significantly correlated (P < 0.05). Serum miR-181 levels were higher in patients with serum HBV DNA > 10(3) IU/ml (P = 0.017), histologic activity index (HAI) >8 (P = 0.001) and fibrosis score >4 (P < 0.0001). Liver HBV DNA levels were higher in patients with abnormal alanine aminotransferase (ALT) values (P = 0.004), serum HBV DNA levels > 10(3) IU/ml (P = 0.034) and fibrosis score >4 (P = 0.006). Using multivariate logistic regression analysis, serum miR-181b was identified as an independent predictor of disease progression (OR 4.172, 95 % CI 1.838-9.473, P = 0.009 for HAI >8; OR 5.387, 95 % CI 2.067-14.036, P = 0.001 for fibrosis score >4). CONCLUSIONS: Serum miR-181b is correlated with liver and serum HBV DNA levels as well as disease progression in CHB.

Artificial intelligence CT radiomics to predict early recurrence of intrahepatic cholangiocarcinoma: a multicenter study.

OBJECTIVES: In this multicenter study, we sought to develop and validate a preoperative model for predicting early recurrence (ER) risk after curative resection of intrahepatic cholangiocarcinoma (ICC) through artificial intelligence (AI)-based CT radiomics approach. MATERIALS AND METHODS: A total of 311 patients (Derivation: 160; Internal and two external validations: 36, 74 and 61) from 8 medical centers who underwent curative resection were collected retrospectively. In derivation cohort, radiomics and clinical-radiomics models for ER prediction were constructed by LightGBM (a machine learning algorithm). A clinical model was also developed for comparison. Model performance was validated in internal and two external cohorts by ROC. In addition, we investigated the interpretability of the LightGBM model. RESULTS: The combined clinical-radiomics model that included 15 radiomic features and 3 clinical features (CA19-9 > 1000 U/ml, vascular invasion and tumor margin), resulting in the area under the curves (AUCs) of 0.974 (95% CI 0.946-1.000) in the derivation cohort, and 0.871-0.882 (95% CI 0.672-0.962) in the internal and external validation cohorts, respectively, which are higher than the AJCC 8th TNM staging system (AUCs: 0.686-0.717, p all < 0.05). Especially, the sensitivity of this machine learning model could reach 94.6% on average for all the cohorts. CONCLUSIONS: This AI-driven combined radiomics model may provide as a useful tool to preoperatively predict ER and improve therapeutic management of ICC patients.

Polysomnographic characteristics of daytime sleepiness in obstructive sleep apnea syndrome.

PURPOSE: The study is intended to explore the nocturnal sleep determinants for excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Consecutive patients (n = 182) who had an apnea/hypopnea index (AHI) greater than 5 times per hour were used in this study. EDS (n = 32) was considered present whenever the Epworth sleepiness scale (ESS) score was >10 and the multiple sleep latency test (MSLT) score was <5 min. Absence of EDS (no EDS, n = 48) was determined in patients with an ESS score of <10 and a MSLT score of >10 min. RESULTS: Compared to no EDS patients, EDS patients exhibited (1) greater AHI and time length of SaO(2) <95%, lower nocturnal SaO(2) during separate rapid eye movement (REM) and NREM periods, and lower total mean and minimum SaO(2) during total recording period; (2) shortened latency to sleep and to REM sleep, and increased total sleep time and sleep efficiency; and (3) increases in the brief arousal index and duration of sleep stage 1. In addition, stepwise logistic regression analysis showed that the arousal index, the time length of SaO(2) <95%, and the latency to REM were independent predictors of EDS. CONCLUSIONS: The results suggest that EDS in OSAS patients are characterized by the following aspects of nocturnal sleep: (1) severe sleep apnea/hypopnea and hypoxemia, (2) fragmented sleep, (3) low quality of sleep, and (4) high pressure of sleep drive.

Kaempferol Inhibits Hepatic Stellate Cell Activation by Regulating miR-26b-5p/Jag1 Axis and Notch Pathway.

Kaempferol, a natural flavonoid molecule, has demonstrated anti-inflammatory, antimicrobial and antioxidant activities. Recent studies have shown the beneficial effects of kaempferol on liver fibrosis. Notch pathway has been reported to be involved in the aberrant activation of hepatic stellate cells (HSCs). However, whether Notch pathway plays a key role in the anti-fibrotic effects of kaempferol is largely unknown. In this study, kaempferol significantly suppressed liver fibrosis in CCl4 mice, with reduced collagen deposition as well as restored liver function. In vitro, kaempferol enhanced the suppression of HSC activation, with a decrease in α-SMA as well as collagen level. It was found that Notch pathway played an important role in kaempferol-reduced the activation of HSCs. Jag1, a ligand of Notch pathway, was obviously inhibited by kaempferol. Overexpression of Jag1 effectively abolished kaempferol-induced HSC inactivation. Furthermore, Jag1 was demonstrated as a target of microRNA-26b-5p (miR-26b-5p). Interestingly, miR-26b-5p inhibitor prevented HSC activation inhibition caused by kaempferol. Further studies indicated that kaempferol inhibited Notch pathway via miR-26b-5p and Jag1, leading to HSC inactivation. Collectively, we demonstrate that kaempferol could inhibit HSC activation, at least in part, via miR-26b-5p-mediated Jag1 axis and Notch pathway. Kaempferol may serve as a promising drug in the application of treating liver fibrosis.

Interfacial Engineering-Triggered Bifunctionality of CoS2 /MoS2 Nanocubes/Nanosheet Arrays for High-Efficiency Overall Water Splitting.

Searching for high-efficiency nonprecious bifunctional electrocatalysts for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is paramount for the advancement of water electrolysis technologies and the associated renewable energy devices. Modulation of electronic structure of an electrocatalyst via heterointerface engineering represents an efficient strategy to improve its electrocatalytic performance. Herein, a feasible hydrothermal synthesis of a novel heterostructured catalyst was demonstrated, comprising CoS2 nanocubes and vertically aligned MoS2 nanosheet arrays directly grown on flexible and conductive carbon cloth (CC) substrate (denoted as CoS2 /MoS2 @CC). Thanks to the elaborate interface engineering and vertically aligned nanosheet arrayed architecture, the resultant self-supported CoS2 /MoS2 @CC electrode possessed enriched exposed active sites, modulated electronic configuration, multidimensional mass transport channels, and outstanding mechanical strength, thereby affording exceptional electrocatalytic performances towards the HER and OER in alkaline electrolyte with overpotentials of 71 and 274 mV at 10 mA cm-2 , respectively. In addition, a two-electrode electrolyzer assembled by CoS2 /MoS2 @CC required a cell voltage of 1.59 V at 10 mA cm-2 with nearly 100 % faradaic efficiency and remarkable durability, showing great potential for scalable and economical water electrolysis.

Capacities and efficient computation of first-passage probabilities.

A reversible diffusion process is initialized at position x_{0} and run until it first hits any of several targets. What is the probability that it terminates at a particular target? We propose a computationally efficient approach for estimating this probability, focused on those situations in which it takes a long time to hit any target. In these cases, direct simulation of the hitting probabilities becomes prohibitively expensive. On the other hand, if the timescales are sufficiently long, then the system will essentially "forget" its initial condition before it encounters a target. In these cases the hitting probabilities can be accurately approximated using only local simulations around each target, obviating the need for direct simulations. In empirical tests, we find that these local estimates can be computed in the same time it would take to compute a single direct simulation, but that they achieve an accuracy that would require thousands of direct simulation runs.