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Abstract This study aims to investigate the relationship between bullying victimization and mobile phone addiction (MPA) among college students, taking into consideration the mediating role of self-control and the moderating role of physical activity. A self-report survey was administered to college students from 4 universities in Guangxi, Liaoning, and Hunan provinces in China. Participants were asked to report their experiences of bullying victimization, level of MPA, self-control, and physical activity. Descriptive statistics, correlation analysis, and regression analysis were conducted to analyze the data. Mediation and moderation models were subsequently established to examine the relationships between variables. The results indicated a positive correlation between bullying victimization and MPA among college students. Additionally, bullying victimization was negatively correlated with self-control. Bullying victimization significantly predicted MPA, and self-control partially mediated this relationship. Furthermore, physical activity moderated the association between bullying victimization and self-control among college students. The findings suggest that self-control plays a partial mediating role in the relationship between bullying victimization and MPA among college students. Moreover, physical activity weakens the association between bullying victimization and self-control. Therefore, promoting physical activity to reduce MPA among college students who have experienced bullying victimization is highly recommended.

Abstract Mesial temporal lobe epilepsy (MTLE) is one of the most intractable epilepsies. Previously, we reported that mitochondrial DNA deletions were associated with epileptogenesis. While the underlying mechanism of mitochondrial DNA deletions during epileptogenesis remain unknown. In this study, a novel somatic mutation of DNA2 gene was identified in the hippocampal tissue of two MTLE patients carrying mitochondrial DNA deletions, and this mutation decreased the full-length expression of DNA2 protein significantly, aborting its normal functions. Then, we knocked down the DNA2 protein in zebrafish, and we demonstrated that zebrafish with DNA2 deficiency showed decreased expression of mitochondrial complex II–IV, and exhibited hallmarks of epileptic seizures, including abnormal development of the zebrafish and epileptiform discharge signals in brain, compared to the Cas9-control group. Moreover, our cell-based assays showed that DNA2 deletion resulted in accumulated mitochondrial DNA damage, abnormal oxidative phosphorylation and decreased ATP production in cells. Inadequate ATP generation in cells lead to declined Na+, K+-ATPase activity and change of cell membrane potential. Together, these disorders caused by DNA2 depletion increased cell apoptosis and inhibited the differentiation of SH-SY5Y into branched neuronal phenotype. In conclusion, DNA2 deficiency regulated the cell membrane potential via affecting ATP production by mitochondria and Na+, K+-ATPase activity, and also affected neuronal cell growth and differentiation. These disorders caused by DNA2 dysfunction are important causes of epilepsy. In summary, we are the first to report the pathogenic somatic mutation of DNA2 gene in the patients with MTLE disease, and we uncovered the mechanism of DNA2 regulating the epilepsy. This study provides new insight into the pathogenesis of epilepsy and underscore the value of DNA2 in epilepsy.

Abstract Background Transdermal delivery of sparingly soluble drugs is challenging due to their low solubility and poor permeability. Deep eutectic solvent (DES)/or ionic liquid (IL)-mediated nanocarriers are attracting increasing attention. However, most of them require the addition of auxiliary materials (such as surfactants or organic solvents) to maintain the stability of formulations, which may cause skin irritation and potential toxicity. Results We fabricated an amphiphilic DES using natural oxymatrine and lauric acid and constructed a novel self-assembled reverse nanomicelle system (DES-RM) based on the features of this DES. Synthesized DESs showed the broad liquid window and significantly solubilized a series of sparingly soluble drugs, and quantitative structure-activity relationship (QSAR) models with good prediction ability were further built. The experimental and molecular dynamics simulation elucidated that the self-assembly of DES-RM was adjusted by noncovalent intermolecular forces. Choosing triamcinolone acetonide (TA) as a model drug, the skin penetration studies revealed that DES-RM significantly enhanced TA penetration and retention in comparison with their corresponding DES and oil. Furthermore, in vivo animal experiments demonstrated that TA@DES-RM exhibited good anti-psoriasis therapeutic efficacy as well as biocompatibility. Conclusions The present study offers innovative insights into the optimal design of micellar nanodelivery system based on DES combining experiments and computational simulations and provides a promising strategy for developing efficient transdermal delivery systems for sparingly soluble drugs.

Abstract Plasma proteins are considered the most informative source of biomarkers for disease diagnosis and monitoring. Mass spectrometry (MS)-based proteomics has been applied to identify biomarkers in plasma, but the complexity of the plasma proteome and the extremely large dynamic range of protein abundances in plasma make the clinical application of plasma proteomics highly challenging. We designed and synthesized zeolite-based nanoparticles to deplete high-abundance plasma proteins. The resulting novel plasma proteomic assay can measure approximately 3000 plasma proteins in a 45 min chromatographic gradient. Compared to those in neat and depleted plasma, the plasma proteins identified by our assay exhibited distinct biological profiles, as validated in several public datasets. A pilot investigation of the proteomic profile of a hepatocellular carcinoma (HCC) cohort identified 15 promising protein features, highlighting the diagnostic value of the plasma proteome in distinguishing individuals with and without HCC. Furthermore, this assay can be easily integrated with all current downstream protein profiling methods and potentially extended to other biofluids. In conclusion, we established a robust and efficient plasma proteomic assay with unprecedented identification depth, paving the way for the translation of plasma proteomics into clinical applications. Graphical Abstract

PLCD3 belongs to the phospholipase C delta group and is involved in numerous biological functions, including cell growth, programmed cell death, and specialization. However, the role of PLCD3 in lung cancer still needs further investigation. This research aimed to investigate if PLCD3 influences glycolytic reprogramming and lung cancer development through the PKC-dependent Rap1 signaling pathway. This study found that PLCD3 was increased in lung cancer tissues. PLCD3 promotes the proliferation and invasion of lung cancer cells by activating the PKC-dependent Rap1 pathway. The detailed process involves PLCD3 triggering PKC, which subsequently stimulates the Rap1 pathway, leading to glycolytic reprogramming that supplies adequate energy and metabolic substrates necessary for the growth and spread of lung cancer cells. Moreover, PLCD3 can also promote the metastasis and invasion of lung cancer cells by activating the Rap1 pathway. This study reveals the mechanism of PLCD3 in lung cancer and provides new ideas for the treatment of lung cancer. Inhibiting PLCD3, PKC, and the Rap1 pathway may be an effective strategy for treating lung cancer.

BackgroundNatural killer (NK) cells are proposed to participate in coronary artery disease (CAD) development. However, little is known about how CAD patients’ NK cells respond to different stimulatory factors in terms of proliferation capability.Methods and resultsTwenty-nine CAD patients’ peripheral blood NK cells were isolated and individually treated with IL-2, IL-12, IL-15, IL-18, IL-21, cortisone acetate, hydrocortisone, or ascorbic acid for 36 hours, followed by cell cycle analysis using flow cytometry. The ratio of S and G2/M phase cell number to total cell number was defined as a proliferation index (PrI) and used for proliferative capability indication. The results showed that these eight factors resulted in different life cycle changes in the 29 NK cell samples. Remarkably, 28 out of 29 NK cell samples showed an obvious increase in PrI upon ascorbic acid treatment. The serum lactate dehydrogenase (LDH) level of the 29 CAD patients was measured. The results showed a negative correlation between serum LDH level and the CAD patients’ NK cell PrI upon stimulation of interleukins, but not the non-interleukin stimulators. Consistently, a retrospective analysis of 46 CAD patients and 32 healthy donors showed that the circulating NK cell number negatively correlated with the serum LDH level in CAD patients. Unexpectedly, addition of LDH to NK cells significantly enhanced the production of IFN-γ, IL-10 and TNF-α, suggesting a strong regulatory role on NK cell’s function.ConclusionAscorbic acid could promote the proliferation of the CAD patients’ NK cells; LDH serum level may function as an indicator for NK cell proliferation capability and an immune-regulatory factor.

Tongue cancer, a prevalent form of oral malignancy, particularly manifests as tongue squamous cell carcinoma (TSCC), which holds the highest incidence among oral squamous cell carcinoma cases, representing 43.4 % of occurrences. Presently, surgical resection stands as the primary treatment for TSCC, with no effective pharmaceutical interventions identified. This study aims to search for the potential anti-tumor properties and molecular mechanisms of a rearranged abietane diterpenoid extracted from Clerodendrum mandarinorum. Within this investigation, six known rearranged abietane diterpenoids (1–6) were isolated and characterized from C. mandarinorum. Notably, compound 1 demonstrated the most robust inhibitory effect against CAL-27 cells. Pharmacological assays further substantiated that compound 1 significantly restrained the proliferation, migration, and invasion of CAL-27 cells. Moreover, it was revealed that compound 1 directly interacted with TGFβR2, a pivotal receptor in the downstream signaling pathways of TGF-β/Smad and PI3K/AKT. Transcriptome analysis provided additional confirmation of these observations. Overall, our study highlights the promising potential of compound 1 as a therapeutic agent for the treatment of oral squamous cell carcinoma.

The consideration of students’ emotional and psychological health is crucial to facilitate effective teaching and grading practices. This study set out to shed light on the interplay between self-esteem (S-E), cognitive-emotion regulation (CER), academic enjoyment (AE), and language success (LS) in artificial intelligence (AI)-supported online language learning. To this end, the foreign language learning self-esteem scale, the Cognitive Emotion Control Questionnaire, the foreign language enjoyment scale, and a researcher-made test were distributed to 389 English as a foreign language learners in China. Screening the data with confirmatory factor analysis and structural equation modeling, the effects of S-E, CER, AE, and LS were identified and quantified. These results highlighted the important function that online courses assisted by AI perform in enhancing students’ CER and AE. This implied that students who have cultivated a robust sense of self-efficacy are adept at effectively regulating their cognitive and affective processes in AI-supported language learning. Possible improvements in language education are discussed, as are the study’s broader implications.

Xeroderma pigmentosum is a rare autosomal recessive genodermatoses characterized by a deficiency in nucleotide excision repair. Erythropoietic protoporphyria is a rare inherited metabolic disease caused by the perturbation of heme. Xeroderma pigmentosum-erythropoietic protoporphyria is exceedingly rare. Hereby, we firstly report a young Chinese patient of xeroderma pigmentosum Group A with erythropoietic protoporphyria carrying an XPA Met214AsnfsTer7 frameshift mutation and a homozygous splicing mutation, c.315–48T>C, in the proband’s intron3 of FECH.

Multidrug resistant bacteria have been a global health threat currently and frontline clinical treatments for these infections are very limited. To develop potent antibacterial agents with new bactericidal mechanisms is thus needed urgently to address this critical antibiotic resistance challenge. Natural products are a treasure of small molecules with high bioactive and low toxicity. In the present study, we demonstrated that a natural compound, honokiol, showed potent antibacterial activity against a number of Gram-positive bacteria including MRSA and VRE. Moreover, honokiol in combination with clinically used β-lactam antibiotics exhibits strong synergistic antimicrobial effects against drug-resistant S. aureus strains. Biochemical studies further reveal that honokiol may disrupt the GTPase activity, FtsZ polymerization, cell division. These biological impacts induced by honokiol may ultimately cause bacterial cell death. The in vivo antibacterial activity of honokiol against S. aureus infection was also verified with a biological model of G. mellonella larvae. The in vivo results support that honokiol is low toxic against the larvae and effectively increases the survival rate of the larvae infected with S. aureus. These findings demonstrate the potential of honokiol for further structural advancement as a new class of antibacterial agents with high potency against multidrug-resistant bacteria.

Abstract Background Count time series (e.g., daily deaths) are a very common type of data in environmental health research. The series is generally autocorrelated, while the widely used generalized linear model is based on the assumption of independent outcomes. None of the existing methods for modelling parameter-driven count time series can obtain consistent and reliable standard error of parameter estimates, causing potential inflation of type I error rate. Methods We proposed a new maximum significant ρ correction (MSRC) method that utilizes information of significant autocorrelation coefficient ρ estimate within 5 orders by moment estimation. A Monte Carlo simulation was conducted to evaluate and compare the finite sample performance of the MSRC and classical unbiased correction (UB-corrected) method. We demonstrated a real-data analysis for assessing the effect of drunk driving regulations on the incidence of road traffic injuries (RTIs) using MSRC in Shenzhen, China. Moreover, there is no previous paper assessing the time-varying intervention effect and considering autocorrelation based on daily data of RTIs. Results Both methods had a small bias in the regression coefficients. The autocorrelation coefficient estimated by UB-corrected is slightly underestimated at high autocorrelation (≥ 0.6), leading to the inflation of the type I error rate. The new method well controlled the type I error rate when the sample size reached 340. Moreover, the power of MSRC increased with increasing sample size and effect size and decreasing nuisance parameters, and it approached UB-corrected when ρ was small (≤ 0.4), but became more reliable as autocorrelation increased further. The daily data of RTIs exhibited significant autocorrelation after controlling for potential confounding, and therefore the MSRC was preferable to the UB-corrected. The intervention contributed to a decrease in the incidence of RTIs by 8.34% (95% CI, -5.69–20.51%), 45.07% (95% CI, 25.86–59.30%) and 42.94% (95% CI, 9.56–64.00%) at 1, 3 and 5 years after the implementation of the intervention, respectively. Conclusions The proposed MSRC method provides a reliable and consistent approach for modelling parameter-driven time series with autocorrelated count data. It offers improved estimation compared to existing methods. The strict drunk driving regulations can reduce the risk of RTIs.

Abstract An increasing number of studies have focused on the role of NEDD4-2 in regulating neuronal excitability and the mechanism of epilepsy. However, the exact mechanism has not yet been elucidated. Here, we explored the roles of NEDD4-2 and the CLC-2 channel in regulating neuronal excitability and mesial temporal lobe epilepsy (MTLE) pathogenesis. First, chronic MTLE models were induced by lithium-pilocarpine in developmental rats. Coimmunoprecipitation analysis revealed that the interaction between CLC-2 and NEDD4-2. Western blot analyses indicated that NEDD4-2 expression was downregulated, while phosphorylated (P-) NEDD4-2 and CLC-2 expression was upregulated in adult MTLE rats. Then, the primary hippocampal neuronal cells were isolated and cultured, and the NEDD4-2 was knocked down by shRNA vector, resulting in decreased protein levels of CLC-2. While CLC-2 absence caused increased NEDD4-2 in cells. Next, in an epileptic cell model induced by a Mg2+-free culture, whole-cell current-clamp recording demonstrated that NEDD4-2 deficiency inhibited the spontaneous action potentials of cells, and CLC-2 absence caused more significant decrease in the spontaneous action potentials of cells. In conclusion, we herein revealed that NEDD4-2 regulates the expression of CLC-2, which is involved in neuronal excitability, and participates in the pathogenesis of MTLE.

Biliary atresia (BA) is a severe and progressive biliary obstructive disease in infants that requires early diagnosis and new therapeutic targets. This study employed bioinformatics methods to identify diagnostic biomarkers and potential therapeutic targets for BA. Our analysis of mRNA expression from Gene Expression Omnibus datasets revealed 3,273 differentially expressed genes between patients with BA and those without BA (nBA). Weighted gene coexpression network analysis determined that the turquoise gene coexpression module, consisting of 298 genes, is predominantly associated with BA. The machine learning method then filtered out the top 2 important genes, CXCL8 and TMSB10, from the turquoise module. The area under receiver operating characteristic curves for TMSB10 and CXCL8 were 0.961 and 0.927 in the training group and 0.819 and 0.791 in the testing group, which indicated a high diagnostic value. Besides, combining TMSB10 and CXCL8, a nomogram with better diagnostic performance was built for clinical translation. Several studies have highlighted the potential of CXCL8 as a therapeutic target for BA, while TMSB10 has been shown to regulate cell polarity, which was related to BA progression. Our analysis with qRT PCR and immunohistochemistry also confirmed the upregulation of TMSB10 at mRNA and protein levels in BA liver samples. These findings highlight the sensitivity of CXCL8 and TMSB10 as diagnostic biomarkers and their potential as therapeutic targets for BA.

Abstract Serological tests for Epstein–Barr virus (EBV) antibodies have been widely conducted for the screening of nasopharyngeal carcinoma (NPC) in endemic areas. Further risk stratification of NPC can be achieved through plasma lipoprotein and metabolic profiles. A total of 297 NPC patients and 149 EBV‐positive participants are enrolled from the NCT03919552 and NCT05682703 cohorts for plasma nuclear magnetic resonance (NMR) metabolomic analysis. Small, dense very low density lipoprotein particles (VLDL‐5) and large, buoyant low density lipoprotein particles (LDL‐1) are found to be closely associated with nasopharyngeal carcinogenesis. Herein, an NMR‐based risk score (NRS), which combines lipoprotein subfractions and metabolic biomarkers relevant to NPC, is developed and well validated within a multicenter cohort. Combining the median cutoff value of the NRS (N50) with that of the serological test for EBV antibodies, the risk stratification model achieves a satisfactory performance in which the area under the curve (AUC) is 0.841 (95% confidence interval: 0.811‐0.871), and the positive predictive value (PPV) reaches 70.08% in the combined cohort. These findings not only suggest that VLDL‐5 and LDL‐1 particles can serve as novel risk factors for NPC but also indicate that the NRS has significant potential in personalized risk prediction for NPC.

Background and objectiveBleeding following endoscopic variceal ligation (EVL) may occur as a result of numerous factors, including a diameter of esophageal varices (EV) that is too large to be completely ligated. The present study aimed to develop an artificial intelligence-based endoscopic virtual ruler (EVR) to measure the diameter of EV with a view to finding more suitable cases for EVL.MethodsThe present study was a multicenter retrospective study that included a total of 1,062 EVLs in 727 patients with liver cirrhosis with EV, who underwent EVL from April 2016 to March 2023. Patients were divided into early rebleeding (n = 80) and non-rebleeding groups (n = 982) according to whether postoperative bleeding occurred at 6 weeks. The characteristics of patient baseline data, the status of rebleeding at 6 weeks after surgery and the survival status at 6 weeks after rebleeding were analyzed.ResultsThe early rebleeding rate following 1,062 EVL procedures was 7.5%, and the mortality rate at 6 weeks after bleeding was 16.5%. Results of the one-way binary logistic regression analysis demonstrated that the risk factors for early rebleeding following EVL included: high TB (P = 0.009), low Alb (P = 0.001), high PT (P = 0.004), PVT (P = 0.026), HCC (P = 0.018), high Child-Pugh score (P < 0.001), Child-Pugh grade C(P < 0.001), high MELD score(P = 0.004), Japanese variceal grade F3 (P < 0.001), diameter of EV (P < 0.001), and number of ligature rings (P = 0.029). Results of the multifactorial binary logistic regression analysis demonstrated that Child-Pugh grade C (P = 0.007), Japanese variceal grade F3 (P = 0.009), and diameter of EV (P < 0.001) may exhibit potential in predicting early rebleeding following EVL. ROC analysis demonstrated that the area under curve (AUC) for EV diameter was 0.848, and the AUC for Japanese variceal grade was 0.635, which was statistically significant (P < 0.001). Thus, results of the present study demonstrated that EV diameter was more optimal in predicting early rebleeding following EVL than Japanese variceal grade criteria. The cut-off value of EV diameter was calculated to be 1.35 cm (sensitivity, 70.0%; specificity, 89.2%).ConclusionIf the diameter of EV is ≥1.4 cm, there may be a high risk of early rebleeding following EVL surgery; thus, we recommend caution with EVL.

During activities of daily living (ADLs), the wrist is mainly engaged in positioning and directing the hand. Researches have demonstrated that restoring wrist mobility can significantly enhance the manipulation ability, reduce body distortion caused by motion compensation, and improve the quality of life for amputees. However, most daily activities, particularly the delicate ones, place high demands on the ability of wrist to maintain a certain rotation angle, also known as non-back-drivable ability, which poses a challenge to the design of prosthetic wrists. To address this issue, various solutions have been proposed, including motor holding brakes, high reduction ratio reducers, and worm gears. However, the motor holding brake only functions after a power outage and cannot continuously prevent torque from the load end. The latter two solutions may alter the transmission ratio, resulting in reduced movement speed and transmission efficiency. Therefore, how to design a miniaturized non-back-drivable mechanism without changing the transmission ratio so that the forearm rotational freedom can be locked at any position for any duration is a problem to be solved in the research of prosthetic wrist designs. This paper presents a line-contact based non-back-drivable clutch (NBDC) that does not cause changes in the transmission ratio, ensuring the motion performance of the prosthetic limb. At the same time, it does not introduce additional friction in the forward transmission process, guaranteeing the overall efficiency. Most importantly, it only allows the torque transmitting from the motor to the load, prevents the load reversely from driving back even in a power failure condition, significantly improving the stability, safety, and comfort. Detailed kinematic and static analyses of the working process has been conducted, and transient dynamics simulation has been performed to verify its effectiveness. Through experiments, it is demonstrated that the self-locking torque of the output end could reach approximately 600 Nmm, and the unlocking torque of the input end is about 80 Nmm, which can be effectively integrated in prosthetic wrist rotation joints, contributing to the performance, safety and energy saving of prosthetic joint systems.

ObjectivesThe study aims to examine the associations between exercise self-efficacy, motivation, physical activity, and body composition among emerging adults.DesignCross-sectional.MethodsA convenience sample of 147 emerging adults participated in the Releasing Weight (RELEW) project. The InBody720 analyzer was used to measure body composition, and the International Physical Activity Questionnaire-Short, the Shortened Physical Activity Self-Efficacy Scale, and the Treatment Self-Regulation Questionnaire were used to measure self-reported physical activity, self-efficacy, and motivation. Structural Equation Modeling was used to exam the complex relationships among multiple variables. in this study. The Partial least squares structural equation modeling analysis with bootstrapping in Smart PLS 3 was employed to explore the path coefficients and t-values for the relationships that were thought to exist. Significance was determined using a threshold of p < 0.05.ResultsThe mean age of 147 participants was 18.5 ± 1.87, of whom 51.7% were female, recruited for this study. Exercise self-efficacy has a significant positive correlation with exercise motivation (r = 0.220, p = 0.008) and physical activity (r = 0.279, p < 0.001). Exercise motivation does not demonstrate significant associations with physical activity (r = 0.094, p = 0.298). Utilizing SEM, the model explained 9.2% of exercise self-efficacy, 11.8% of physical activity, and 68.3% of body composition variance. Mediation analysis revealed that exercise self-efficacy partially mediated the relationship between exercise motivation and physical activity (β = 0.106, t = 2.538, p < 0.05), and physical activity partially mediated the relationship between exercise self-efficacy and body composition (β = −0.296, t = 4.280, p < 0.001).ConclusionThis study sheds light on the complex relationships among motivation, self-efficacy, physical activity and body composition during emerging adulthood. Our results highlight the mediating role of self-efficacy and its impact on physical activity behaviors, offering valuable insights for targeted interventions and policy development to improve health outcomes in this demographic.

Numerous researches have reported on the regulatory network of liver regeneration induced by partial hepatectomy (PH). However, information on key molecules and/or signaling pathways regulating the termination stage of liver regeneration remains limited. In this study, we identify hepatic mitotic arrest deficient 1 (MAD1) as a crucial regulator of transforming growth factor β (TGF-β) in the hepatocyte to repress liver regeneration. MAD1 has a low expression level at the rapid proliferation phase but significantly increases at the termination phase of liver regeneration. We show that MAD1 deficiency accelerates hepatocyte proliferation and enhances mitochondrial biogenesis and respiratory. Mechanistically, MAD1 deficiency in hepatocytes enhances mitochondrial function and promotes hepatocyte proliferation by suppressing TGF-β signaling. Our study reveals MAD1 as a novel suppressor of hepatocyte proliferation, which may provide a new therapeutic target for the recovery of liver function after liver transplant and partial hepatectomy.

Abstract Background As an indicator of tumor invasiveness, microvascular invasion (MVI) is a crucial risk factor for postoperative relapse, metastasis, and unfavorable prognosis in hepatocellular carcinoma (HCC). Nevertheless, the genetic mechanisms underlying MVI, particularly for Chinese patients, remain mostly uncharted. Methods We applied deep targeted sequencing on 66 Chinese HCC samples. Focusing on the telomerase reverse transcriptase (TERT) promoter (TERTp) and TP53 co‐mutation (TERTp+/TP53+) group, gene set enrichment analysis (GSEA) was used to explore the potential molecular mechanisms of the TERTp+/TP53+ group on tumor progression and metastasis. Additionally, we evaluated the tumor immune microenvironment of the TERTp+/TP53+ group in HCC using multiplex immunofluorescence (mIF) staining. Results Among the 66 HCC samples, the mutated genes that mostly appeared were TERT, TP53, and CTNNB1. Of note, we found 10 cases with TERTp+/TP53+, of which nine were MVI‐positive and one was MVI‐negative, and there was a co‐occurrence of TERTp and TP53 (p

Abstract Adenotonsillectomy is the most common daytime surgery performed on children. Anesthesiologists must select the optimal combination of drugs to ensure effective anesthesia effect and prompt recovery in children. The optimal induction dose of ciprofol in children is unclear. In this study, we aim to investigate the effect of different doses of ciprofol on anesthesia induction in children undergoing daytime adenotonsillectomy and provide a reference for clinical use. 144 children aged 3–12 years, ASA I-II, undergoing daytime adenotonsillectomy, were included in this clinical trial. The children were randomly divided into three groups and given 0.4 mg/kg (C4), 0.6 mg/kg (C6), or 0.8 mg/kg (C8) of ciprofol for anesthesia induction. The primary outcome was intubation conditions. Vital signs and injection pain were also recorded. The rates of unacceptable intubation conditions were 30.6%, 8.7%, and 8.2% in the C4, C6, and C8 groups (P value

Abstract Background Microvascular invasion (MVI) is the main factor affecting the prognosis of patients with hepatocellular carcinoma (HCC). The aim of this study was to identify accurate diagnostic biomarkers from urinary protein signatures for preoperative prediction. Methods We conducted label-free quantitative proteomic studies on urine samples of 91 HCC patients and 22 healthy controls. We identified candidate biomarkers capable of predicting MVI status and combined them with patient clinical information to perform a preoperative nomogram for predicting MVI status in the training cohort. Then, the nomogram was validated in the testing cohort (n = 23). Expression levels of biomarkers were further confirmed by enzyme-linked immunosorbent assay (ELISA) in an independent validation HCC cohort (n = 57). Results Urinary proteomic features of healthy controls are mainly characterized by active metabolic processes. Cell adhesion and cell proliferation-related pathways were highly defined in the HCC group, such as extracellular matrix organization, cell–cell adhesion, and cell–cell junction organization, which confirms the malignant phenotype of HCC patients. Based on the expression levels of four proteins: CETP, HGFL, L1CAM, and LAIR2, combined with tumor diameter, serum AFP, and GGT concentrations to establish a preoperative MVI status prediction model for HCC patients. The nomogram achieved good concordance indexes of 0.809 and 0.783 in predicting MVI in the training and testing cohorts. Conclusions The four-protein-related nomogram in urine samples is a promising preoperative prediction model for the MVI status of HCC patients. Using the model, the risk for an individual patient to harbor MVI can be determined.

With the development of landslide monitoring system, many attempts have been made to predict landslide failure-time utilizing monitoring data of displacements. Classical models (e.g., Verhulst, GM (1,1), and Saito models) that consider the characteristics of landslide displacement to determine the failure-time have been investigated extensively. In practice, monitoring is continuously implemented with monitoring data-set updated, meaning that the predicted landslide life expectancy (i.e., the lag between the predicted failure-time and time node at each instant of conducting the prediction) should be re-evaluated with time. This manner is termed “dynamic prediction”. However, the performances of the classical models have not been discussed in the context of the dynamic prediction yet. In this study, such performances are investigated firstly, and disadvantages of the classical models are then reported, incorporating the monitoring data from four real landslides. Subsequently, a more qualified ensemble model is proposed, where the individual classical models are integrated by machine learning (ML)-based meta-model. To evaluate the quality of the models under the dynamic prediction, a novel indicator termed “discredit index (β)” is proposed, and a higher value of β indicates lower prediction quality. It is found that Verhulst and Saito models would produce predicted results with significantly higher β, while GM (1,1) model would indicate results with the highest mean absolute error. Meanwhile, the ensemble models are found to be more accurate and qualified than the classical models. Here, the performance of decision tree regression-based ensemble model is the best among the various ML-based ensemble models.

The use of a resin to selectively separate thiomolybdate from a tungsten (W) feed solution is a well-known protocol for achieve high-purity W products; however, the regeneration of saturated resin is laborious. In this study, poly(diallyl dimethyl ammonium chloride) (PDADMA) was used to modify ultrasound-pretreated montmorillonite (Mt) for W and molybdenum (Mo) separation for the first time, and the resultant tetrathiomolybdate (MoS42-)-loaded composite was further tested to remove heavy metals instead of regeneration. Among the three variables of ultrasound pretreatment, that is, Mt concentration, ultrasound power, and treatment time, the Mt concentration exhibited the most significant influence followed by ultrasound power on the separation performance of W and Mo. Compared to the distance of the interlayer space and the surface charge of the modified Mt, the PDADMA content showed a closer correlation with the W/Mo separation coefficient. Assisted by Box–Behnken design, with Mt concentration of 6.9 g/L, ultrasound power of 593.8 W, and treatment time of 13.8 min, the composite with the greatest separation coefficient was obtained. The adsorption of Cu(II) on the optimal W/Mo separation-derived composite was ascribed to the formation of Cu-S complexes, while that of Pb(II) was attributed to complexation and surface precipitation. In contrast, ion exchange with the initially loaded anions, reduction by sulfide to Cr(III), and formation of Cr(III)-S complexes accounted for Cr(VI) removal. The adsorption of Cu(II) and Pb(II) equilibrated faster and showed higher acid-resistance than that of Cr(VI). The adsorption capacities for Cu(II), Pb(II), and Cr(VI) were 0.535, 1.398, and 0.882 mmol/g, respectively. Applying PDADMA to modify Mt as a reagent for W/Mo separation was feasible, and the derived composite was capable of removing cationic and anionic heavy metals.

As an interstitial fibrosis disease characterized by diffuse alveolitis and structural alveolar disorders, idiopathic pulmonary fibrosis (IPF) has high lethality but lacks limited therapeutic drugs. A hospital preparation used for the treatment of viral pneumonia, Qingfei Tongluo mixture (QFTL), is rumored to have protective effects against inflammatory and respiratory disease. This study aims to confirm whether it has a therapeutic effect on bleomycin-induced IPF in rats and to elucidate its mechanism of action. Male SD rats were randomly divided into the following groups: control, model, CQ + QFTL (84 mg/kg chloroquine (CQ) + 3.64 g/kg QFTL), QFTL-L, M, H (3.64, 7.28, and 14.56 g/kg, respectively) and pirfenidone (PFD 420 mg/kg). After induction modeling and drug intervention, blood samples and lung tissue were collected for further detection. Body weight and lung coefficient were examined, combined with hematoxylin and eosin (H&E) and Masson staining to observe lung tissue lesions. The enzyme-linked immunosorbent assay (ELISA) and the hydroxyproline (HYP) assay kit were used to detect changes in proinflammatory factors (transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β)) and HYP. Immunohistochemistry and Western blotting were performed to observe changes in proteins related to pulmonary fibrosis (α-smooth muscle actin (α-SMA) and matrix metalloproteinase 12 (MMP12)) and autophagy (P62 and mechanistic target of rapamycin (mTOR)). Treatment with QFTL significantly improved the adverse effects of bleomycin on body weight, lung coefficient, and pathological changes. Then, QFTL reduced bleomycin-induced increases in proinflammatory mediators and HYP. The expression changes of pulmonary fibrosis and autophagy marker proteins are attenuated by QFTL. Furthermore, the autophagy inhibitor CQ significantly reversed the downward trend in HYP levels and α-SMA protein expression, which QFTL improved in BLM-induced pulmonary fibrosis rats. In conclusion, QFTL could effectively attenuate bleomycin-induced inflammation and pulmonary fibrosis through mTOR-dependent autophagy in rats. Therefore, QFTL has the potential to be an alternative treatment for IPF in clinical practice.

Oral submucous fibrosis (OSF) is a chronic premalignant disease associated with betel quid chewing. Epidemiological studies indicate that there are approximately 5 million individuals suffering from OSF worldwide, with a concerning malignancy transformation rate of up to 4.2 %. When OSF progresses to oral squamous cell carcinoma (OSCC), the 5-year survival rate for OSCC drops to below 60 %. Therefore, early screening and diagnosis are essential for both preventing and effectively treating OSF and its potential malignant transformation. Numerous studies have shown that the malignant transformation of OSF is associated with various factors, including epigenetic reprogramming, epithelial-mesenchymal transition, hypoxia, cell cycle changes, immune regulation disturbances, and oxidative damage. This review article focuses on the unraveling the potential mechanisms underlying the malignant transformation of OSF, as well as the abnormal expression of biomarkers throughout this transformative process, with the aim of aiding early screening for carcinogenic changes in OSF. Furthermore, we discuss the significance of utilizing blood and saliva components from patients with OSF, along with optical diagnostic techniques, in the early screening of OSF malignant transformation.

As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.

Background: This study aimed to examine the prevalence and associated factors of malnutrition in older community-dwellers and explore the interaction between associated factors. Methods: A total of 474,467 older community-dwellers aged 65 or above were selected in Guangzhou, China. We used a two-step methodology to detect the associated factors of malnutrition and constructed logistic regression models to explore the influencing factors and interactive effects on three patterns of malnutrition. Results: The prevalence of malnutrition was 22.28%. Older adults with both hypertension and diabetes (RERI = 0.13), both meat or fish diet and hypertension (RERI = 0.79), and both meat or fish diet and diabetes (RERI = 0.81) had positive additive interaction effects on the risk of obesity, whereas those on a vegetarian diet with hypertension (RERI = −0.25) or diabetes (RERI = −0.19) had negative additive interaction effects. Moreover, the interactions of physical activity with a meat or fish diet (RERI = −0.84) or dyslipidemia (RERI = −0.09) could lower the risk of obesity. Conclusions: Malnutrition was influenced by different health factors, and there were interactions between these influencing factors. Pertinent dietary instruction should be given according to different nutritional status indexes and the prevalence of metabolic diseases to avoid the occurrences of malnutrition among older adults.

In the evolving field of machine learning, deploying fair and transparent models remains a formidable challenge. This study builds on earlier research, demonstrating that neural architectures exhibit inherent biases by analyzing a broad spectrum of transformer-based language models from base to x-large configurations. This article investigates movie reviews for genre-based bias, which leverages the Word Embedding Association Test (WEAT), revealing that scaling models up tends to mitigate bias, with larger models showing up to a 29% reduction in prejudice. Alternatively, this study also underscores the effectiveness of prompt-based learning, a facet of prompt engineering, as a practical approach to bias mitigation, as this technique reduces genre bias in reviews by more than 37% on average. This suggests that the refinement of development practices should include the strategic use of prompts in shaping model outputs, highlighting the crucial role of ethical AI integration to weave fairness seamlessly into the core functionality of transformer models. Despite the basic nature of the prompts employed in this research, this highlights the possibility of embracing structured prompt engineering to create AI systems that are ethical, equitable, and more responsible for their actions.

This paper studied the impact of high-speed railway linesonagricultural outputin the regions along their routes. It also investigated the heterogeneity of this impactbased on the terrain characteristics. The results of empirical testsusing county-level data show that ahigh-speed railway line can bring higher agricultural “dividends” to counties along the line. Notably, low altitude areas and regionswith gentle terrain exhibit a more pronounced promotional effect on local agricultural output. High-speed railways mainly promote agricultural output by promoting the mechanization of agriculture in counties along the route, thus reinvigorating the agricultural population and the development of specialty agriculture. Ourfindingsprovide quasi-microscopic evidence of the potential benefits of transportation infrastructure construction to break down geographical barriers and facilitate production factor flow, and providesa theoretical basis for the economic spillover effects of high-speed railway construction.

AbstractBackground Given its progressive deterioration in the clinical course, noninvasive assessment and risk stratification for the severity of renal fibrosis in chronic kidney disease (CKD) are required. We aimed to develop and validate an end-to-end multilayer perceptron (MLP) model for assessing renal fibrosis in CKD patients based on real-time two-dimensional shear wave elastography (2D-SWE) and clinical variables.Methods From April 2019 to December 2021, a total of 162 patients with CKD who underwent a kidney biopsy and 2D-SWE examination were included in this single-center, cross-sectional, and prospective clinical study. 2D-SWE was performed to measure the right renal cortex stiffness, and the corresponding elastic values were recorded. Patients were categorized into two groups according to their histopathological results: mild and moderate-severe renal fibrosis. The patients were randomly divided into a training cohort (n = 114) or a test cohort (n = 48). The MLP classifier using a machine learning algorithm was used to construct a diagnostic model incorporating elastic values with clinical features. Discrimination, calibration, and clinical utility were used to appraise the performance of the established MLP model in the training and test sets, respectively.Results The developed MLP model demonstrated good calibration and discrimination in both the training [area under the receiver operating characteristic curve (AUC) = 0.93; 95% confidence interval (CI) = 0.88 to 0.98] and test cohorts [AUC = 0.86; 95% CI = 0.75 to 0.97]. A decision curve analysis and a clinical impact curve also showed that the MLP model had a positive clinical impact and relatively few negative effects.Conclusions The proposed MLP model exhibited the satisfactory performance in identifying the individualized risk of moderate-severe renal fibrosis in patients with CKD, which is potentially helpful for clinical management and treatment decision-making.

Glioblastoma is an immunologically cold tumour, with poor CD8 + T cell infiltration and enrichment in immunosuppressive tumour-associated myeloid cells. Here, the authors generate a bispecific lipid nanoparticle targeting CD47 and PD-L1, combined with a STING agonist, to promote anti-tumour immunity.

As sorafenib is a first-line drug for treating advanced hepatocellular carcinoma, sorafenib resistance has historically attracted attention. However, most of this attention has been focused on a series of mechanisms related to drug resistance arising after sorafenib treatment. In this study, we used proteomic techniques to explore the potential mechanisms by which pretreatment factors affect sorafenib resistance. The degree of redundant pathway PI3K/AKT activation, biotransformation capacity, and autophagy level in hepatocellular carcinoma patients prior to sorafenib treatment might affect their sensitivity to sorafenib, in which ADH1A and STING1 are key molecules. These three factors could interact mechanistically to promote tumor cell survival, might be malignant features of tumor cells, and are associated with hepatocellular carcinoma prognosis. Our study suggests possible avenues of therapeutic intervention for patients with sorafenib-resistance and the potential application of immunotherapy with the aim of improving the survival of such patients.

Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4 (CXCR4) have been shown to regulate neural regeneration after stroke. However, whether stromal cell-derived factor-1 receptor CXCR7, which is widely distributed in the developing and adult central nervous system, participates in neural regeneration remains poorly understood. In this study, we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral cortex and striatum. Starting on day 7 after injury, CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days. Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting corticospinal tract fibers in rats with cerebral ischemia, increased the expression of vesicular glutamate transporter 1 and growth-related protein 43, markers of the denervated spinal cord synapses, and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum. In addition, CXCR7 antibody increased the expression of CXCR4 in the striatum, increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway, and improved rat motor function. These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration, synaptogenesis, and myelin regeneration, which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.

Using data from ALFALFA, xGASS, H i -MaNGA, and the Sloan Digital Sky Survey (SDSS), we identify a sample of 47 “red but H i -rich” (RR) galaxies with near-UV (NUV) − r > 5 and unusually high H i -to-stellar mass ratios. We compare the optical properties and local environments between the RR galaxies and a control sample of “red and H i -normal” (RN) galaxies that are matched in stellar mass and color. The two samples are similar in the optical properties typical of massive red (quenched) galaxies in the local Universe. The RR sample tends to be associated with slightly lower-density environments and has lower clustering amplitudes and smaller neighbor counts at scales from several hundred kiloparsecs to a few megaparsecs. The results are consistent with the RR galaxies being preferentially located at the center of low-mass halos, with a median halo mass ∼10 ^12 h ^−1 M _⊙ compared to ∼10 ^12.5 h ^−1 M _⊙ for the RN sample. This result is confirmed by the SDSS group catalog, which reveals a central fraction of 89% for the RR sample, compared to ∼60% for the RN sample. If assumed to follow the H i size–mass relation of normal galaxies, the RR galaxies have an average H i -to-optical radius ratio of R _HI / R _90 ∼ 4, four times the average ratio for the RN sample. We compare our RR sample with similar samples in previous studies, and quantify the population of RR galaxies using the SDSS complete sample. We conclude that the RR galaxies form a unique but rare population, accounting for only a small fraction of the massive quiescent galaxy population. We discuss the formation scenarios of the RR galaxies.

Landslide susceptibility mapping is a crucial tool for analyzing geohazards in a region. Recent publications have popularized data-driven models, particularly machine learning-based methods, owing to their strong capability in dealing with complex nonlinear problems. However, a significant proportion of these models have neglected qualitative aspects during analysis, resulting in a lack of interpretability throughout the process and causing inaccuracies in the negative sample extraction. In this study, Scoops 3D was employed as a physics-informed tool to qualitatively assess slope stability in the study area (the Hubei Province section of the Three Gorges Reservoir Area). The non-landslide samples were extracted based on the calculated factor of safety (FS). Subsequently, the random forest algorithm was employed for data-driven landslide susceptibility analysis, with the area under the receiver operating characteristic curve (AUC) serving as the model evaluation index. Compared to the benchmark model (i.e., the standard method of utilizing the pure random forest algorithm), the proposed method's AUC value improved by 20.1%, validating the effectiveness of the dual-driven method (physics-informed data-driven).d.

External causes like changes in reservoir level and intense rainfall can cause reservoir landslides. Exploring the factors that govern landslide deformation and analyzing its stability evolution is essential in mitigating the associated risks. The Sanzhouxi landslide, which has experienced ongoing movements and has been implemented a professional monitoring system, is chosen for analysis in this paper. A combination of geological survey and analysis of monitoring data is utilized to explore landslide deformation characteristics. A data mining method, grey relation analysis (GRA), is subsequently performed to determine the causes of landslide deformation. Furthermore, the stability of the Sanzhouxi landslide in response to reservoir level fluctuation and rainfall for each day over an entire year is assessed using the Morgenstern-Price (MP) approach in 2D GeoStudio software. Such a process illustrates clearly how the landslide stability alters with external triggers changing. The findings reveal that the landslide deforms variably in spatial and temporal. The reservoir level rising contributes to landslide deformation primarily, while rainfall has a secondary impact. The factor of safety (FS) of the Sanzhouxi landslide drops from 1.17 to 1.07 during high reservoir water level periods and remain the same or increase in other periods except for some transitory moments while decreasing only by about 2% under the effect of rainfall. The daily FS results validate the dominant influence of reservoir level fluctuation on the stability of the landslide. The comprehensive understanding of landslide movement based on deformation characteristics, triggering factor identification, and daily stability validation, contributes to realizing nearly real-time prediction and evaluating the risk due to slope movements in similar geological settings worldwide.

Diabetes retinopathy (DR) is a common complication associated with diabetes. This study aimed to investigate ameliorative effect of black raspberry anthocyanins (BRAs) on DR and underlying inhibition mechanism of protein tyrosine phosphatase 1B (PTP1B)-endoplasmic reticulum stress (ERS) with retinal pigment epithelial cells apoptosis exposed to high glucose and tunicamycin and DR rats induced by STZ and high-fat and high-sugar diet. The results showed that TG and TC levels were markedly decreased, and disarrangement of retinas was markedly improved after BRA administration. Moreover, after pre-incubation with BRAs, morphological changes and mitochondrial membrane potential were significantly improved, whereas the apoptosis rates, activities of PTP1B and Caspase-1, and reactive oxygen species levels were significantly decreased. Finally, BRAs exhibited an efficient combination with GRP78, and they significantly suppressed protein expression of axis PTP1B-ERS. The results offer a basis for mastering ameliorated DR with BRAs and further first enhanced the mechanism of inhibiting axis PTP1B-ERS.

Abstract Background Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal cancers worldwide accompany with an extremely poor prognosis. Therefore, this study aims to screen for new molecules affecting ESCC and explore their mechanisms of action to provide ideas for targeted therapies for ESCC. Methods Firstly, we screened out the membrane protein SCARA5 by high-throughput sequencing of the ESCC patient tissues, and RT-qPCR and WB were used to verify the differential expression of SCARA5 in esophageal cell lines, and IHC analyzed the expression localization of SCARA5 in ESCC tissue. Then, flow cytometry, wound healing assay, Transwell assay and CCK-8 assay were used to explore the effects of SCARA5 on cell cycle, migration and invasion as well as cell proliferation activity of esophageal squamous carcinoma cells. Meanwhile, transmission electron microscopy was used to detect changes in cellular mitochondrial morphology, and flow cytometry were used to detect changes in intracellular reactive oxygen metabolism, and immunofluorescence and flow cytometry were used to detect changes in intracellular Fe2+. Mechanistically, co-immunoprecipitation was used to detect whether SCARA5 binds to ferritin light chain, and ferroptosis-related protein expression was detected by WB. Finally, the tumor xenograft model was applied to validation the role of SCARA5 tumor growth inhibition in vivo. Results We found that SCARA5 was aberrantly decreased in ESCC tissues and cell lines. Furthermore, we confirmed that SCARA5 suppressed the cell cycle, metastasis and invasion of ESCC cells. Meanwhile, we also found that overexpression of SCARA5 caused changes in mitochondrial morphology, accumulation of intracellular reactive oxygen species and increased intracellular Fe2+ in ESCC cells, which induced ferroptosis in ESCC cells. Mechanically, we validated that SCARA5 combined with ferritin light chain and increased intracellular Fe2+. As well as, overexpression SCARA5 induced ferroptosis by increasing ferritin light chain in nude mice subcutaneous tumors and inhibited the growth of nude mice subcutaneous tumors. Conclusion Collectively, our findings demonstrated that SCARA5 suppressed the proliferation and metastasis of ESCC by triggering ferroptosis through combining with ferritin light chain.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrous interstitial lung disease of unknown etiology. IPF is also considered to be among the independent risk factors for lung cancer, increasing the risk of lung cancer by 7% and 20%. The incidence of IPF complicated with lung cancer, especially non-small cell lung cancer (NSCLC), is increasing gradually, but there is no consensus on unified management and treatment. IPF and NSCLC have similar pathological features. Both appear in the surrounding area of the lung. In pathients with IPF complicated with NSCLC, NSCLC often develops from the honeycomb region of IPF, but the mechanism of NSCLC induced by IPF remains unclear. In addition, IPF and NSCLC have similar genetic, molecular and cellular processes and common signal transduction pathways. The universal signal pathways targeting IPF and NSCLC will become potential therapeutic drugs for IPF complicated with NSCLC. This article examines the main molecular mechanisms involved in IPF and NSCLC and the research progress of drugs under development targeting these signal pathways.

Abstract Background Hematopoietic stem cell transplantation (HSCT) is the main treatment for acute radiation sickness, especially after fatal radiation. The determination of HSCT for radiation patients is mainly based on radiation dose, hemogram and bone marrow injury severity. This study aims to explore a better biomarker of acute radiation injury from the perspective of systemic immune response. Methods C57BL/6J female mice were exposed to total body irradiation (TBI) and partial body irradiation (PBI). Changes in haptoglobin (Hp) level in plasma were shown at different doses and time points after the exposure and treatment with amifostine or bone marrow transplantation. Student’s t-test/two tailed test were used in two groups. To decide the Hp levels as a predictor of the radiation dose in TBI and PBI, multiple linear regression analysis were performed. The ability of biomarkers to identify two groups of different samples was determined by the receiver operating characteristic (ROC) curve. The results were expressed as mean ± standard deviation (SD). Significance was set at P value

Hepatic miR-182-5p is identified as a key regulator of liver regeneration by stimulating Cyp7a1-mediated cholic acid production in hepatocytes and activating hedgehog (Hh) signaling, consequently increasing cell proliferation.

Abstract Alternative RNA splicing is one of the most important mechanisms of posttranscriptional gene regulation, which contributes to protein diversity in eukaryotes. It is well known that RNA splicing dysregulation is a critical mechanism in tumor pathogenesis and the rationale for the promising splice-switching therapeutics for cancer treatment. Although we have a comprehensive understanding of DNA mutations, abnormal gene expression profiles, epigenomics, and proteomics in lung adenocarcinoma (LUAD), little is known about its aberrant alternative splicing profiles. Here, based on the multi-omics data generated from over 1000 samples, we systematically studied the RNA splicing alterations in LUAD and revealed their biological and clinical implications. We identified 3688 aberrant alternative splicing events (AASEs) in LUAD, most of which were alternative promoter and exon skip. The specific regulatory roles of RNA binding proteins, somatic mutations, and DNA methylations on AASEs were comprehensively interrogated. We dissected the functional implications of AASEs and concluded that AASEs mainly affected biological processes related to tumor proliferation and metastasis. We also found that one subtype of LUAD with a particular AASEs pattern was immunogenic and had a better prognosis and response rate to immunotherapy. These findings revealed novel events related to tumorigenesis and tumor immune microenvironment and laid the foundation for the development of splice-switching therapies for LUAD.

Abstract Hydrogen‐doped In2O3 (In2O3:H) is highly conductive while maintaining extraordinary transparency, thus making it a very attractive material for applications in optoelectronic devices such as (multijunction) solar cells or light‐emitting devices. However, the corresponding metal/In2O3:H contacts may exhibit undesirably high resistances, significantly deteriorating device performance. To gain insight into the underlying efficiency‐limiting mechanism, hard X‐ray photoelectron spectroscopy is employed to in‐situ monitor annealing‐induced changes in the chemical structure of the Ag/In2O3:H interface system that is further complemented by ex‐situ electron microscopy analyses and contact resistance measurements. The observed evolution of the Ag‐ and In‐related photoelectron line intensities can be explained by significant intermixing across the Ag/In2O3:H interface. The corresponding lineshape broadening of the Ag 3d spectra is attributed to the formation of Ag2O and AgO, which becomes significant at temperatures above approximately 160 °C. However, after annealing to 300 °C, instead of the formation of an insulating AgOx interfacial layer, it is found i) In to be rather homogeneously distributed in the complete Ag/In2O3:H stack, ii) Ag diffusing into the In2O3:H, and iii) an improvement of the contact resistance rather than its often‐reported deterioration.

Molecular testing of indeterminate thyroid nodules informs about the presence of point mutations, insertions/deletions, copy number variants, RNA fusions, transcript alterations and miRNA expression. American Thyroid Association (ATA) guidelines suggest molecular testing of indeterminate thyroid nodules may be considered to supplement risk of malignancy (ROM). Although these recommendations have been incorporated in clinical practices in the United States, molecular testing of indeterminate thyroid nodules is not common practice in Asia. Here, we performed molecular testing of 140 indeterminate nodules from Chinese patients using a novel molecular platform composed of RNA and DNA‐RNA classifiers, which is similar to Afirma GEC and ThyroSeq v3. Compared with reports from North America, the new RNA and DNA‐RNA classifiers had a higher positive predictive value (p1 = 0.000 and p2 = 0.020) but a lower negative predictive value (p1 = 0.004 and p2 = 0.098), with no significant differences in sensitivity (p1 = 0.625 and p2 = 0.179) or specificity (p1 = 0.391 and p2 = 0.264). Out of 58 resected nodules, 10 were borderline and 33 malignant, indicating a 74.1% ROM, which was higher than reports in North America (10–40% ROM). Our findings emphasize molecular testing with the newly reported RNA and DNA‐RNA classifiers can be used as a ‘rule‐in’ test when ROM is high.

Circular RNAs are highly stable single-stranded circular RNAs and enriched in the brain. Previous studies showed that circRNAs, as part of competing endogenous RNAs (ceRNAs) network, play an important role in neurodegenerative and psychiatric diseases. However, the mechanism of circRNA-related ceRNA networks in postoperative cognitive dysfunction (POCD) has not been elucidated yet. POCD usually occurs in elderly patients and is characterized by hippocampal dysfunction. Here, aged C57BL/6 mice were subjected to exploratory laparotomy under sevoflurane anesthesia, and this POCD model was verified by Morris water maze test. Whole-transcriptome sequencing was performed on the hippocampus of control group (Con) and surgery group. One hundred and seventy-seven DEcircRNAs, 221 DEmiRNAs and 2,052 DEmRNAs were identified between two groups. A ceRNA network was established with 92 DEcircRNAs having binding sites with 76 DEmiRNAs and 549 target DEmRNAs. In functional enrichment analysis, a pathological pattern of POCD was highlighted in the ceRNA network: Abnormal metabolic process in neural cells, including oxygen metabolism, could promote apoptosis and then affect the synaptic function, which may undermine the neural plasticity and eventually lead to changes in cognitive function and other behavioral patterns. In conclusion, this specific ceRNA network of circRNAs–miRNAs–mRNAs has provided novel insights into the regulatory mechanisms of POCD and revealed potential therapeutic gene targets.

Soil thickness, intended as depth to bedrock, is a key input parameter for many environmental models. Nevertheless, it is often difficult to obtain a reliable spatially exhaustive soil thickness map in wide-area applications, and existing prediction models have been extensively applied only to test sites with shallow soil depths. This study addresses this limitation by showing the results of an application to a section of Wanzhou County (Three Gorges Reservoir Area, China), where soil thickness varies from 0 to ∼40 m. Two different approaches were used to derive soil thickness maps: a modified version of the geomorphologically indexed soil thickness (GIST) model, purposely customized to better account for the peculiar setting of the test site, and a regression performed with a machine learning algorithm, i.e., the random forest, combined with the geomorphological parameters of GIST (GIST-RF). Additionally, the errors of the two models were quantified, and validation with geophysical data was carried out. The results showed that the GIST model could not fully contend with the high spatial variability of soil thickness in the study area: the mean absolute error was 10.68 m with the root-mean-square error (RMSE) of 12.61 m, and the frequency distribution residuals showed a tendency toward underestimation. In contrast, GIST-RF returned a better performance with the mean absolute error of 3.52 m and RMSE of 4.56 m. The derived soil thickness map could be considered a critical fundamental input parameter for further analyses.

BackgroundSolid predominant adenocarcinoma (SPA) has been reported to be a subtype with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma (LUAD). However, the underlying mechanisms remain largely unknown and the suitability of immunotherapy for SPA has not been investigated.MethodsWe conducted a multi-omics analysis of 1078 untreated LUAD patients with clinicopathologic, genomic, transcriptomic, and proteomic data from both public and internal cohorts to determine the underlying mechanisms of poor prognosis and differential therapeutic responses of SPA and to investigate the potential of immunotherapy for SPA. The suitability of immunotherapy for SPA was further confirmed in a cohort of LUAD patients who received neoadjuvant immunotherapy in our center.ResultsAlong with its aggressive clinicopathologic behaviors, SPA had significantly higher tumor mutation burden (TMB) and number of pathways altered, lower TTF-1 and Napsin-A expression, higher proliferation score and a more immunoresistant microenvironment than non-solid predominant adenocarcinoma (Non-SPA), accounting for its worse prognosis. Additionally, SPA had significantly lower frequency of therapeutically targetable driver mutations and higher frequency of EGFR/TP53 co-mutation which was related to resistance to EGFR tyrosine kinase inhibitors, indicating a lower potential for targeted therapy. Meanwhile, SPA was enriched for molecular features associated with poor response to chemotherapy (higher chemoresistence signature score, lower chemotherapy response signature score, hypoxic microenvironment, and higher frequency of TP53 mutation). Instead, muti-omics profiling revealed that SPA had stronger immunogenicity and was enriched for positive biomarkers for immunotherapy (higher TMB and T cell receptor diversity; higher PD-L1 expression and more immune cell infiltration; higher frequency of gene mutations predicting efficacious immunotherapy, and elevated expression of immunotherapy-related gene signatures). Furthermore, in the cohort of LUAD patients who received neoadjuvant immunotherapy, SPA had higher pathological regression rates than Non-SPA and patients with major pathological response were enriched in SPA, confirming that SPA was more prone to respond to immunotherapy.ConclusionsCompared with Non-SPA, SPA was enriched for molecular features associated with poor prognosis, unsatisfactory response to chemotherapy and targeted therapy, and good response to immunotherapy, indicating more suitability for immunotherapy while less suitability for chemotherapy and targeted therapy.

Prior studies revealed varying effects of resource scarcity on individuals’ general categorization tendency. However, little is known about when and why such differences occur. Based on the self-regulatory model of resource scarcity, we examine whether resource scarcity generates higher or lower general categorization tendency depending on the perceived mutability of the resource discrepancy. We conducted two online experiments to test the hypotheses. The results affirmed that when individuals consider the resource discrepancy to be mutable, they are more likely to seek abundance to compensate for resource scarcity, thus reducing their general categorization tendency. In contrast, perceiving the scarcity as immutable triggers the intention to restore a sense of control undermined by the scarcity, increasing individuals’ general categorization tendency. Our findings provide insights into the downstream consequences of resource scarcity and offer significant managerial implications for coping strategies.

Abstract Transparent electrodes (TEs) with high chemical stability and excellent flexibility are critical for flexible optoelectronic devices, such as photodetectors, solar cells, and light-emitting diodes. Ultrathin metal electrode (thickness less than 20 nm) has been a promising TE candidate, but the fabrication can only be realized by vacuum-based technologies to date, and require tedious surface engineering of the substrates, which are neither ideal for polymeric based flexible applications nor suitable for roll-to-roll large-scale manufacture. This paper presents high-performance nanostructured transparent metal electrodes formation via displacement–diffusion-etch (DDE) process, which enables the solution-processed sub-20-nm-thick ultrathin gold electrodes (UTAuEs) on a wide variety of hard and soft substrates. UTAuEs fabricated on flexible polyethylene terephthalate (PET) substrates show a high chemical/environmental stability and superior bendability to commercial flexible indium–tin-oxide (ITO) electrodes. Moreover, flexible organic solar cells made with UTAuEs show similar power conversion efficiency but much enhanced flexibility, in comparison to that of ITO-based devices.