A multi-variable predictive warning model for cervical cancer using clinical and SNPs data.

Introduction: Cervical cancer is the fourth most common cancer among female worldwide. Early detection and intervention are essential. This study aims to construct an early predictive warning model for cervical cancer and precancerous lesions utilizing clinical data and simple nucleotide polymorphisms (SNPs). Methods: Clinical data and germline SNPs were collected from 472 participants. Univariate logistic regression, least absolute shrinkage selection operator (LASSO), and stepwise regression were performed to screen variables. Logistic regression (LR), support vector machine (SVM), random forest (RF), decision tree (DT), extreme gradient boosting(XGBoost) and neural network(NN) were applied to establish models. The receiver operating characteristic (ROC) curve was used to compare the models' efficiencies. The performance of models was validated using decision curve analysis (DCA). Results: The LR model, which included 6 SNPs and 2 clinical variables as independent risk factors for cervical carcinogenesis, was ultimately chosen as the most optimal model. The DCA showed that the LR model had a good clinical application. Discussion: The predictive model effectively foresees cervical cancer risk using clinical and SNP data, aiding in planning timely interventions. It provides a transparent tool for refining clinical decisions in cervical cancer management.

Hydroxyl-Binding Energy-Induced Kinetic Gap Narrowing between Acidic and Alkaline Hydrogen Oxidation Reaction on Intermetallic Ru3 Sn7 Catalyst.

Developing highly efficient catalysts toward alkaline hydrogen oxidation reaction (HOR) and narrowing the kinetic gap between acidic and alkaline electrolytes are of great importance for the practical application of alkaline exchange membrane fuel cell . Herein, ordered Ru3 Sn7 /C intermetallic compound has been developed for the HOR under alkaline and acidic conditions. The authors demonstrate that the ordered intermetallic Ru3 Sn7 /C shows much enhanced HOR activity, stability, and CO-tolerance compared with its disordered RuSn solid solution alloy counterpart. More importantly, the authors find that the kinetic gap of HOR between acidic and alkaline media is significantly narrowed in the as-synthesized intermetallic Ru3 Sn7 /C catalysts. Combined experiment results and theoretical calculations, the authors understand that promoted hydroxyl-binding energy on Ru3 Sn7 /C derived from the intermetallic-induced strong electron interaction is responsible for the accelerated alkaline HOR performance and narrowed kinetic gap.

The Role of Discrepant Reactive Intermediates on Ru-Ru2 P Heterostructure for pH-Universal Hydrogen Oxidation Reaction.

Developing highly efficient electrocatalysts for hydrogen oxidation reaction (HOR) under alkaline media is essential for the commercialization of alkaline exchange membrane fuel cell (AEMFC). However, the kinetics of HOR in alkaline media is complicated, resulting in orders of magnitude slower than that in acid, even for the state-of-the-art Pt/C. Here, we find that Ru-Ru2 P/C heterostructure shows HOR performance with a non-monotonous variation in a whole pH region. Unexpectedly, an inflection point located at pH≈7 is observed, showing an anomalous behavior that HOR activity under alkaline media surpasses acidic media. Combining experimental results and theoretical calculations, we propose the roles of discrepant reactive intermediates for pH-universal HOR, while H* and H2 O* adsorption strengths are responsible for acidic HOR, and OH* adsorption strength is essential for alkaline HOR. This work not only sheds light on fundamentally understanding the mechanism of HOR but also provides new designing principles for pH-targeted electrocatalysts.

Neurocognitive Dynamics of Prosodic Salience over Semantics during Explicit and Implicit Processing of Basic Emotions in Spoken Words.

How language mediates emotional perception and experience is poorly understood. The present event-related potential (ERP) study examined the explicit and implicit processing of emotional speech to differentiate the relative influences of communication channel, emotion category and task type in the prosodic salience effect. Thirty participants (15 women) were presented with spoken words denoting happiness, sadness and neutrality in either the prosodic or semantic channel. They were asked to judge the emotional content (explicit task) and speakers' gender (implicit task) of the stimuli. Results indicated that emotional prosody (relative to semantics) triggered larger N100, P200 and N400 amplitudes with greater delta, theta and alpha inter-trial phase coherence (ITPC) and event-related spectral perturbation (ERSP) values in the corresponding early time windows, and continued to produce larger LPC amplitudes and faster responses during late stages of higher-order cognitive processing. The relative salience of prosodic and semantics was modulated by emotion and task, though such modulatory effects varied across different processing stages. The prosodic salience effect was reduced for sadness processing and in the implicit task during early auditory processing and decision-making but reduced for happiness processing in the explicit task during conscious emotion processing. Additionally, across-trial synchronization of delta, theta and alpha bands predicted the ERP components with higher ITPC and ERSP values significantly associated with stronger N100, P200, N400 and LPC enhancement. These findings reveal the neurocognitive dynamics of emotional speech processing with prosodic salience tied to stage-dependent emotion- and task-specific effects, which can reveal insights into understanding language and emotion processing from cross-linguistic/cultural and clinical perspectives.

Ponatinib modulates the metabolic profile of obese mice by inhibiting adipose tissue macrophage inflammation.

Obesity-induced metabolic syndrome is a rapidly growing conundrum, reaching epidemic proportions globally. Chronic inflammation in obese adipose tissue plays a key role in metabolic syndrome with a series of local and systemic effects such as inflammatory cell infiltration and inflammatory cytokine secretion. Adipose tissue macrophages (ATM), as one of the main regulators in this process, are particularly crucial for pharmacological studies on obesity-related metabolic syndrome. Ponatinib, a multi-targeted tyrosine kinase inhibitor originally used to treat leukemia, has recently been found to improve dyslipidemia and atherosclerosis, suggesting that it may have profound effect on metabolic syndrome, although the mechanisms underlying have not yet been revealed. Here we discovered that ponatinib significantly improved insulin sensitivity in leptin deficient obese mice. In addition to that, ponatinib treatment remarkably ameliorated high fat diet-induced hyperlipidemia and inhibited ectopic lipid deposition in the liver. Interestingly, although ponatinib did not reduce but increase the weight of white adipose tissue (WAT), it remarkably suppressed the inflammatory response in WAT and preserved its function. Mechanistically, we showed that ponatinib had no direct effect on hepatocyte or adipocyte but attenuated free fatty acid (FFA) induced macrophage transformation from pro-inflammatory to anti-inflammatory phenotype. Moreover, adipocytes co-cultured with FFA-treated macrophages exhibited insulin resistance, while pre-treat these macrophages with ponatinib can ameliorate this process. These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.

Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker.

BACKGROUND: Cervical squamous cell carcinoma (SCC) is known to arise through increasingly higher-grade squamous intraepithelial lesions (SILs) or cervical intraepithelial neoplasias (CINs). This study aimed to describe sequential molecular changes and identify biomarkers in cervical malignant transformation. METHODS: Multidimensional data from five publicly available microarray and TCGA-CESC datasets were analyzed. Immunohistochemistry was carried out on 354 cervical tissues (42 normal, 62 CIN1, 26 CIN2, 47 CIN3, and 177 SCC) to determine the potential diagnostic and prognostic value of identified biomarkers. RESULTS: We demonstrated that normal epithelium and SILs presented higher molecular homogeneity than SCC. Genes in the region (e.g., 3q, 12q13) with copy number alteration or HPV integration were more likely to lose or gain expression. The IL-17 signaling pathway was enriched throughout disease progression with downregulation of IL17C and decreased Th17 cells at late stage. Furthermore, we identified AURKA, TOP2A, RFC4, and CEP55 as potential causative genes gradually upregulated during the normal-SILs-SCC transition. For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89). They had equivalent diagnostic performance alone to the combination of p16INK4a and Ki-67. Meanwhile, increased expression of RFC4 significantly and independently predicted favorable outcomes in multi-institutional cohorts of SCC patients. CONCLUSIONS: Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes during cervical carcinogenesis. RFC4 is proposed as a novel surrogate biomarker for determining HSIL and HSIL+, and an independent prognostic biomarker for SCC.

Biomimetic Mechanoswitchable Interfaces for High-Performance Spatial Gas Bubble Maneuvering.

The on-demand manipulation of gas bubbles in aqueous ambient environments is fundamental to many fields such as microfluidics and biochemical microanalysis. However, most bubble manipulation strategies are limited to restricted locomotion on the confined surfaces without spatial convenience of transport. Herein, we report a kind of biomimetic bubble manipulator with mechanoswitchable interfaces (MSIs), featuring the advantages of parallel bubble control and spatial maneuvering flexibility. By the synergic action between Janus aluminum membrane and superaerophilic microfiber array, the gas-MSI interfacial adhesion can be reversibly switched to achieve capturing/releasing underwater bubbles. Moreover, the adhesion force of MSI can be readily tuned by diverse experimental parameters including surface roughness, fiber number, diameter, and spacing of the neighboring microfibers, which are further systematically investigated. Relying on this mobile platform, we demonstrate a series of powerful applications including bubble parallel control, bubble array regrouping, arbitrary bubble transport and even manipulating underwater solids through bubbles, which are otherwise challenging for conventional approaches. We envision that this versatile platform will bring new insights into potential applications, such as cross-species sample control and handheld gas microsyringe.

6 Circulating miRNAs can be used as Non-invasive Biomarkers for the Detection of Cervical Lesions.

Background: Cervical cancer is the most common malignant tumor in the female reproductive system, while the efficacy of routine screening strategy is unsatisfied. New molecular tests need to be developed. miRNAs participate in many pathologic processes, and circulating miRNAs are promising non-invasive biomarkers in tumors. Objectives: This study aimed to identify the circulating miRNAs associated with both cervical cancer and cervical intraepithelial neoplasia (CIN), and establish a non-invasive classifier for cervical lesions using circulating miRNAs. Methods: This study consisted of 5 steps: miRNAs screening, miRNAs validation, classifier establishment, independent validation and in silico analyses. Three cohorts were included in our study: In screening stage, 24 samples including 14 cases and 10 controls were retrieved; In validation stage, 380 samples including 200 cases and 180 controls were recruited; In independent validation stage, 47 samples comprising 26 cases and 21 controls were included. miRNAs were quantified by RT-qPCR. A classifier was built with random forest algorithm using validation samples and selected miRNAs, which were then validated in an independent cohort. To explore the function of selected miRNAs, in silico analyses were performed. Target genes of selected miRNAs were predicted by the overlap of three online tools. Enrichment analyses were executed with predicted target genes. Differential analysis of target genes was carried out with open access expression assay datasets of cervical tissues. Results: 6 miRNAs (hsa-miR-26b-5p, hsa-miR-146b-5p, hsa-miR-191-5p, hsa-miR-484, hsa-miR-574-3p, hsa-miR-625-3p) were screened out from 754 miRNAs. They were associated with cervical lesions and were selected to establish a classifier. The accuracy of the classifier were 0.7218 (0.7117, 0.7319) in validation samples, which was 0.7021 in the independent cohort. 958 target genes were predicted and enriched in 23 pathways (MAPK, human papillomavirus infection and Wnt signaling pathway, etc.). 55 genes were identified as the most likely target genes by differential analysis. Conclusion: The 6 circulating miRNAs were related to cervical lesions and could serve as non-invasive biomarkers.

Magnetism-Actuated Superhydrophobic Flexible Microclaw: From Spatial Microdroplet Maneuvering to Cross-Species Control.

The flexible maneuvering of microliter liquid droplets is significant in both fundamental science and practical applications. However, most current strategies are limited to the rigid locomotion on confined geographies platforms, which greatly hinder their practical uses. Here, we propose a magnetism-actuated superhydrophobic flexible microclaw (MSFM) with hierarchical structures for water droplet manipulation. By virtue of precise femtosecond laser patterning on magnetism-responsive poly(dimethylsiloxane) (PDMS) films doped with carbonyl iron powder, this MSFM without chemical contamination exhibits powerful spatial droplet maneuvering advantages with fast response (<100 ms) and lossless water transport (∼50 cycles) in air. We further performed quantitative analysis of diverse experimental parameters including petal number, length, width, and iron element proportion in MSFM impacting the applicable maneuvering volumes. By coupling the advantages of spatial maneuverability and fast response into this versatile platform, typical unique applications are demonstrated such as programmable coalescence of droplets, collecting debris via droplets, tiny solid manipulation in aqueous severe environments, and harmless living creature control. We envision that this versatile MSFM should provide great potential for applications in microfluidics and cross-species robotics.

FeCl2 Catalyzed Three-Component Reactions of Phospholes, Pyrrolidine, and Ketones (Aldehydes): Chemoselective Synthesis of 1-Phosphafulvenes.

We have developed an unprecedented approach for the synthesis of transient 1-phosphafulvenes through three component reactions of phospholes. The generation of 1-phosphafulvenes was demonstrated by in situ [6 + 4] cycloaddition with 2H-phospholes and [6 + 6] self-dimerization. The [6 + 4] and [6 + 6] reaction pathway could be modulated by the starting ketones and aldehydes. The construction of 1-phosphafulvenes is illustrated by a proposed mechanism combining nucleophilic addition of phospholide to the iminium or isomerized azomethine ylide and a [1,5]-shift of phosphole.

GJA1 Expression and Its Prognostic Value in Cervical Cancer.

Gap Junction Protein Alpha 1 (GJA1) belongs to the gap junction family and has been widely studied in cancers. We evaluated the role of GJA1 in cervical cancer (CC) using public data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. The difference of GJA1 expression level between CC and normal tissues was analyzed by the Gene Expression Profiling Interactive Analysis (GEPIA), six GEO datasets, and the Human Protein Atlas (HPA). The relationship between clinicopathological features and GJA1 expression was analyzed by the chi-squared test and the logistic regression. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were used to assessing the effect of GJA1 expression on survival. Gene set enrichment analysis (GSEA) was used to screen the signaling pathways regulated by GJA1. Immune Cell Abundance Identifier (ImmuCellAI) was chosen to analyze the immune cells affected by GJA1. The expression of GJA1 in CC was significantly lower than that in normal tissues based on the GEPIA, GEO datasets, and HPA. Both the chi-squared test and the logistic regression showed that high-GJA1 expression was significantly correlated with keratinization, hormone use, tumor size, and FIGO stage. The Kaplan-Meier curves suggested that high-GJA1 expression could indicate poor prognosis (p = 0.0058). Multivariate analysis showed that high-GJA1 expression was an independent predictor of poor overall survival (HR, 4.084; 95% CI, 1.354-12.320; p = 0.013). GSEA showed many cancer-related pathways, such as the p53 signaling pathway and the Wnt signaling pathway, were enriched in the high-GJA1-expression group. Immune cell abundance analysis revealed that the abundance of CD8 naive, DC, and neutrophil was significantly increased in the high-GJA1-expression group. In conclusion, GJA1 can be regarded as a potential prognostic marker of poor survival and therapeutic target in CC. Moreover, many cancer-related pathways may be the critical pathways regulated by GJA1. Furthermore, GJA1 can affect the abundance of immune cells.

Redox response, antibacterial and drug package capacities of chitosan-α-lipoic acid conjugates.

Chitosan-α-lipoic acid (CS-LA) conjugates were prepared by amino reaction. The methotrexate (MTX) was successfully loaded within CS-LA copolymer by the ring-opening polymerizations of disulfide bond under the action of reducing agent. The obtained copolymer was investigated by fourier transform infrared spectrometer (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and nuclear magnetic resonance (1H NMR) analysis. The ring-opening polymerization process effected on rheological properties were studied. The graft of LA increased the apparent viscosity of CS-LA, and the loaded of MTX by redox reduced its apparent viscosity enormously. The load of MTX under the action of DTT decreased the apparent viscosity and moduli of CS-LA-MTX hydrogel. In dynamic oscillatory experiment, the package of MTX reduced the rigidity of CS-LA and damaged the gel structure of CS-LA. The antimicrobial ability of CS-LA against E. coli was processed by the inhibition zone and growth curves. The modification of LA raised the antibacterial activity of CS-LA. The cytotoxicity assay of CS-LA-MTX to prostate cancer cells (RM-1) was examined. The load of MTX within CS-LA-MTX greatly enhanced the cytotoxicity to RM-1 cells. In summary, CS-LA hydrogel may provide a new copolymer carrier for drug package in food and biomedical application.