RESUMEN

OBJECTIVE: The prediction of sepsis, especially early diagnosis, has received a significant attention in biomedical research. In order to improve current medical scoring system and overcome the limitations of class imbalance and sample size of local EHR (electronic health records), we propose a novel knowledge-transfer-based approach, which combines a medical scoring system and an ordinal logistic regression model. MATERIALS AND METHODS: Medical scoring systems (i.e. NEWS, SIRS and QSOFA) are generally robust and useful for sepsis diagnosis. With local EHR, machine-learning-based methods have been widely used for building prediction models/methods, but they are often impacted by class imbalance and sample size. Knowledge distillation and knowledge transfer have recently been proposed as a combination approach for improving the prediction performance and model generalization. In this study, we developed a novel knowledge-transfer-based method for combining a medical scoring system (after a proposed score transformation) and an ordinal logistic regression model. We mathematically confirmed that it was equivalent to a specific form of the weighted regression. Furthermore, we theoretically explored its effectiveness in the scenario of class imbalance. RESULTS: For the local dataset and the MIMIC-IV dataset, the VUS (the volume under the multi-dimensional ROC surface, a generalization measure of AUC-ROC for ordinal categories) of the knowledge-transfer-based model (ORNEWS) based on the NEWS scoring system were 0.384 and 0.339, respectively, while the VUS of the traditional ordinal regression model (OR) were 0.352 and 0.322, respectively. Consistent analysis results were also observed for the knowledge-transfer-based models based on the SIRS/QSOFA scoring systems in the ordinal scenarios. Additionally, the predicted probabilities and the binary classification ROC curves of the knowledge-transfer-based models indicated that this approach enhanced the predicted probabilities for the minority classes while reducing the predicted probabilities for the majority classes, which improved AUCs/VUSs on imbalanced data. DISCUSSION: Knowledge transfer, which combines a medical scoring system and a machine-learning-based model, improves the prediction performance for early diagnosis of sepsis, especially in the scenarios of class imbalance and limited sample size.

RESUMEN

Rational designs of polysaccharide-based hydrogels with organ-like three-dimensional architecture provide a great possibility for addressing the shortages of allograft tissues and organs. However, spatial-temporal control over structure in bulk hydrogel and acquire satisfied mechanical properties remain an intrinsic challenge to achieve. Here, we show how electric-field assisted molecular self-assembly can be coupled to a directional reaction-diffusion (RD) process to produce macroscopic hydrogel in a controllable manner. The electrical energy input was not only to generate complex molecule gradients and initiate the molecular self-assembly, but also to guide/facilitate the RD processes for the gel rapid growth via a cascade construction interaction. The hydrogel mechanical properties can be tuned and enhanced by using an interpenetrating biopolymer network and multiple ionic crosslinkers, leading to a wide-range of mechanical modulus to match with biological organs or tissues. We demonstrate diverse 3D macroscopic hydrogels can be easily prepared via field-assisted directional reaction-diffusion and specific joint interactions. The humility-triggered dissipation of functional gradients and antibacterial performance confirm that the hydrogels can serve as an optically variable soft device for wound management. Therefore, this work provides a general approach toward the rational fabrication of soft hydrogels with controlled architectures and functionality for advanced biomedical systems.

RESUMEN

BACKGROUND: SEPT9 is a pivotal cytoskeletal GTPase that regulates diverse biological processes encompassing mitosis and cytokinesis. While previous studies have implicated SEPT9 in tumorigenesis and development; comprehensive pan-cancer analyses have not been performed. This study aims to systematically explore its role in cancer screening, prognosis, and treatment, addressing this critical gap. METHODS: Gene and protein expression data containing clinical information were obtained from public databases for pan-cancer analyses. Additionally, clinical samples from 90 patients with lung squamous cell carcinoma (LUSC) were used to further experimentally validate the clinical significance of SEPT9. In addition, the molecular docking tool was used to analyze the affinities between SEPT9 protein and drugs. RESULTS: SEPT9 is highly expressed in various cancers, and its aberrant expression correlates with genetic alternations and epigenetic modifications, leading to adverse clinical outcomes. Take LUSC as an example, additional dataset analyses and immunohistochemical experiments further confirm the diagnostic and prognostic values as well as the clinical relevance of the SEPT9 gene and protein. Functional enrichment, single-cell expression, and immune infiltration analyses revealed that SEPT9 promotes malignant tumor progression and modulates the immune microenvironments, enabling patients to benefit from immunotherapy. Moreover, drug sensitivity and molecular docking analyses showed that SEPT9 is associated with the sensitivity and resistance of multiple drugs and has stable binding activity with them, including Vorinostat and OTS-964. To harness its prognostic and therapeutic potential in LUSC, a mitotic spindle-associated prognostic model including SEPT9, HSF1, ARAP3, KIF20B, FAM83D, TUBB8, and several clinical characteristics, was developed. This model not only improves clinical outcome predictions but also reshapes the immune microenvironment, making immunotherapy more effective for LUSC patients. CONCLUSION: This is the first study to systematically analyze the role of SEPT9 in cancers and innovatively apply the mitotic spindle-associated model to LUSC, fully demonstrating its potential as a valuable biomarker for cancer screening and prognosis, and highlighting its application value in promoting immunotherapy and chemotherapy, particularly for LUSC.

Asunto(s)

RESUMEN

OBJECTIVE: To explore the clinical phenotype and genetic etiology for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease (ADPKD). METHODS: A pedigree with ADPKD diagnosed at the Department of Gynaecology of the First Affiliated Hospital of Zhengzhou University in December 2020 was selected as the study subject. Clinical data of the pedigree was collected, and whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing of the proband and her relatives. RESULTS: Fetal ultrasonography showed increased volume and parenchymal echogenicity in both kidneys. The fetus was found to harbor c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene, which were respectively inherited from its mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1+PM2_supporting+PP3). CONCLUSION: The c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene probably underlay the ADPKD in the fetus. Above finding has provided guidance for the genetic counseling and prenatal diagnosis for this pedigree.

Asunto(s)

RESUMEN

Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline's additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures.

RESUMEN

BACKGROUND: Overall Survival (OS) and Progression-Free Interval (PFI) as survival times have been collected in The Cancer Genome Atlas (TCGA). It is of biomedical interest to consider their dependence in pathway detection and survival prediction. We intend to develop novel methods for integrating PFI as condition based on parametric survival models for identifying pathways associated with OS and predicting OS. RESULTS: Based on the framework of conditional probability, we developed a family of frailty-based parametric-models for this purpose, with exponential or Weibull distribution as baseline. We also considered two classes of existing methods with PFI as a covariate. We evaluated the performance of three approaches by analyzing RNA-seq expression data from TCGA for lung squamous cell carcinoma and lung adenocarcinoma (LUNG), brain lower grade glioma and glioblastoma multiforme (GBMLGG), as well as skin cutaneous melanoma (SKCM). Our focus was on fourteen general cancer-related pathways. The 10-fold cross-validation was employed for the evaluation of predictive accuracy. For LUNG, p53 signaling and cell cycle pathways were detected by all approaches. Furthermore, three approaches with the consideration of PFI demonstrated significantly better predictive performance compared to the approaches without the consideration of PFI. For GBMLGG, ten pathways (e.g., Wnt signaling, JAK-STAT signaling, ECM-receptor interaction, etc.) were detected by all approaches. Furthermore, three approaches with the consideration of PFI demonstrated better predictive performance compared to the approaches without the consideration of PFI. For SKCM, p53 signaling pathway was detected only by our Weibull-baseline-based model. And three approaches with the consideration of PFI demonstrated significantly better predictive performance compared to the approaches without the consideration of PFI. CONCLUSIONS: Based on our study, it is necessary to incorporate PFI into the survival analysis of OS. Furthermore, PFI is a survival-type time, and improved results can be achieved by our conditional-probability-based approach.

Asunto(s)

RESUMEN

A narrow genetic basis limits further the improvement of modern Gossypium hirsutum cultivar. The abundant genetic diversity of wild species provides available resources to solve this dilemma. In the present study, a chromosome segment substitution line (CSSL) population including 553 individuals was established using G. darwinii accession 5-7 as the donor parent and G. hirsutum cultivar CCRI35 as the recipient parent. After constructing a high-density genetic map with the BC1 population, the genotype and phenotype of the CSSL population were investigated. A total of 235 QTLs, including 104 QTLs for fiber-related traits and 132 QTLs for seed-related traits, were identified from four environments. Among these QTLs, twenty-seven QTLs were identified in two or more environments, and twenty-five QTL clusters consisted of 114 QTLs. Moreover, we identified three candidate genes for three stable QTLs, including GH_A01G1096 (ARF5) and GH_A10G0141 (PDF2) for lint percentage, and GH_D01G0047 (KCS4) for seed index or oil content. These results pave way for understanding the molecular regulatory mechanism of fiber and seed development and would provide valuable information for marker-assisted genetic improvement in cotton.

Asunto(s)

RESUMEN

The cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS)-dependent pathway is a key DNA-sensing pathway that recognizes cytosolic DNA and plays a crucial role in initiating innate immune responses against pathogenic microbes and cancer. Various molecules have been identified as regulators of the cGAS-dependent pathway that controls innate immune responses. However, despite the important roles of Stimulator-of-interferon genes (STING) in the cGAS-dependent pathway, the regulation of its activation has not been elucidated. Here, we show that the E3 ubiquitin ligase, RING finger protein 39 (RNF39), interacts with STING in macrophages and HERK293T cells. Moreover, RNF39 accelerates DNA-sensing pathways by promoting lysine (K)63-linked ubiquitination of STING, and then facilitating the formation of STING-TBK1 complex. Concordantly, Rnf39 deficiency inhibits innate immune responses triggered by DNA viral infection and accelerates viral replication. Furthermore, herpes simplex virus-1 (HSV-1) infection induces RNF39 expression in an IFN-I-dependent manner. Thus, we outline a novel mechanism for controlling STING activation and a feedback mechanism for controlling antiviral immune responses. RNF39 could be a priming intervention target for the prevention and treatment of viral diseases, especially DNA viral infections.

RESUMEN

Pyridaben is a broad-spectrum, contact-killing acaricide that can be used to control a variety of harmful food and plant mites. Pyridaben displays cardiotoxicity and liver toxicity toward fish, but the effects on fish embryonic development have not been characterized. We exposed early zebrafish embryos to 20, 30, and 40 µg/L concentrations of pyridaben. The exposure caused developmental abnormalities, including delayed embryonic shield formation, yolk sac resorption, decreases in body length, reduced pigmentation, and delays in hatching. Pyridaben caused a significant increase in the transcription level of the endoderm marker foxa2, but the transcription levels of the ectoderm development marker foxb1a and the mesoderm development marker snaila were not significantly altered. The transcription levels of the genes SOX17 in early embryos were significantly reduced. After exposure to pyridaben, catalase (CAT) activity and glutathione (GSH) content were increased, and cyclin D1, that is involved in early embryonic development, was abnormally expressed. This study shows that pyridaben causes anomalous development in zebrafish embryos by interfering with the cell cycle order of early embryonic development and inducing excessive oxidative stress. Colivelin, an agonist of the STAT3 signaling pathway, acted as a salvage drug to restore the cell cycle order during embryonic development following exposure to pyridaben. Thus, the toxic effects may be caused by pyridaben's regulation of the STAT3 signaling pathway.

Asunto(s)

RESUMEN

PURPOSE: To establish a radiomics nomogram based on MRI radiomics features combined with clinical characteristics for distinguishing pleomorphic adenoma (PA) from warthin tumor (WT). METHODS: 294 patients with PA (n = 159) and WT (n = 135) confirmed by histopathology were included in this study between July 2017 and June 2023. Clinical factors including clinical data and MRI features were analyzed to establish clinical model. 10 MRI radiomics features were extracted and selected from T1WI and FS-T2WI, used to establish radiomics model and calculate radiomics scores (Rad-scores). Clinical factors and Rad-scores were combined to serve as crucial parameters for combined model. Through Receiver operator characteristics (ROC) curve and decision curve analysis (DCA), the discriminative values of the three models were qualified and compared, the best-performing combined model was visualized in the form of a radiomics nomogram. RESULTS: The combined model demonstrated excellent discriminative performance for PA and WT in the training set (AUC=0.998) and testing set (AUC=0.993) and performed better compared with the clinical model and radiomics model in the training set (AUC=0.996, 0.952) and testing model (AUC=0.954, 0.849). The DCA showed that the combined model provided more overall clinical usefulness in distinguishing parotid PA from WT than another two models. CONCLUSION: An analytical radiomics nomogram based on MRI radiomics features, incorporating clinical factors, can effectively distinguish between PA and WT.

RESUMEN

A novel type of colorimetric/fluorescent nanopaper indicator has been developed from the melt-extruded poly (vinyl alcohol-co-ethylene) nanofibers with surface anchored metal-organic frameworks (MOFs) by an interfacial coordination strategy. Specifically, the fluorescein isothiocyanate molecules could be anchored to the nanofiber surface by nickel ions and co-assembled into a hydrophilic nanocoating via a dynamic water/alcohol solvent evaporation method. Interestingly, this hydrophilic surface enables fast adsorption of moistures and interaction with biological amine vapors, resulting a saffron cake-layer of MOF nanocrystals with ultra-sensitive colorimetric/fluorescent responses based on an alkaline pH/ammonia induced competitive coordination mechanism. Finally, these porous nanofibrous matrix and active nanocoating make the nano-paper an ultra-sensitive optical platform for in-situ monitoring of the shrimp freshness from mins to weeks. Therefore, this composite film shows great potential into advanced paper-based indicators for food quality control and safety in processing industry.

Asunto(s)

RESUMEN

The tumor microenvironment demonstrates great immunophenotypic heterogeneity, which has been leveraged in traditional immune-hot/cold tumor categorization based on the abundance of intra-tumoral immune cells. By incorporating the spatial immune contexture, the tumor immunophenotype was further elaborated into immune-inflamed, immune-excluded, and immune-desert. However, the mechanisms underlying these different immune phenotypes are yet to be comprehensively elucidated. In this review, we discuss how tumor cells and the tumor microenvironment interact collectively to shape the immune landscape from the perspectives of tumor cells, immune cells, the extracellular matrix, and cancer metabolism, and we summarize potential therapeutic options according to distinct immunophenotypes for personalized precision medicine.

RESUMEN

A Na2S2O8-initiated sulfonylation of pyridyl phosphonium salts with sulfinate salts in aqueous media has been developed for facile access to 4-pyridyl sulfones. The reactions, which employed pyridyl phosphonium salts as efficient pyridylation agents via C-P bond activation, showed both broad substrate generality and good functional group compatibility. In addition, the scale-up synthesis and the late-stage modification of pharmaceutically active complex molecules (e.g., loratadine, bisacodyl) could also be successfully realized.

RESUMEN

BACKGROUND: CD8+ T cells have been recognized as crucial factors in the prognosis of melanoma. However, there is currently a lack of gene markers that accurately describe their characteristics and functions in acral melanoma (AM), which hinders the development of personalized medicine. METHODS: Firstly, we explored the composition differences of immune cells in AM using single-cell RNA sequencing (scRNA-seq) data and comprehensively characterized the immune microenvironment of AM in terms of composition, developmental differentiation, function, and cell communication. Subsequently, we constructed and validated a prognostic risk scoring model based on differentially expressed genes (DEGs) of CD8+ T cells using the TCGA-SKCM cohort through Lasso-Cox method. Lastly, immunofluorescence staining was performed to validate the expression of four genes (ISG20, CCL4, LPAR6, DDIT3) in AM and healthy skin tissues as included in the prognostic model. RESULTS: The scRNA-seq data revealed that memory CD8+ T cells accounted for the highest proportion in the immune microenvironment of AM, reaching 70.5%. Cell-cell communication analysis showed extensive communication relationships among effector CD8+ T cells. Subsequently, we constructed a prognostic scoring model based on DEGs derived from CD8+ T cell sources. Four CD8+ T cell-related genes were included in the construction and validation of the prognostic model. Additionally, immunofluorescence results demonstrated that ISG20 and CCL4 were downregulated, while LPAR6 and DDIT3 were upregulated in AM tissues compared to normal skin tissues. CONCLUSION: Identifying biomarkers based on the expression levels of CD8+ T cell-related genes may be an effective approach for establishing prognostic models in AM patients. The independently prognostic risk evaluation model we constructed provides new insights and theoretical support for immunotherapy in AM.

Asunto(s)

RESUMEN

Oligodendrocyte precursor cells (OPCs) migrate extensively using blood vessels as physical scaffolds in the developing central nervous system. Although the association of OPCs with the vasculature is critical for migration, the regulatory mechanisms important for OPCs proliferative and oligodendrocyte development are unknown. Here, a correlation is demonstrated between the developing vasculature and OPCs response during brain development. Deletion of endothelial stimulator of interferon genes (STING) disrupts angiogenesis by inhibiting farnesyl-diphosphate farnesyltransferase 1 (FDFT1) and thereby reducing cholesterol synthesis. Furthermore, the perturbation of metabolic homeostasis in endothelial cells increases interleukin 17D production which mediates the signal transduction from endothelial cells to OPCs, which inhibits oligodendrocyte development and myelination and causes behavioral abnormalities in adult mice. Overall, these findings indicate how the endothelial STING maintains metabolic homeostasis and contributes to oligodendrocyte precursor cells response in the developing neocortex.

RESUMEN

Rechargeable magnesium batteries (RMBs) are a highly promising energy storage system due to their high volumetric capacity and intrinsic safety. However, the practical development of RMBs is hindered by the sluggish Mg2+ diffusion kinetics, including at the cathode-electrolyte interface (CEI) and within the cathode bulk. Herein, we propose an efficient strategy to manipulate the interfacial chemistry and coordination structure in oligolayered V2O5 (L-V2O5) for achieving rapid Mg2+ diffusion kinetics. In terms of the interfacial chemistry, the specific exposed crystal planes in L-V2O5 possess strong electron donating ability, which helps to promote the degradation dynamics of C-F/C-S bonds in the electrolyte, thereby establishing the inorganic-organic interlocking CEI layer for rapid Mg2+ diffusion. In terms of the coordination structure, the straightened V-O structure in L-V2O5 provides efficient ions diffusion path for accelerating Mg2+ diffusion in the cathode. As a result, the L-V2O5 delivers a high reversible capacity (355.3 mA h g-1 at 0.1 A g-1) and an excellent rate capability (161 mAh g-1 at 1 A g-1). Impressively, the interdigital micro-RMBs is firstly assembled, exhibiting excellent flexibility and practicability. This work gives deeper insights into the interface and interior ions diffusion for developing high-kinetics RMBs.

RESUMEN

Bioaerosols have attracted increasing attention as novel contaminants because of their potential role in the spread of disease. In this study, sampling sites were established in a landfill in northwestern China with the aim of investigating the emission and diffusion characteristics of bioaerosols. The results revealed that the counts of airborne bacteria released by landfill cover area (LCA) and waste dumping area (WDA) located in the landfill area reached 18 193 ± 30 CFU/m3 and 10 948 ± 105 CFU/m3, respectively. These two aeras were the main sources of bioaerosol generation. Meanwhile, Corynebacterium spp., Bacteroidetes spp., and Pseudomonas spp. were identified as potential pathogens. A Gaussian model was applied to simulate the diffusion of the bioaerosols; the influence distance was calculated as 12 km from the boundary of the landfill site. The potential health risks of bioaerosol exposure to on-site workers and nearby residents were calculated and evaluated in terms of aerosol concentration, particle size, and pathogenic bacteria. The present study promotes the recognition of the emission behavior of microorganisms in aerosol particles and provides a basis for controlling bioaerosol contamination from landfill sites, particularly those located in cold and arid northwestern regions of China.

RESUMEN

[This corrects the article DOI: 10.3389/fphar.2020.586725.].

RESUMEN

A comprehensive evaluation of the relationship between the densities of various cell types in the breast cancer tumor microenvironment and patient prognosis is currently lacking. Additionally, the absence of a large patch-level whole slide imaging (WSI) dataset of breast cancer with annotated cell types hinders the ability of artificial intelligence to evaluate cell density in breast cancer WSI. We first employed Lasso-Cox regression to build a breast cancer prognosis assessment model based on cell density in a population study. Pathology experts manually annotated a dataset containing over 70,000 patches and used transfer learning based on ResNet152 to develop an artificial intelligence model for identifying different cell types in these patches. The results showed that significant prognostic differences were observed among breast cancer patients stratified by cell density score (P = 0.0018), with the cell density score identified as an independent prognostic factor for breast cancer patients (P < 0.05). In the validation cohort, the predictive performance for overall survival (OS) was satisfactory, with area under the curve (AUC) values of 0.893 (OS) at 1-year, 0.823 (OS) at 3-year, and 0.861 (OS) at 5-year intervals. We trained a robust model based on ResNet152, achieving over 99% classification accuracy for different cell types in patches. These achievements offer new public resources and tools for personalized treatment and prognosis assessment.