External Dataset Research Articles

WaSPred: A reliable AI-based water solubility predictor for small molecules

A rapid and reliable evaluation of the aqueous solubility of small molecules is a hot topic for the scientific community and represents a field of particular interest in drug discovery. In fact, aqueous solubility significantly impacts various aspects that collectively influence a drug’s overall pharmacokinetics, including absorption, distribution and metabolism. For this reason, in silico approaches that provide fast and cost-effective solubility predictions, can serve as invaluable tools in the early stages of drug development. Although additional molecular features should be considered, accurate solubility predictions can help medicinal chemists rationally planning the synthesis of compounds more likely to exhibit desirable pharmacokinetic properties and in selecting the most promising candidates for further biological testing (e.g., cellular assays) from an initial pool of hit compounds with detected preliminary bioactivity. In this context, we herein report the development and evaluation of WaSPred, our AI-based water solubility predictor for small molecules. WaSPred not only showed high reliability in water solubility predictions performed on structurally heterogeneous compounds, belonging to multiple external datasets, but also demonstrated superior performance compared to a set of other commonly used water solubility predictors, thus confirming its state-of the-art robustness and its usefulness as an in silico approach for water solubility evaluations..

Application of machine-learning models to predict the ganciclovir and valganciclovir exposure in children using a limited sampling strategy.

Intravenous ganciclovir and oral valganciclovir display significant variability in ganciclovir pharmacokinetics, particularly in children. Therapeutic drug monitoring currently relies on the area under the concentration-time (AUC). Machine-learning (ML) algorithms represent an interesting alternative to Maximum-a-Posteriori Bayesian-estimators for AUC estimation. The goal of our study was to develop and validate an ML-based limited sampling strategy (LSS) approach to determine ganciclovir AUC0-24 after administration of either intravenous ganciclovir or oral valganciclovir in children. Pharmacokinetic parameters from four published population pharmacokinetic models, in addition to the World Health Organization growth curve for children, were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles of children. Different ML algorithms were trained to predict AUC0-24 based on different combinations of two or three samples. Performances were evaluated in a simulated test set and in an external data set of real patients. The best estimation performances in the test set were obtained with the Xgboost algorithm using a 2 and 6 hours post dose LSS for oral valganciclovir (relative mean prediction error [rMPE] = 0.4% and relative root mean square error [rRMSE] = 5.7%) and 0 and 2 hours post dose LSS for intravenous ganciclovir (rMPE = 0.9% and rRMSE = 12.4%). In the external data set, the performance based on these two sample LSS was acceptable: rMPE = 0.2% and rRMSE = 16.5% for valganciclovir and rMPE = -9.7% and rRMSE = 17.2% for intravenous ganciclovir. The Xgboost algorithm developed resulted in a clinically relevant individual estimation using only two blood samples. This will improve the implementation of AUC-targeted ganciclovir therapeutic drug monitoring in children.

Audio Deep Fake Detection with Sonic Sleuth Model

Information dissemination and preservation are crucial for societal progress, especially in the technological age. While technology fosters knowledge sharing, it also risks spreading misinformation. Audio deepfakes—convincingly fabricated audio created using artificial intelligence (AI)—exacerbate this issue. We present Sonic Sleuth, a novel AI model designed specifically for detecting audio deepfakes. Our approach utilizes advanced deep learning (DL) techniques, including a custom CNN model, to enhance detection accuracy in audio misinformation, with practical applications in journalism and social media. Through meticulous data preprocessing and rigorous experimentation, we achieved a remarkable 98.27% accuracy and a 0.016 equal error rate (EER) on a substantial dataset of real and synthetic audio. Additionally, Sonic Sleuth demonstrated 84.92% accuracy and a 0.085 EER on an external dataset. The novelty of this research lies in its integration of datasets that closely simulate real-world conditions, including noise and linguistic diversity, enabling the model to generalize across a wide array of audio inputs. These results underscore Sonic Sleuth’s potential as a powerful tool for combating misinformation and enhancing integrity in digital communications.

The role of artificial intelligence in optimizing management of atrial fibrillation in acute ischemic stroke.

Atrial fibrillation (AF) is a severe condition associated with high morbidity and mortality, including an increased risk of stroke and poor outcomes poststroke. Our understanding of the prognosis in AF remains poor. Machine learning (ML) has been applied to the diagnosis, management, and prognosis of AF in the context of stroke but remains suboptimal for clinical use. This article endeavors to provide a comprehensive overview of current ML applications to AF patients at risk of stroke, as well as poststroke patients without AF. Strategies to develop effective ML involve the validation of a variety of ML algorithms across internal and external datasets as well as exploring their predictive powers in hypothetical and realistic settings. Recent literature of this rapidly evolving field has displayed much promise. However, further testing and innovation of medical artificial intelligence are required before its imminent introduction to ensure complete patient trust within the community. Prioritizing this research is imperative for advancing the optimization of ongoing care for AF patients, as well as the management of stroke patients with AF.

Deep learning-driven ultrasound-assisted diagnosis: optimizing GallScopeNet for precise identification of biliary atresia.

Biliary atresia (BA) is a severe congenital biliary developmental abnormality threatening neonatal health. Traditional diagnostic methods rely heavily on experienced radiologists, making the process time-consuming and prone to variability. The application of deep learning for the automated diagnosis of BA remains underexplored. This study introduces GallScopeNet, a deep learning model designed to improve diagnostic efficiency and accuracy through innovative architecture and advanced feature extraction techniques. The model utilizes data from a carefully constructed dataset of gallbladder ultrasound images. A dataset comprising thousands of ultrasound images was employed, with the majority used for training and validation and a subset reserved for external testing. The model's performance was evaluated using five-fold cross-validation and external assessment, employing metrics such as accuracy and the area under the receiver operating characteristic curve (AUC), compared against clinical diagnostic standards. GallScopeNet demonstrated exceptional performance in distinguishing BA from non-BA cases. In the external test dataset, GallScopeNet achieved an accuracy of 81.21% and an AUC of 0.85, indicating strong diagnostic capabilities. The results highlighted the model's ability to maintain high classification performance, reducing misdiagnosis and missed diagnosis. GallScopeNet effectively differentiates between BA and non-BA images, demonstrating significant potential and reliability for early diagnosis. The system's high efficiency and accuracy suggest it could serve as a valuable diagnostic tool in clinical settings, providing substantial technical support for improving diagnostic workflows.

Jun modulates endoplasmic reticulum stress-associated ferroptosis in dorsal root ganglia neurons during neuropathic pain by regulating Timp1

Neuropathic pain (NP) is a complex disorder caused by lesions or diseases affecting the somatosensory nervous system, severely impacting patients' quality of life. Recent studies suggest ferroptosis may be involved in NP induction, but its precise mechanisms remain unclear. We used GO and KEGG pathway enrichment analyses to functionally annotate ferroptosis-related differentially expressed genes (FRDs). Through STRING and the maximum cluster centrality (MCC) algorithm, we identified five hub FRDs (Jun, Timp1, Egfr, Cdkn1a, Cdkn2a). Single-cell analysis revealed significant expression of Jun and Timp1 in neurons. Our study confirmed the association between ferroptosis and endoplasmic reticulum stress (ERS) in NP and validated changes in hub FRD expression across various NP animal models. In vitro experiments demonstrated that Jun regulates neuronal ferroptosis and ERS, particularly by modulating Timp1 expression. Transcription factor prediction and JASPAR binding site analysis elucidated the regulatory network involving Jun. ROC curve analysis of external datasets highlighted the diagnostic potential of hub FRDs and ERS-related differentially expressed genes (ERSRDs) in NP. Using the Comparative Toxicogenomics Database (CTD), we identified estradiol (E2) as a potential therapeutic drug targeting hub FRDs and ERSRDs. Molecular docking predicted its binding sites with Jun and Timp1, and in vivo experiments confirmed that E2 alleviated NP and reversed the expression of Jun and Timp1. This study underscores the crucial role of Jun and Timp1 in the interplay between ferroptosis and ERS, offering new insights and promising avenues for NP treatment.

Identification of an immune-related genes signature in lung adenocarcinoma to predict survival and response to immune checkpoint inhibitors

BackgroundAlthough advances in immune checkpoint inhibitor (ICI) research have provided a new treatment approach for lung adenocarcinoma (LUAD) patients, their survival is still unsatisfactory, and there are issues in the era of response prediction to immunotherapy.MethodsUsing bioinformatics methods, a prognostic signature was constructed, and its predictive ability was validated both in the internal and external datasets (GSE68465). We also explored the tumor-infiltrating immune cells, mutation profiles, and immunophenoscore (IPS) in the low-and high-risk groups.ResultsAs far as we are aware, this is the first study which introduces a novel prognostic signature model using BIRC5, CBLC, S100P, SHC3, ANOS1, VIPR1, LGR4, PGC, and IGKV4.1. According to multivariate analysis, the 9-immune-related genes (IRGs) signature provided an independent prognostic factor for the overall survival (OS). The low-risk group had better OS, and the tumor mutation burden (TMB) was significantly lower in this group. Moreover, the risk scores were negatively associated with the tumor-infiltrating immune cells, like CD8+ T cells, macrophages, dendritic cells, and NK cells. In addition, the IPS were significantly higher in the low-risk group as they had higher gene expression of immune checkpoints, suggesting that ICIs could be a promising treatment option for low-risk LUAD patients.ConclusionThe combination of these 9-IRGs not only could efficiently predict overall survival of LUAD patients but also show a powerful association with the expression of immune checkpoints and response to ICIs based on IPS; hoping this model paves the way for better stratification and management of patients in clinical practice.

Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation

Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.

Enhancing the convenience of frailty index assessment for elderly Chinese people with machine learning methods.

Frailty is a state that is closely associated with adverse health outcomes in the aging process. The frailty index (FI), which measures frailty in terms of cumulative deficits, has been widely used for frailty assessment in elderly people, and its advantage of self-reported information collection makes it applicable to a broader group of elderly people. Our study aims to simplify the Frailty Index Assessment Scale, while maintaining its reliability and accuracy, to easily and quickly assess frailty in elderly people. In this study, participants (age ≥ 65 years) from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), which had 13,339, 372 and 1214 participants in 2008, 2011, and 2014, respectively, were used. The 2008 dataset was split into 80% for training and 20% for internal validation, and the data from 2011 to 2014 as external validation. In order to obtain effective predictors, we used Lasso regression, Boruta algorithm and random forest classifier score for feature selection. We used six models for predictive model construction and evaluated the models in the validation dataset. Model performance was measured by area under the curve (AUC), accuracy and F1 score. Logistic regression was found to be the best performing and most interpretable algorithm with AUC, accuracy and F1 of 0.974, 0.932 and 0.880 for the validation dataset, respectively. The AUCs for the external independent validation dataset were 0.963 and 0.977, respectively. Subgroup analysis showed that the model had good predictive power in both males and females. The predictive power was stronger among the elderly people over 80 years old, with AUC, accuracy and F1 of 0.973,0.914, and 0.893, respectively. The model also obtained good predictive power in the case of FI measured by different indicators. The model showed good robustness in the follow-up assessment of frailty status in elderly people, with the AUC remaining above 0.95 and accuracy above 0.9 over the long-term follow-up. Using machine learning techniques, we have successfully developed a simple frailty assessment prediction model based on 10 key features to shorten the frailty assessment scale with near full-scale accuracy. A user-friendly website was created to facilitate the application of this prediction model ( https://healthy-aging.shinyapps.io/Frailty_Assessment/ ).

CDT1 is a Potential Therapeutic Target for the Progression of NAFLD to HCC and the Exacerbation of Cancer

Aims: This study aimed to identify potential therapeutic targets in the progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC), with a focus on genes that could influence disease development and progression. Background: Hepatocellular carcinoma, significantly driven by non-alcoholic fatty liver disease, represents a major global health challenge due to late-stage diagnosis and limited treatment options. This study utilizes bioinformatics to analyze data from GEO and TCGA, aiming to uncover molecular biomarkers that bridge NAFLD to HCC. Through identifying critical genes and pathways, our research seeks to advance early detection and develop targeted therapies, potentially improving prognosis and personalizing treatment for NAFLD-HCC patients. Objective: Identify key genes that differ between NAFLD and HCC; Analyze these genes to understand their roles in disease progression; Validate the functions of these genes in NAFLD to HCC transition. Methods: Initially, we identified a set of genes differentially expressed in both NAFLD and HCC using second-generation sequencing data from the GEO and TCGA databases. We then employed a Cox proportional hazards model and a Lasso regression model, applying machine learning techniques to the large sample data from TCGA. This approach was used to screen for key disease-related genes, and an external dataset was utilized for model validation. Additionally, pseudo-temporal sequencing analysis of single-cell sequencing data was performed to further examine the variations in these genes in NAFLD and HCC. Results: The machine learning analysis identified IGSF3, CENPW, CDT1, and CDC6 as key genes. Furthermore, constructing a machine learning model for CDT1 revealed it to be the most critical gene, with model validation yielding an ROC value greater than 0.80. The single-cell sequencing data analysis confirmed significant variations in the four predicted key genes between the NAFLD and HCC groups. Conclusion: Our study underscores the pivotal role of CDT1 in the progression from NAFLD to HCC. This finding opens new avenues for early diagnosis and targeted therapy of HCC, highlighting CDT1 as a potential therapeutic target.

Identification of novel hub genes and immune infiltration in atopic dermatitis using integrated bioinformatics analysis

The aim of this study was to identify key genes and investigate the immunological mechanisms of atopic dermatitis (AD) at the molecular level via bioinformatics analysis. Gene expression profiles (GSE32924, GSE107361, GSE121212, and GSE230200) were obtained for screening common differentially expressed genes (co-DEGs) from the gene expression omnibus database. Functional enrichment analysis, protein–protein interaction network and module construction, and identification of common hub genes were performed. Hub genes were validated using receiver operating characteristic curve analysis based on GSE130588 and GSE16161. NetworkAnalyst was used to detect microRNAs (miRNAs) and transcription factors (TFs) associated with the hub genes. The immune cell infiltration was analyzed using the CIBERSORT algorithm to further analyze the correlation between hub genes and immune cells. A total of 146 co-DEGs were obtained, showing significant enrichment in cytokine–cytokine receptor interaction and JAK-STAT signaling pathway. Seven hub genes were identified by Cytoscape and validated with external datasets. Subsequent prediction of miRNAs and TFs targeting these hub genes revealed their regulatory roles. Analysis of immune cell infiltration and correlation revealed a significant positive correlation between CCL22 expression and the number of dendritic cells activated. The identified hub genes represent potential diagnostic and therapeutic targets in the immunological pathogenesis of AD.

External validation of an artificial intelligence multi-label deep learning model capable of ankle fracture classification

BackgroundAdvances in medical imaging have made it possible to classify ankle fractures using Artificial Intelligence (AI). Recent studies have demonstrated good internal validity for machine learning algorithms using the AO/OTA 2018 classification. This study aimed to externally validate one such model for ankle fracture classification and ways to improve external validity.MethodsIn this retrospective observation study, we trained a deep-learning neural network (7,500 ankle studies) to classify traumatic malleolar fractures according to the AO/OTA classification. Our internal validation dataset (IVD) contained 409 studies collected from Danderyd Hospital in Stockholm, Sweden, between 2002 and 2016. The external validation dataset (EVD) contained 399 studies collected from Flinders Medical Centre, Adelaide, Australia, between 2016 and 2020. Our primary outcome measures were the area under the receiver operating characteristic (AUC) and the area under the precision-recall curve (AUPR) for fracture classification of AO/OTA malleolar (44) fractures. Secondary outcomes were performance on other fractures visible on ankle radiographs and inter-observer reliability of reviewers.ResultsCompared to the weighted mean AUC (wAUC) 0.86 (95%CI 0.82–0.89) for fracture detection in the EVD, the network attained wAUC 0.95 (95%CI 0.94–0.97) for the IVD. The area under the precision-recall curve (AUPR) was 0.93 vs. 0.96. The wAUC for individual outcomes (type 44A-C, group 44A1-C3, and subgroup 44A1.1-C3.3) was 0.82 for the EVD and 0.93 for the IVD. The weighted mean AUPR (wAUPR) was 0.59 vs 0.63. Throughout, the performance was superior to that of a random classifier for the EVD.ConclusionAlthough the two datasets had considerable differences, the model transferred well to the EVD and the alternative clinical scenario it represents. The direct clinical implications of this study are that algorithms developed elsewhere need local validation and that discrepancies can be rectified using targeted training. In a wider sense, we believe this opens up possibilities for building advanced treatment recommendations based on exact fracture types that are more objective than current clinical decisions, often influenced by who is present during rounds.

Using an Ensemble of Segmentation Methods to Detect Vertebral Bodies on Radiographs.

Vertebral compression fractures may indicate osteoporosis but are underdiagnosed and underreported by radiologists. We have developed an ensemble of vertebral body (VB) segmentation models for lateral radiographs as a critical component of an automated, opportunistic screening tool. Our goal is to detect the approximate location of thoracic and lumbar VBs, including fractured vertebra, on lateral radiographs. The Osteoporotic Fractures in Men Study (MrOS) data set includes spine radiographs of 5994 men aged ≥65 years from 6 clinical centers. Two segmentation models, U-Net and Mask-RCNN (Region-based Convolutional Neural Network), were independently trained on the MrOS data set retrospectively, and an ensemble was created by combining them. Primary performance metrics for VB detection success included precision, recall, and F1 score for object detection on a held-out test set. Intersection over union (IoU) and Dice coefficient were also calculated as secondary metrics of performance for the test set. A separate external data set from a quaternary health care enterprise was acquired to test generalizability, comprising diagnostic clinical radiographs from men and women aged ≥65 years. The trained models achieved F1 score of U-Net = 83.42%, Mask-RCNN = 86.30%, and ensemble = 88.34% in detecting all VBs, and F1 score of U-Net = 87.88%, Mask-RCNN = 92.31%, and ensemble = 97.14% in detecting severely fractured vertebrae. The trained models achieved an average IoU per VB of 0.759 for U-Net and 0.709 for Mask-RCNN. The trained models achieved F1 score of U-Net = 81.11%, Mask-RCNN = 79.24%, and ensemble = 87.72% in detecting all VBs in the external data set. An ensemble model combining predictions from U-Net and Mask-RCNN resulted in the best performance in detecting VBs on lateral radiographs and generalized well to an external data set. This model could be a key component of a pipeline to detect fractures on all vertebrae in a radiograph in an automated, opportunistic screening tool under development.

Identification and evaluation of candidate COVID-19 critical genes and medicinal drugs related to plasma cells

The ongoing COVID-19 pandemic, caused by the SARS-CoV-2 virus, represents one of the most significant global health crises in recent history. Despite extensive research into the immune mechanisms and therapeutic options for COVID-19, there remains a paucity of studies focusing on plasma cells. In this study, we utilized the DESeq2 package to identify differentially expressed genes (DEGs) between COVID-19 patients and controls using datasets GSE157103 and GSE152641. We employed the xCell algorithm to perform immune infiltration analyses, revealing notably elevated levels of plasma cells in COVID-19 patients compared to healthy individuals. Subsequently, we applied the Weighted Gene Co-expression Network Analysis (WGCNA) algorithm to identify COVID-19 related plasma cell module genes. Further, positive cluster biomarker genes for plasma cells were extracted from single-cell RNA sequencing data (GSE171524), leading to the identification of 122 shared genes implicated in critical biological processes such as cell cycle regulation and viral infection pathways. We constructed a robust protein-protein interaction (PPI) network comprising 89 genes using Cytoscape, and identified 20 hub genes through cytoHubba. These genes were validated in external datasets (GSE152418 and GSE179627). Additionally, we identified three potential small molecules (GSK-1070916, BRD-K89997465, and idarubicin) that target key hub genes in the network, suggesting a novel therapeutic approach. These compounds were characterized by their ability to down-regulate AURKB, KIF11, and TOP2A effectively, as evidenced by their low free binding energies determined through computational analyses using cMAP and AutoDock. This study marks the first comprehensive exploration of plasma cells’ role in COVID-19, offering new insights and potential therapeutic targets. It underscores the importance of a systematic approach to understanding and treating COVID-19, expanding the current body of knowledge and providing a foundation for future research.

ChemAP: predicting drug approval with chemical structures before clinical trial phase by leveraging multi-modal embedding space and knowledge distillation

Recent studies showed that the likelihood of drug approval can be predicted with clinical data and structure information of drug using computational approaches. Predicting the likelihood of drug approval can be innovative and of high impact. However, models that leverage clinical data are applicable only in clinical stages, which is not very practical. Prioritizing drug candidates and early-stage decision-making in the de novo drug development process is crucial in pharmaceutical research to optimize resource allocation. For early-stage decision-making, we need a computational model that uses only chemical structures. This seemingly impossible task may utilize the predictive power with multi-modal features including clinical data. In this work, we introduce ChemAP (Chemical structure-based drug Approval Predictor), a novel deep learning scheme for drug approval prediction in the early-stage drug discovery phase. ChemAP aims to enhance the possibility of early-stage decision-making by enriching semantic knowledge to fill in the gap between multi-modal and single-modal chemical spaces through knowledge distillation techniques. This approach facilitates the effective construction of chemical space solely from chemical structure data, guided by multi-modal knowledge related to efficacy, such as clinical trials and patents of drugs. In this study, ChemAP achieved state-of-the-art performance, outperforming both traditional machine learning and deep learning models in drug approval prediction, with AUROC and AUPRC scores of 0.782 and 0.842 respectively on the drug approval benchmark dataset. Additionally, we demonstrated its generalizability by outperforming baseline models on a recent external dataset, which included drugs from the 2023 FDA-approved list and the 2024 clinical trial failure drug list, achieving AUROC and AUPRC scores of 0.694 and 0.851. These results demonstrate that ChemAP is an effective method in predicting drug approval only with chemical structure information of drug so that decision-making can be done at the early stages of drug development process. To the best of our knowledge, our work is the first of its kind to show that prediction of drug approval is possible only with structure information of drug by defining the chemical space of approved and unapproved drugs using deep learning technology.

Galileo-an Artificial Intelligence tool for evaluating pre-implantation kidney biopsies.

Pre-transplant procurement biopsy interpretation is challenging, also because of the low number of renal pathology experts. Artificial intelligence (AI) can assist by aiding pathologists with kidney donor biopsyassessment. Herein we present the "Galileo" AI tool, designed specifically to assist the on-call pathologist with interpreting pre-implantation kidney biopsies. A multicenter cohort of whole slide images acquired from core-needle and wedge biopsies of the kidney was collected. A deep learning algorithm was trained to detect the main findings evaluated in the pre-implantation setting (normal glomeruli, globally sclerosed glomeruli, ischemic glomeruli, arterioles and arteries). The model obtained on the Aiforia Create platform was validated on an external dataset by three independent pathologists to evaluate the performance of the algorithm. Galileo demonstrated a precision, sensitivity, F1 score and total area error of 81.96%, 94.39%, 87.74%, 2.81% and 74.05%, 71.03%, 72.5%, 2% in the training and validation sets, respectively. Galileo was significantly faster than pathologists, requiring 2min overall in the validation phase (vs 25, 22 and 31min by 3 separate human readers, p < 0.001). Galileo-assisted detection of renal structures and quantitative information was directly integrated in the final report. The Galileo AI-assisted tool shows promise inspeeding up pre-implantation kidney biopsy interpretation, as well as inreducing inter-observer variability. This toolmay represent a starting point for further improvements based on hardendpoints such as graft survival.

Exploring Potential Biomarkers and Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma Based on Bioinformatics.

Cutaneous squamous cell carcinoma (cSCC) ranks as the second most common malignancy in clinical practice and poses a significant threat to public health due to its high malignancy. In this study, we aimed to explore potential biomarkers and molecular mechanisms of cSCC. Differentially expressed genes (DEGs) from GSE66359 and GSE117247 datasets were identified using R software. We conducted enrichment analyses and screened hub genes through protein-protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA). To assess the diagnostic performance of these genes, we generated ROC curves using both internal and external datasets (GSE45164) and validated the expression levels of these genes in cSCC tissues through immunohistochemistry. Subsequently, we predicted the target miRNAs and lncRNAs for hub genes using online databases and constructed competing endogenous RNA (ceRNA) networks. In total, we identified 505 upregulated DEGs and 522 downregulated DEGs. Through PPI and WGCNA analyses, we identified four hub genes exhibiting robust diagnostic performance in internal and external datasets (AUC > 0.9) and selected three previously unreported genes for further analysis. Immunohistochemistry demonstrated significantly elevated CCNA2, CCNB2, and UBE2C expression in cSCC tissues compared to normal skin tissues. Finally, we constructed three ceRNA networks, namely NEAT1/H19-hsa-miR-148a-3p-CCNA2 and NEAT1-hsa-miR-140-3p-UBE2C. In conclusion, we have identified CCNA2, CCNB2, and UBE2C as novel biomarkers for cSCC, and the NEAT1/H19-hsa-miR-148a-3p-CCNA2 and NEAT1-hsa-miR-140-3p-UBE2C ceRNA networks may represent molecular mechanisms under-lying cSCC progression. The findings of this study offer new diagnostic and therapeutic options for cSCC patients.

Functional evaluation of TMEM176B and its predictive role for severe respiratory viral infection through integrated analysis of single-cell and bulk RNA-sequencing.

Transmembrane protein 176B (TMEM176B), localized mainly on the endosomal membrane, has been reported as an immune regulatory factor in malignant diseases. However, the biological function of this molecule remains undetermined during respiratory viral infections. To investigate the functions and prognostic value of this gene, six gene sets were selected from the Gene Expression Omnibus database for research. First, the function of TMEM176B and its co-expressed genes were evaluated at different levels (cell, peripheral blood, lung tissue). Afterwards, a machine learning algorithm was utilized to analyze the relationship between TMEM176B and its interacting genes with prognosis. After importance evaluation and variable screening, a prognostic model was established. Finally, the reliability of the model was further verified through external data sets. In vitro experiments were conducted to validate the function of TMEM176B. TMEM176B and its co-expressed genes are involved in multiple processes such as inflammasome activation, myeloid immune cell development, and immune cell infiltration. Machine learning further screened 27 interacting gene modules including TMEM176B as prognostic models for severe respiratory viral infections, with the area under the ROC curve (AUCs) of 0.986 and 0.905 in derivation and external validation sets, respectively. We further confirmed that viral load as well as NLRP3 activation and cell death were significantly enhanced in TMEM176B-/- THP-1-differentiated macrophages via in vitro experiments. Our study revealed that TMEM176B is involved in a wide range of biological functions in respiratory viral infections and has potential prognostic value, which is expected to bring new insights into the clinical management of severe respiratory viral infection hosts.

Genetic parameters for methane production, intensity, and yield predicted from milk mid-infrared spectra throughout lactation in Holstein dairy cows

Genetic selection to reduce methane (CH4) emissions is a promising solution for reducing the environmental impact of dairy cattle production. Before such a selection program can be implemented, however, it is necessary to have a better understanding of the genetic determinism of CH4 emissions and how this might influence other traits of interest. In this study, we performed a genetic analysis of 6 CH4 traits predicted from milk mid-infrared spectra. We predicted 4 CH4 traits in g/d (MeP, calculated using different prediction equations), one in g/kg of fat- and protein-corrected milk (MeI), and one in g/kg of dry matter intake (MeY). Using an external data set, we determined these prediction equations to be applicable in the range of 70 to 200 DIM. We then estimated genetic parameters in this DIM range using random regression models on a large data set of 829,025 spectra collected between January 2013 and February 2023 from 167,514 first- and second-parity Holstein cows. The 6 CH4 traits were found to be genetically stable throughout and across lactations, with average genetic correlations within a lactation ranging from 0.93 to 0.98, and those between lactations ranging from 0.92 to 0.98. All 6 CH4 traits were also found to be heritable, with average heritability ranging from 0.24 to 0.45. The average pairwise genetic correlations between the 6 CH4 traits ranged from -0.15 to 0.77, revealing that they are genetically distinct, including the 4 measurements of MeP. Of the 6 traits, 2 measures of MeP and MeI did not present antagonistic genetic correlations with milk yield, fat and protein contents, and SCS, and can probably be included in breeding goals with limited impact on other traits of interest.

Development of the machine learning model that is highly validated and easily applicable to predict radiographic knee osteoarthritis progression.

Many models using the aid of artificial intelligence have been recently proposed to predict the progression of knee osteoarthritis. However, previous models have not been properly validated with an external data set or have reported poor predictive performances. Therefore, the purpose of this study was to design a machine learning model for knee osteoarthritis progression, focusing on high validation quality and clinical applicability. A retrospective analysis was conducted on prospectively collected data, using the Osteoarthritis Initiative data set (5966 knees) for model development and the Multicenter Osteoarthritis Study data set (3392 knees) for validation. The analysis aimed to predict Kellgren-Lawrence grade (KLG) progression over 4-5 years in knees with initial KLG of 0, 1, or 2. Possible predictors included demographics, comorbidities, history of meniscectomy, gait speed, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and radiological findings. The Random Forest algorithm was employed for the predictive model development. Baseline KLG, contralateral knee osteoarthritis, lateral joint space narrowing (JSN) grade, BMI, medial JSN grade, and total WOMAC score were six features selected for the model in descending order of importance. Odds ratios of baseline KLG, contralateral knee osteoarthritis, and lateral JSN grade were 1.76, 2.59, and 4.74, respectively (all p < 0.001). The area-under-the-curve of the ROC curve in the validation set was 0.76 with an accuracy of 0.68 and an F1-score of 0.56. The progression of knee osteoarthritis in 4 ~ 5 years could be well-predicted using easily available variables. This simple and validated model may aid surgeons in knee osteoarthritis patient management.