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Dissecting genetic variance structure and evaluating genomic prediction models for single-cross hybrids derived from Stiff Stalk and Non-Stiff Stalk maize heterotic groups.

The early 20th-century discovery of heterosis and the establishment of heterotic groups transformed maize (Zea mays L.) into a keystone of global agriculture. However, maize breeding faces two significant challenges: the gradual decline of general combining ability (GCA) variance within heterotic groups and the impracticality of testing all possible single crosses in the early stages of a breeding program. Here, we developed genomic best linear unbiased prediction (GBLUP)-based multikernel models, using additive and two alternative nonadditive genomic relationship matrices, to estimate the variance components associated with the general combining ability of Stiff Stalk (SS) and Non-Stiff Stalk (NSS) heterotic groups and the specific combining ability arising from their crosses. We further applied these models to predict the performance of untested single-cross combinations under varying levels of parental information. We showed that the SS and NSS groups retained significant GCA variance across traits in both early- and late-maturity groups. The SS group, in contrast, exhibited no detectable GCA variance in grain yield for the intermediate-flowering subset of hybrids, highlighting a limitation for future genetic improvement. Furthermore, our results showed that GBLUP-based multikernel models effectively identified superior hybrids when parental information was available. In the absence of this information, however, these models underperformed compared to covariance-based approaches. Both nonadditive matrices yielded similar results, indicating that they capture comparable genetic relationship patterns despite their distinct formulations. Overall, this study sheds light on the future use of US maize commercial germplasm and demonstrates how GBLUP-based multikernel models can improve the efficiency of hybrid breeding programs.

Zea mays

Pilot study of allele-specific multi-InDel markers for the detection of extremely unbalanced DNA mixtures.

Mixtures are common in forensic casework, and they represent one of the most challenging types of biological evidence. Traditional short tandem repeat analyses are often associated with limitations when dealing with extremely unbalanced mixtures because alleles from minor contributors can easily be masked by those of major contributors. Consequently, researchers have developed new technologies and methods for improving the analysis of mixtures, spanning upstream DNA extraction and downstream software analysis. Among these, strategies combining allele-specific amplification with compound markers have drawn particular interest because of their ability to selectively detect minor contributors in complex mixtures. In this study, we screened multi-InDels across the entire genome, designed allele-specific primers compatible with the capillary electrophoresis platform, and further explored their potential in unbalanced DNA mixtures and cell-free fetal DNA (cffDNA). Ultimately, a set comprising 10 multi-InDels was developed, and this included two groups of primers that separately amplified the long alleles (L primer set) and short alleles (S primer set). The results demonstrated that each primer pair could detect the minor component at a 1:1000 mixture ratio, whereas the L and S primer sets successfully detected the minor contributors at mixture ratios of 1:200 and 1:500, respectively. Furthermore, in the cffDNA analysis, 60 of 78 informative markers were successfully detected, with the complete detection of all informative markers achieved in 18 mother-child reference pairs. Overall, allele-specific amplification-based multi-InDel markers enabled the sensitive detection of minor contributors, providing a potential strategy for the analysis of unbalanced two-person mixtures.

Allelic-specific amplification

Target-Site Selection by Transcription Factors: Roles of DNA, Chromatin, and Cofactor-Mediated Regulation.

Transcription factors (TFs) are sequence-specific DNA-binding proteins that regulate gene-expression programs and cell fate. The ability of a defined combination of four TFs to reprogram differentiated cells into induced pluripotent stem cells illustrates the powerful role of TFs in determining cellular identity. However, TFs usually recognize short and degenerate DNA motifs of approximately 6-12 base pairs, generating thousands to millions of potential motif matches in mammalian genomes. In living cells, TFs occupy only a restricted subset of these sites, indicating that motif presence alone is insufficient for functional target selection. Several layers of regulation contribute to this selective occupancy, including DNA methylation, nucleosome organization, histone modifications, chromatin remodeling, TF oligomerization, TF availability and localization, and cofactors that regulate DNA-binding domains. This review outlines how DNA/chromatin features and TF-centered mechanisms contribute to target-site selection. The principal aim is to highlight DNA-binding domain-directed cofactor regulation as an underappreciated mechanism that modulates TF-DNA binding and may help explain selective genomic occupancy.

Target-site selection

Genomic and Developmental Models to Predict Cognitive and Adaptive Outcomes in Autistic Children.

IMPORTANCE: Although early signs of autism are often observed between 18 and 36 months of age, there is considerable uncertainty regarding future development. Clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). OBJECTIVE: To predict ID in children diagnosed with autism. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study involved the development and validation of models integrating genetic variants and developmental milestones to predict ID. Models were trained, cross-validated, and tested for generalizability across 3 autism cohorts: Simons Foundation Powering Autism Research (SPARK), Simons Simplex Collection, and MSSNG. Autistic participants were assessed older than 6 years of age for ID. Study data were analyzed from January 2023 to July 2024. EXPOSURES: Ages at attaining early developmental milestones, occurrence of language regression, polygenic scores for cognitive ability and autism, rare copy number variants, de novo loss-of-function and missense variants impacting constrained genes. MAIN OUTCOMES AND MEASURES: The out-of-sample performance of predictive models was assessed using the area under the receiver operating characteristic curve (AUROC), positive predictive values (PPVs), and negative predictive values (NPVs). RESULTS: A total of 5633 autistic participants (4574 male [81.2%]) were included in this analysis. On average, participants were diagnosed with autism at 4 (IQR, 3-7) years of age and assessed for ID at 11 (8-14) years of age, with 1159 participants (20.6%) being diagnosed with ID. The model integrating all predictors yielded an AUROC of 0.653 (95% CI, 0.625-0.681), and this predictive performance was cross-validated and generalized across cohorts. This modest performance reflected that only a subset of individuals carried large-effect variants, high polygenic scores, or presented delayed milestones. However, combinations of genetic variants that are typically not considered clinically relevant by diagnostic laboratories achieved PPVs of 55% and correctly identified 10% of individuals developing ID. The addition of polygenic scores to developmental milestones specifically improved NPVs rather than PPVs. Notably, the ability to stratify ID probabilities using genetic variants was up to 2-fold higher in individuals with delayed milestones compared with those with typical development. CONCLUSIONS AND RELEVANCE: Results of this prognostic study suggest that the growing number of neurodevelopmental condition-associated variants cannot, in most cases, be used alone for predicting ID. However, models combining different classes of variants with developmental milestones provide clinically relevant individual-level predictions that could be useful for targeting early interventions.

Humans

Machine learning prognostic model and drug survival analysis for lung adenocarcinoma in the context of radiotherapy.

BACKGROUND: Patients with lung adenocarcinoma (LUAD) receiving radiotherapy represent an important but underexplored clinical subgroup. These patients often undergo concomitant pharmacologic treatments, yet the prognostic impact and underlying determinants of such combined regimens remain poorly understood. OBJECTIVE: This retrospective observational study aimed to develop and validate a radiotherapy-specific machine learning prognostic model for LUAD and to compare survival across concomitant pharmacologic regimens. METHODS: In this retrospective observational study, using genomic and clinical data from TCGA, a radiotherapy-specific prognostic model for LUAD was developed and validated through ten machine learning algorithms. Survival analyses were conducted across distinct concomitant pharmacologic strategies, followed by functional enrichment to elucidate molecular mechanisms underlying differential outcomes. RESULTS: Demonstrating robust prognostic abilities, the model efficiently sorted patients into high- and low-risk categories. Both treatment type and risk score independently predicted overall survival, with significant interaction effects. Low-risk patients receiving targeted or combination therapy-mainly erlotinib, gefitinib, or bevacizumab-exhibited substantially improved survival compared with those receiving conventional chemotherapy. Enrichment of "Exogenous peptide presentation," "MHC class II assembly," "Peptide-MHC II assembly," and "Symbiotic interaction" pathways indicated immune modulation and host-tumor crosstalk as key mediators of treatment efficacy. CONCLUSION: This study establishes a radiotherapy-specific prognostic model for lung adenocarcinoma, demonstrating distinct molecular and therapeutic heterogeneity and highlighting the superior survival benefit of targeted combination therapy in low-risk patients.

Humans

Transcriptome-wide association analysis of Alzheimer's disease: construction and clinical validation of transcriptomic risk scores.

Early identification of individuals at high risk for Alzheimer's disease (AD) is crucial for disease prevention and intervention. This study aims to develop AD-specific transcriptomic risk scores (TRSs) through multi-tissue transcriptome-wide association study (TWAS) and to evaluate its clinical utility in AD diagnosis and risk prediction. Using GWAS summary statistics combined with expression quantitative trait loci (eQTL) data from 14 tissues, a multi-tissue TWAS approach was applied to identify AD-associated genes. Peripheral blood RNA expression data from the ADNI and GEO databases were used to construct the AD-specific TRSs. The associations of TRSs with AD pathological features and cognitive function were assessed in two independent cohorts. Furthermore, the diagnostic performance, differential diagnostic capability, and risk prediction efficiency of TRSs were evaluated. The TWAS identified 131 genes significantly associated with AD. The TRSs were significantly elevated in patients with AD and mild cognitive impairment (MCI) compared to cognitively normal (CN) individuals, and showed significant correlations with AD pathological markers and cognitive performance. When combined with APOE4 status, the TRSs demonstrated robust diagnostic ability for AD and MCI. When combined with age, the TRSs showed good diagnostic performance in distinguishing AD from frontotemporal dementia (FTD) (AUC = 0.86). Additionally, the TRSs effectively predicted the risk of progression to AD in non-AD individuals (HR = 1.74). The AD-specific TRSs developed in this study shows promising clinical utility in AD diagnosis, differential diagnosis, and risk prediction, providing valuable translational medical evidence for early screening and precision prevention of Alzheimer's disease.

Humans

Predicting telomerase reverse transcriptase promoter mutation status in glioblastoma by whole-tumor multi-sequence magnetic resonance texture analysis.

OBJECTIVE: This study aimed to determine the feasibility of preoperative multi-sequence magnetic resonance texture analysis (MRTA) for predicting TERT promoter mutation status in IDH-wildtype glioblastoma (IDHwt GB). METHODS: The clinical and imaging data of 111 patients with IDHwt GB at our hospital between November 2018 and June 2023 were retrospectively analyzed as the training set, and those of 23 patients with IDHwt GB between July 2023 and November 2023 were interpreted as the validation set. We used molecular sequencing results to classify the training set into TERT promoter mutation and wildtype groups. Textural features of the whole-tumor volume were extracted, including T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery, apparent diffusion coefficient (ADC) map, and contrast-enhanced T1-weighted imaging (CE-T1). All textural features were obtained using open-source pyradiomics. After feature selection, logistic regression was used to build prediction models, and a nomogram was generated. Finally, the model was validated using validation cohort. RESULTS: The CE-T1_Model (AUC 0.704) had a better predictive ability than the T2_Model (AUC 0.684) and ADC_Model (AUC 0.624). The MRI_Combined_Model (CE-T1, T2, and ADC texture features) (AUC 0.780) had a better predictive ability than the Clinical_Model (AUC 0.758). The Combined_Model (CE-T1, T2, ADC texture features, and clinical features) had the best predictive performance (AUC 0.871), with a sensitivity, specificity, and accuracy of 82.60 %, 83.30 %, and 80.18 %, respectively. The AUC, sensitivity, specificity, and accuracy in the validation cohort were 0.775, 86.70 %, 75.00 %, and 69.57 %, respectively. CONCLUSIONS: Whole-tumor multi-sequence MRTA can be used as non-invasive quantitative parameters to assist in the preoperative clinical prediction of TERT promoter mutation status in IDHwt GB.

Humans

Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders.

INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity. OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group. METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral. RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants. CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.

Humans

ADAM10's combined influence on the diagnostic usefulness of IL 22, IL 10, IL-17 A, and IL-17D in autism spectrum disorders: Predicted role on gut leakiness as co-morbidity.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing global prevalence but a lack of reliable diagnostic biomarkers. Emerging evidence suggests that immune dysregulation, gut-brain axis dysfunction, and increased intestinal permeability play key roles in ASD pathophysiology. This study investigated the combined diagnostic value of ADAM10 and cytokines (IL-10, IL-22, IL-17 A, and IL-17D). Multivariable logistic regression produces an improved ROC curve that improves diagnostic accuracy over individual markers by combining numerous predictors into a single risk score (linear predictor). The technique, which frequently raises individual marker AUCs, entails modelling a binary result, calculating the probability, and visualizing ROC based on the projected probabilities. In this case-control study, plasma levels of ADAM10, IL-10, IL-22, IL-17 A, and IL-17D were measured in 37 male children with ASD and 37 age-matched controls. Group comparisons, correlation analyses, and receiver operating characteristic (ROC) curve analyses, including combined ROC models, were performed. ADAM10, IL-22, and IL-17 A levels were significantly reduced in children with ASD compared to controls, whereas IL-10 and IL-17D showed no significant differences. ADAM10, IL-17 A, and IL-22 demonstrated good diagnostic performance, with AUC values of 0.886, 0.855, and 0.812, respectively. In contrast, IL-10 and IL-17D showed poor discriminatory ability, with AUC values of 0.524 and 0.599, respectively. Combined ROC analysis markedly improved diagnostic accuracy, with all panels including ADAM10 achieving AUC values above 0.90, and some reaching as high as 0.988, with high sensitivity and specificity. The combination of ADAM10 with selected cytokines significantly enhances diagnostic performance compared to individual markers, supporting a link between immune dysregulation, barrier dysfunction, and gut permeability in ASD.

Humans

Target and biomarker exploration portal for drug discovery.

MOTIVATION: The discovery of novel drug targets and precision biomarkers remains a major challenge in drug development, with traditional differential expression analysis often overlooking key regulatory proteins. Here, we present a novel, web-based bioinformatics tool, the Target and Biomarker Exploration Portal (TBEP), designed to accelerate the drug discovery process by integrating large-scale biomedical data with network analysis techniques. RESULTS: TBEP harnesses machine-learning approaches to mine and combine multimodal datasets, including human genetics, functional genomics, and protein-protein interaction networks, to decode causal disease mechanisms and uncover novel therapeutic targets and precision biomarkers for specific phenotypes. A unique feature of the tool is its ability to process large-scale data in real-time, facilitated by an efficient cloud-based architecture. Additionally, the tool incorporates an integrated large language model (LLM), which assists researchers in exploring and interpreting complex biological relationships within the generated networks and multi-omics data using natural language (English). By offering an intuitive, interactive interface, the LLM enhances the exploration of biological insights, making it easier for scientists to derive actionable conclusions. This powerful integration of network analysis, multi-omics data, and LLM provides a robust framework for accelerating the identification of novel drug targets. AVAILABILITY AND IMPLEMENTATION: The tool is publicly available at https://tbep.missouri.edu. The source code, documentation and installation instructions are available at GitHub repository: https://github.com/mizzoudbl/tbep.

Drug Discovery

Effectiveness of STK Spray® for semen stain localization on solid surfaces: A specificity and sensitivity study.

Semen identification is a crucial step in sexual assault cases. The aim of this study was to assess STK Spray®, a presumptive test for semen, under controlled conditions including, simulated crime scene stains detection. Easy to use, it can be sprayed directly onto different surfaces and visualized under UV light. Several tests were performed on five different substrates (ceramic tile, drywall, metal, wood, and faux leather). The spray was able to enhance semen fluorescence, especially in diluted samples, with characteristic "globular" spots. Although it showed good specificity, false positives could be obtained with 10% bleach. The fluorescence signals were quantified using ImageJ™ and showed a statistically significant substrate-dependent variability. Mixture analysis indicated that saliva did not interfere with detection of semen, while urine partially suppressed the signal and blood markedly affected its interpretation. Simulation tests with UV lamp comparisons confirmed the importance of choosing the right detection method and the utility of this presumptive test in combination with additional immunochromatographic tests. A preliminary signal retention test showed stable fluorescence for up to two years when stains were stored appropriately. Finally, complete DNA profiles (100% of alleles) were obtained from all samples (n = 24) after exposure to the reagent and UV light. Because of its ability to enhance semen signal, especially on specific surfaces, and its rapidity of use and detection, STK Spray® may represent a useful aid in the preliminary screening phase.

Humans

TCRspec: A Recognition Interface-Informed Multimodal Method for TCR-pMHC Specificity Prediction.

Specific recognition between T-cell receptors (TCRs) and peptide-major histocompatibility complexes (pMHCs) is central to adaptive immunity, yet accurate prediction of TCR-pMHC specificity remains challenging. Existing models mainly rely on sequence features or isolated molecular structures, limiting their ability to capture interface-level determinants within the ternary recognition complex. Here, we constructed the multimodal TCR-pMHC ternary complex (MM-TCR) data set, integrating paired TCR-pMHC sequences, V/J gene annotations, and modeled TCR-pMHC complex structures refined by short molecular dynamics-based relaxation. Based on MM-TCR, we developed TCRspec, an interpretable multimodal framework combining sequence embeddings, gene-usage features, and complex-level structural representations. Under a stringent CD-HIT TCR-cluster-disjoint split, TCRspec achieved an average AUROC of 0.896 and AUPRC of 0.882 across seven antigen-specific test data sets, outperforming representative baseline models. Cross-validation and ablation analyses confirmed the contribution of ternary complex structural information and MD-refined structures. In independent OOD peptide-TCR systems, TCRspec retained discriminative performance and identified model-inferred peptide positions associated with TCR recognition, providing a structure-informed framework for TCR specificity prediction.

Receptors, Antigen, T-Cell

Comprehensive genomic analysis of antibiotic resistance plasmids in animal-associated Staphylococcus aureus in France.

UNLABELLED: In Staphylococcus aureus, an animal pathogen and zoonotic agent, plasmids play a pivotal role in the acquisition and spread of antibiotic resistance genes (ARGs). This study investigated the plasmid content of 329 S. aureus isolates from livestock and companion animals collected in France between 2010 and 2021. Plasmids (n = 211) were identified from 139 isolates. The major families identified-rep7a, rep20, and rep10-were associated with specific resistance genes (str, cat, blaZ, erm(C)) and exhibited widespread horizontal transfer across different S. aureus sequence types (STs) and animal hosts. In temporal analysis, the rep7a/str and rep7a/cat plasmids circulating in horses were progressively replaced by a rep7a plasmid carrying both str and cat genes. The study also highlighted the presence of mosaic plasmids, which combined elements from different bacterial species/genera, confirming the broad host range of S. aureus plasmids and their ability to acquire ARGs from diverse sources. Moreover, the occurrence of hybrid plasmids (carrying multiple rep genes) underscores the plasticity of these vectors of ARGs. This study emphasizes the need to investigate the mechanisms driving the spread and persistence of antibiotic-resistant plasmids in S. aureus, with a view to developing strategies aimed at combating antibiotic resistance. IMPORTANCE: The spread of antibiotic resistance in Staphylococcus aureus is a growing concern, particularly in animals that can serve as reservoirs for resistant strains. This study highlights the crucial role of plasmids in transmitting resistance genes among different animal hosts and S. aureus lineages. The characterization of 329 isolates collected over 10 years revealed how certain plasmid families are associated with specific resistance genes and how they evolve over time. The occurrence of mosaic and hybrid plasmids further underscores the ability of S. aureus to acquire resistance from diverse bacterial sources. These findings provide key insights into the mechanisms shaping antibiotic resistance in this pathogen and emphasize the fact that understanding plasmid-driven resistance is essential for developing effective interventions to limit the spread of multidrug-resistant S. aureus in both veterinary and human medicine.

Animals

Adding Rib Mobilization to Diaphragm Release Techniques in Patients With Non-Specific Neck Pain: Randomized Controlled Trial.

BACKGROUND: Non-specific neck pain (NSNP) is a frequent issue that can negatively affect both mobility and function. Recently, there has been growing interest in newer therapeutic approaches, including rib mobilization and diaphragm release techniques, as potential ways to address NSNP and support better outcomes for those affected. PURPOSE: To find out the immediate effects of how (DRT) combined with (RMT) affects the level of pain and the extent to which patients' functional abilities are improved in cases of NSNP. METHODS: For this prospective RCT, 96 participants aged 20 to 45 years were randomly assigned to one of three equal groups based on their pain score (VAS). Group B engaged in (DRT) for 40 minutes, three times weekly for 8 weeks, in contrast to Group A, which got both RMT combined with DRT. Group C (active control) received advice and some exercises. Measurements were collected before and after the intervention; the primary outcomes included pain severity, evaluated using a visual analog scale (VAS); active neck range of motion (ROM), measured with a cervical range of motion (CROM) device; and neck flexion endurance. Additionally, the secondary outcome of neck-related disability was assessed using the Neck Disability Index (NDI). RESULTS: No statistically significant difference was identified among the three groups at baseline; nevertheless, a treatment effect emerged after 8 weeks (p = 0.001 and f-value = 4.15, ƞ2 = 0.306). A statistically significant time-treatment interaction was seen when comparing the pre- and post-treatment periods in groups A and B (p = 0.001, f-value = 3.16, ƞ2 = 0.251). CONCLUSION: The addition of rib mobilization to diaphragm release techniques in patients with non-specific neck pain resulted in statistically significant improvements in pain intensity, cervical flexion, right lateral rotation, left lateral rotation, right rotation, and neck flexor endurance, with moderate to large effect sizes for pain reduction and cervical motion. However, no statistically significant differences were observed between groups for cervical extension, left rotation, or the Neck Disability Index (NDI), and only a marginal clinical improvement in NDI was noted in Group A. The observed benefits in the combined intervention group may not be attributable solely to rib mobilization. The increased treatment complexity and greater therapist interaction inherent in the combined approach could also have influenced the outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT07133646.

Humans

GBFN: A gated bimodal fusion network leveraging foundation model embeddings for cancer drug sensitivity prediction.

Despite recent progress in deep learning for cancer drug sensitivity prediction, many existing models still rely on task-specific representation learning or relatively simple multimodal fusion, which may limit their ability to capture complex drug-cell interactions. To address this issue, we developed GBFN, a gated bimodal fusion network for continuous IC50 prediction that integrates pretrained drug and cell-line representations. Specifically, drug embeddings were obtained from SMI-TED, whereas cell-line embeddings were derived from transcriptomic profiles using BulkFormer. These two modalities were then combined through a dimension-wise gated fusion module and used to predict IC50 values in matched drug-cell line pairs. On the CCLE-based benchmark, GBFN outperformed representative neural baselines, including GraphDRP, TGSA, and TransEDRP, and achieved the best overall performance, with an R² of 0.8714 and an RMSE of 0.8938. Moreover, ablation analysis showed that the model using drug features and cell-line expression data with gated fusion performed better than the corresponding model using direct concatenation, indicating that the improvement was associated with the fusion strategy rather than with the input modalities alone. In addition, cell-line expression data were more informative than mutation data in the present setting, and adding mutation data to the model using drug features and expression data did not further improve performance. Across major cancer types, GBFN maintained generally high cell-line-level predictive performance, and perturbation-based attribution identified biologically relevant transcriptomic programs in selected drug-cell line settings. Together, these findings support GBFN as a compact and effective framework for continuous drug response prediction.

Humans

MicroRNAs signatures in small extracellular vesicles for psychological resilience in young adults using machine learning.

AIMS: Psychological resilience refers to an individual's capacity to adapt to adverse events. MicroRNAs (miRNAs) play a crucial role in regulating post-transcriptional processes, while small extracellular vesicles (sEVs) act as transport vehicles. This study aimed to employ genome-wide profiling to identify and validate differences in the expression of resilience-associated sEV-miRNAs between low resilience (LR) and high resilience (HR) in young adults. METHODS: Eighty participants were divided into LR or HR based on the Connor - Davidson Resilience Scale (CD-RISC). The expression levels of the target sEV-miRNAs in LR and HR were compared and analyzed. RESULTS: Expression analyses demonstrated significant differences in let-7b, miR-151b, miR-335, and miR-193a between LR and HR (p&#x2009;<&#x2009;0.01), with let-7b showing the highest discriminative ability. The AUC values for each sEV-miRNA ranged from 0.74 to 0.94, based on logistic regression and three machine learning models: random forest, support vector machine, and eXtreme gradient boosting. Based on leave-one-out cross-validation in different models, the combined four sEV-miRNAs demonstrated strong performance for detecting LR (AUC&#x2009;=&#x2009;0.87-0.90). Sex-specific differences were also observed, with female participants showing more pronounced resilience signatures in targeted sEV-miRNAs. CONCLUSIONS: These findings suggest that sEV-miRNAs hold potential as biomarkers for psychological resilience in young adults.

Humans

Enhancing the utility of adeno-associated virus gene transfer through inducible tissue-specific expression.

The ability to regulate both the timing and specificity of gene expression mediated by viral vectors will be important in maximizing its utility. We describe the development of an adeno-associated virus (AAV)-based vector with tissue-specific gene regulation, using the ARGENT dimerizer-inducible system. This two-vector system based on AAV serotype 9 consists of one vector encoding a combination of reporter genes from which expression is directed by a ubiquitous, inducible promoter and a second vector encoding transcription factor domains under the control of either a heart- or liver-specific promoter, which are activated with a small molecule. Administration of the vectors via either systemic or intrapericardial injection demonstrated that the vector system is capable of mediating gene expression that is tissue specific, regulatable, and reproducible over induction cycles. Somatic gene transfer in vivo is being considered in therapeutic applications, although its most substantial value will be in basic applications such as target validation and development of animal models.

Animals

PUS7-dependent &#x3a8; reshapes specific synaptic gene exons to facilitate fear extinction memory formation.

RNA modifications serve as dynamic regulators of neural plasticity through their ability to fine-tune transcript stability and splicing. Pseudouridine (&#x3a8;), an evolutionarily conserved RNA modification catalyzed by pseudouridine synthases, plays established roles in neurodevelopment, yet its functional significance in activity-dependent behavioral adaptation remains poorly defined. Here, we investigate &#x3a8;-mediated epitranscriptomic regulation within the infralimbic prefrontal cortex (ILPFC), a brain region requiring precise synaptic remodeling for the clinically relevant form of fear extinction memory. Combining transcriptome-wide pseudouridylation profiling with behavioral analysis in mice, we identified selective &#x3a8; enrichment at exons of synaptic regulatory genes within ILPFC during fear extinction learning. Fear extinction in the ILPFC drives concomitant exonic &#x3a8; deposition and upregulation of synaptogenic transcripts, processes that involve pseudouridine synthase PUS7. Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction memory formation without altering baseline fear expression, establishing a causal link between &#x3a8;-dependent RNA processing and activity-dependent synaptic structural remodeling in this microcircuit. Our findings demonstrate that PUS7-mediated &#x3a8; modification spatiotemporally regulates activity-dependent RNA dynamics in the ILPFC, providing the evidence that epitranscriptomic mechanisms precisely coordinate synaptic gene expression within behaviorally defined brain sub-region. This work bridges molecular RNA biology with systems neuroscience, revealing a novel mechanism for activity-dependent regulation of fear extinction in ILPFC.

Animals