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PubMed2026

Metabolic engineering of Candida yeasts for biotechnological applications.

Candida yeasts represent a versatile yet underexploited platform for industrial biotechnology. These yeasts utilize a remarkably broad range of carbon sources, particularly for hydrophobic carbon sources, coupled with robust growth and diverse biosynthetic capacities, making them promising hosts for sustainable production of chemicals, fuels, and proteins. Despite these advantages, industrial deployment of Candida species has been hindered by concerns regarding opportunistic pathogenicity and the historical lack of efficient genetic manipulation tools, leading to a substantial gap between metabolic potential and practical utilization. Recent advances in functional genomics, genome editing, and systems metabolic engineering are rapidly overcoming these barriers, enabling more precise and efficient strain development. In this review, we systematically summarize recent progress in the metabolic engineering of Candida species as microbial cell factories, with particular emphasis on expanding genetic toolkits, utilizting renewable and non-conventional carbon sources, and biosynthesizing high-value compounds. In addition, we propose a biosafety-oriented classification framework to support their safe industrial deployment. Finally, we discuss current challenges and emerging opportunities, emphasizing that the synergy of synthetic biology and artificial intelligence-driven design holds the key to unlocking the biotechnological potential of Candida yeasts.

Candida↗

PubMed2026

Phylogenomics and female reproductive morphology reframe the classification of the Halymeniales (Rhodophyta).

The red algal order Halymeniales (Rhodophyta) exhibits remarkable morphological and taxonomic diversity but its higher-level relationships remain poorly resolved. Here, we present a comprehensive phylogenomic analysis based on newly generated plastid (170 protein-coding genes), mitochondrial (23 genes), and complete nuclear ribosomal cistron sequences from 56 taxa, complemented with an expanded rbcL dataset encompassing 334 sequences. Our results provide a robust phylogenomic framework for the Halymeniales, offering a taxonomic backbone for future systematic studies. The analyses consistently recover six early-diverging lineages (Acrodiscus, Isabbottia, Norrissia, Pachymenia, Zymurgia, and Tsengia) and two strongly supported larger clades (Halymenia s.l. and Grateloupia s.l.). While most small and recently described genera are monophyletic, several traditional genera (e.g., Halymenia, Cryptonemia, Grateloupia) are poly- or paraphyletic, requiring considerable taxonomic revision. At the family level, the data indicate that reinstatement of the Grateloupiaceae sensu Kim et al. (2021) would entail a revised circumscription of the Halymeniaceae and the recognition of at least five small families to accommodate the early-diverging lineages. Although such a revised classification would result in monophyletic families, it is not supported by morpho-anatomical characters. Instead, we propose a more stable two-family system, recognizing a broadly circumscribed Halymeniaceae that is sister to the Tsengiaceae. Female reproductive characters, particularly the structure of carpogonial and auxiliary cell ampullae, support this two-family system and further characterize many genus-level clades, although substantial convergence across lineages exists.

Phylogeny↗

PubMed2026

Uce-based phylogeny and classification of Megachilini.

The generic-level classification of the bee tribe Megachilini (Megachilidae) has remained controversial due to poor phylogenetic resolution at the base of the group, particularly among the brood parasitic genera and the numerous dauber ("Chalicodoma s. l.") lineages. We present a phylogenomic analysis of Megachilini based on ultraconserved elements (UCEs), sampling 52 ingroup taxa with emphasis on the dauber lineages. We also present a combined UCE + six-gene analysis to improve taxon coverage, resulting in a dataset with 127 ingroup taxa. Maximum likelihood, coalescent, and Bayesian analyses of multiple UCE matrices recover largely congruent topologies with substantially improved support relative to previous studies. Our results strongly support the monophyly of Megachilini, the early divergence of Noteriades and Gronoceras, and a single origin of brood parasitism. All remaining non-parasitic Megachilini form a moderately supported clade sister to the brood parasitic lineage. The leafcutter bees are monophyletic and nested within dauber lineages. Several major dauber clades are consistently recovered, including an exclusively Australian clade corresponding to the Hackeriapis group of subgenera, while several recognized subgenera are paraphyletic. The lineage known as Morphella, previously placed in synonymy with the subgenus Callomegachile, was not closely related to that subgenus and is here treated as a valid subgenus. Divergence-time analyses place the crown age of Megachilini in the late Eocene to early Oligocene, with major extant lineages diversifying during the Miocene. Limited morphological diagnosability of several clades indicates that splitting non-parasitic lineages into numerous genera would result in an impractical classification that would widen the gap between taxonomists and non-specialists and exacerbate the taxonomic impediment in bees. We therefore advocate retaining a single genus Megachile for non-parasitic Megachilini (excluding Noteriades and Gronoceras), as the classification best supported by phylogenomic evidence and most robust to future taxon sampling.

Animals↗

PubMed2026

Transcranial Photobiomodulation Variables Assessment Battery: Development and Validation.

Transcranial photobiomodulation (tPBM) response variability is partly driven by biophysical characteristics such as skin tone and hair properties that attenuate photon penetration, and by lifestyle factors including sleep quality, alcohol use, and nicotine consumption that disrupt the mitochondrial and vascular pathways on which tPBM acts. To date, no validated self-report tool exists to capture these moderators systematically. To address this gap, the tPBM Variables Assessment Battery was developed and psychometrically evaluated. It integrates adapted versions of established measures (Brief Pittsburgh Sleep Quality Index, E-cigarette Dependence Scale, Hair Scale Assessment PRO, Monk Skin Tone Scale, and Heaviness of Smoking Index), validated wellbeing evaluators (Ryff's Psychological Wellbeing), and custom measures (Hairstyle Classification, Hair Color Classification). Face and content validity met recommended expert thresholds, internal consistency was acceptable across adapted subscales, and criterion validity analyses confirmed meaningful associations between the lifestyle components and PROMIS-10 global health outcomes. The battery is low-burden, digitally deployable, and psychometrically defensible, offering a practical tool for characterizing the variables most likely to moderate tPBM response in home-use studies.

Humans↗

PubMed2026

Functional neuroimaging subtypes of obsessive-compulsive disorder: A systematic review and meta-analysis.

Obsessive-compulsive disorder (OCD) exhibits substantial clinical heterogeneity that may reflect underlying neurobiological diversity. Neuroimaging-based subtyping may advance precision psychiatry by identifying biologically distinct subgroups with differential treatment responses. This study systematically synthesized evidence from functional neuroimaging subtyping studies in OCD to identify reproducible neurobiological subtypes, characterize their clinical profiles, and establish a consensus-based classification framework. We reviewed 40 original studies employing machine learning, clustering, normative modeling, or classification approaches, encompassing approximately 8,150 patients. Consensus clustering identified three reproducible neurobiological subtypes. The Limbic-Hyperactive subtype, comprising approximately 40% of patients, exhibited amygdala and insula hyperconnectivity, elevated anxiety levels, predominant contamination and washing symptoms, and favorable response to cognitive-behavioral therapy. The Fronto-Striatal-Hypoconnected subtype, comprising approximately 35% of patients, demonstrated reduced orbitofrontal-striatal connectivity, cognitive inflexibility, predominant checking and ordering symptoms, and a favorable response to selective serotonin reuptake inhibitors. The Global-Disrupted subtype, comprising approximately 25% of patients, exhibited widespread connectivity disruption, greater symptom severity, and poor treatment response. Support vector machine classification achieved 81.5% accuracy for subtype assignment, though classification of OCD versus healthy controls showed limited generalizability in multisite settings (AUC 0.567-0.673). These findings support a neuroimaging-based framework for personalized treatment selection but require prospective validation.

Humans↗

PubMed2026

The impact of body mass index classification on operative characteristics and perioperative outcomes in lumbar microdiscectomy.

INTRODUCTION: Body mass index (BMI) stratification helps classify obesity severity. In patients undergoing microdiscectomy for symptomatic lumbar disc herniation, the effect of obesity on perioperative risk remains incompletely understood. This retrospective single-institution study evaluated whether BMI class influences perioperative risk in a large surgical cohort. METHODS: Adults older than 18 years who underwent primary, elective single-level lumbar microdiscectomy between June 2018 and March 2025 with at least 3 months of follow-up were included. Patients were grouped by BMI: without obesity (WO, BMI < 30), class I (CI, 30-34.9), class II (CII, 35-39.9), and class III (CIII, ≥40). Outcomes were analyzed separately for open microdiscectomy (OM), tubular microdiscectomy (TM), and endoscopic discectomy (ED). Continuous variables were compared using Kruskal-Wallis testing with Dunn post hoc analysis; categorical variables were compared with chi-square tests. Significance was set at p < 0.05. RESULTS: A total of 757 patients were included (OM 422, TM 190, ED 145). Higher obesity classes underwent ED more frequently (p = 0.038). In the OM cohort (WO 258, CI 97, CII 50, CIII 17), CI had a higher proportion of males and CII a lower proportion (p = 0.007). Operative time, length of stay, and estimated blood loss were greatest in CII and CIII patients (all p < 0.001). CII patients also had more emergency department visits within 1 year than other classes (p = 0.026). No differences were found in age, smoking status, disc herniation type, dural tears, intraoperative or postoperative complications, or revision presence/time. In the TM cohort (WO 117, CI 47, CII 21, CIII 5), WO patients were oldest and CIII youngest (p < 0.001), with no other significant differences. In the ED cohort (WO 79, CI 31, CII 20, CIII 15), WO patients were oldest and CIII youngest (p = 0.004). CIII patients had higher estimated blood loss (p = 0.028) and shorter time to revision (p < 0.001), while other variables were similar. CONCLUSIONS: ED was used more often in higher obesity classes. In OM, CII and CIII obesity were associated with longer operative time, longer hospital stay, and greater blood loss, likely due to increased exposure requirements. TM and ED showed few obesity-related differences in complications, suggesting minimally invasive approaches may mitigate obesity-related perioperative risk. However, the retrospective design and small number of CIII patients warrant further study.

Humans↗

PubMed2026

Virtual surgical planning-assisted versus free-hand head and neck reconstruction: Systematic review, meta-analysis, and a novel classification.

Virtual surgical planning (VSP)-assisted reconstruction is increasingly used as an alternative to conventional free-hand (FH) techniques in mandibular and maxillary free-flap reconstruction. This systematic review and meta-analysis compared clinical outcomes and proposed a Reconstruction Complexity-Completeness classification. PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and reference lists were searched from inception to 20 June 2026. Comparative studies were eligible. Risk of bias was assessed using RoB 2 or the Newcastle-Ottawa Scale. Random-effects meta-analyses used restricted maximum likelihood estimation and Hartung-Knapp adjustment. Forty-two studies included 2763 patients (1204 VSP; 1559 FH). VSP significantly reduced operative time (33 studies; MD -64.75 min, 95% CI -83.51 to -46.00), ischemia time (15 studies; MD -37.40 min, 95% CI -48.97 to -25.82), and hospital stay (16 studies; MD -1.75 days, 95% CI -3.43 to -0.08). VSP was associated with significantly lower odds of bony non-union (OR 0.31, 95% CI 0.16-0.59) and malocclusion (OR 0.14, 95% CI 0.03-0.64), whereas flap loss, surgical site infection, and plate exposure did not differ significantly. VSP-assisted reconstruction was associated with improved operative efficiency, shorter hospitalization, and lower odds of bony non-union and malocclusion, while no statistically significant differences were detected in flap loss, surgical site infection, or plate exposure. The proposed classification may support complexity-adjusted reporting and comparison.

Humans↗

PubMed2026

Engineered MXene-based nanozyme platform: NIR-II photothermal and dual enzyme-mimetic potentiated chemodynamic synergy for precision tumor eradication.

The antioxidant defense barrier in the tumor microenvironment, particularly glutathione (GSH), considerably restricts the therapeutic efficacy of chemodynamic therapy (CDT). Moreover, CDT generally exhibits relatively mild therapeutic efficacy owing to its intrinsic reaction kinetics, making it difficult to achieve complete tumor eradication within a short time. To address these issues, we construct a functionalized nanotherapeutic platform, Nb2CTx@Ru-PEG2000-FA (NCRPF), for tumor photothermal ablation and enhanced CDT resulting from GSH depletion. NCRPF possesses three key advantages: 1. Efficient near-infrared II photothermal conversion (η = 42.08%), raising the tumor temperature above 45 °C within 90 s for rapid ablation; 2. Dual peroxidase-like and glutathione peroxidase-like activities, simultaneously depleting GSH and generating a burst of ·OH to eliminate residual tumors; 3. Targeted tumor accumulation with 2.9-fold higher efficiency than passive diffusion. Both in vitro and in vivo results confirm that this combined strategy achieves complete tumor eradication with favorable biosafety. Collectively, the NCRPF nanotherapeutic system provides a powerful new paradigm with high translational potential for the complete eradication of breast cancer.

Animals↗

PubMed2026

Non-parametric differential methylation analysis characterizes histotype-specific promoter regions in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a heterogenous disease with frequent late-stage diagnosis and high mortality rates, for which no reliable screening tests exist. In recent years, epigenetic biomarkers in the form of DNA methylation in CpG-rich regions have gained increased attention in the scientific community due to their robust nature and accessibility, allowing for diagnosis without the need for invasive surgery. In this study, we investigated the aberrant methylation of promoter regions in early stage EOC through non-parametric methods, with the purpose of characterizing candidate epigenetic biomarkers. The approach was used on a cohort of early stage EOC samples, and results were compared to existing programs for differential methylation. Significant regions were then used to construct a CpG panel for stratifying EOC histotypes through predictive classification in external data. Identified promoter regions were highly reproducible across cohorts, and the constructed CpG model stratified histotypes in external cohorts through predictive classification. Comparisons against other DMP and DMR callers showed a degree of homogeneity between results but also revealed promoter regions that were overlooked despite clear signs of aberrant methylation. Finally, EOC histotypes were found to differ in their methylation distribution types, and results indicate that methods sensitive to non-normally distributed data may be poorly suited to compare groups with different distribution types. The non-parametric approach identified aberrantly methylated promoter regions that were highly reproducible across cohorts. Results from predictive classification indicate that these regions may be useful for the purpose of EOC histotype stratification.

Humans↗

PubMed2026

Machine learning-assisted Mn-N-C nanozyme colorimetric sensor array for trace-level detection of biogenic amines in meat.

Accurate detection of biogenic amines (BAs) in meat remains challenging due to their high structural similarity and co-occurrence. Herein, an Mn-N-C nanozyme was synthesized via a metal-organic framework confined pyrolysis strategy, possessing excellent oxidase (OXD)- and peroxidase (POD)-like activities. The dual enzyme-like activity showed Km values of 0.1584 mM (OXD) and 0.1498 mM (POD), respectively, in detection system. Leveraging these properties, a colorimetric sensor array was constructed, enabling the detection of four representative BAs within a concentration range of 2-10 ppm with 100% classification accuracy. In addition, a concentration independent recognition model based on an artificial neural network was developed to address signal nonlinearity interference in meat. The integrated system achieved accurate trace-level identification of BAs in perishable fish, pork, and chicken, demonstrating its applicability for early-stage BAs monitoring and quality deterioration warning during storage and transportation.

Biogenic Amines↗

PubMed2026

Seed-derived mucilage polysaccharides as biomaterials for in vivo tissue regeneration: A systematic review.

Chronic wounds, bone defects, and cartilage injuries represent persistent clinical challenges requiring biomaterial platforms that actively regulate inflammation, oxidative stress, angiogenesis, and extracellular matrix remodeling. Conventional synthetic dressings often provide limited biological activity in these contexts. Seed-derived mucilages - polysaccharide-rich hydrocolloids obtained from chia (Salvia hispanica), flaxseed (Linum usitatissimum), fenugreek (Trigonella foenum-graecum), psyllium (Plantago ovata), guar (Cyamopsis tetragonoloba), quince (Cydonia oblonga) etc. - have emerged as biocompatible, biodegradable, and chemically versatile platforms for tissue engineering. This systematic review, conducted according to PRISMA 2020 guidelines, synthesized in vivo evidence on seed-derived mucilage-based biomaterials across wound healing, bone repair, cartilage regeneration, and related applications. PubMed, Scopus, and Web of Science Core Collection were searched for original in vivo experimental studies published in English between 2020 and 2026. Eligible studies reported at least one measurable regenerative outcome. Data were extracted independently by two reviewers, and methodological quality was assessed using the SYRCLE Risk of Bias tool. Forty-three studies were included. Hydrogels were the dominant biomaterial format, followed by films, scaffolds, sponges, nanoparticle systems, and bilayer or Janus composites. Included systems generally improved wound closure, re-epithelialization, collagen deposition, angiogenesis, antioxidant defense, and inflammatory regulation. However, most studies used small animals with short follow-up periods, and many incorporated nanoparticles or bioactive agents, limiting attribution of efficacy to the mucilage matrix alone. Risk of bias was predominantly unclear due to insufficient reporting of randomization and blinding. Blank mucilage controls, standardized characterization, long-term biosafety data, and clinically relevant models are essential prerequisites for translational progress.

Humans↗

PubMed2026

Female genital mutilation knowledge, attitudes and training needs among health professionals in non-practicing countries: A literature review.

BACKGROUND: With increasing globalization and migration, the number of women affected by female genital mutilation who reside in countries where the practice is not traditionally performed is constantly increasing. Healthcare providers in these settings are required to address the complex health needs of this vulnerable population. We aimed to synthesize recent literature on their knowledge, preparedness, and educational background. METHODS: We conducted a systematic review across PubMed, Scopus and Embase, identifying papers published from January 2015 onwards, examining providers' knowledge, education and attitudes toward female genital mutilation in non-practicing countries. Both quantitative and qualitative observational studies were eligible. Given heterogeneity in study populations, outcome definitions, and assessment tools, findings were synthesized narratively. The review protocol was registered with the International Prospective Register of Systematic Reviews (CRD420251044761). FINDINGS: 1046 records were screened by title and abstract, and 140 full-text articles were assessed for eligibility. 31 studies met the inclusion criteria (23 quantitative, 8 qualitative). Many providers reported clinical experience with women affected by female genital mutilation, yet substantial variability was observed in knowledge, training, and attitudes. Gaps were particularly evident regarding legislation, World Health Organization classification, clinical guidelines, referral pathways, workplace protocols. Midwives and younger professionals tended to demonstrate higher knowledge levels. Training exposure ranged from 5% to 91%, and many participants perceived it as insufficient. Qualitative findings echoed these patterns, highlighting challenges in female genital mutilation classification, legal awareness, documentation systems, the impact of providers' cultural beliefs on care delivery. CONCLUSION: Considerable efforts are needed to equip healthcare providers to deliver high-quality, culturally competent care to women affected by female genital mutilation. Research should develop validated tools to assess preparedness, adopt mixed-methods strategies to capture patient and provider perspectives, and guide standardized, up-to-date training programs, strengthening knowledge in managing female genital mutilation.

Humans↗

PubMed2026

Comparative genomic and proteomic analysis reveals orthogroup structured evolution of tick protease inhibitors.

Protease inhibitors (PIs) play central roles in regulating endogenous proteolysis and host-parasite interactions in ticks. However, the evolutionary architecture underlying their diversification across tick lineages remains insufficiently resolved. Here, we performed a genome-wide comparative analysis of predicted proteomes from 14 tick species to systematically characterize PI repertoires. In total, 4931 putative PIs were identified and grouped into 20 families using the MEROPS classification system. Further, PI families such as Antistasin, WAP-type, and Pacifastin, which have not previously been systematically reported in tick genomes, were classified. Orthogroup inference demonstrated that PI expansion is structured at the level of evolutionary lineages rather than uniformly across families. By stratifying orthogroups according to duplication burden and taxonomic conservation, we identified a broadly conserved single-copy core under strong purifying selection. Motif level analysis of serpin reactive center loops further revealed conservation of inhibitory specificity within single copy orthogroups and diversification of key functional residues in duplication-associated lineages. Integration of secretion prediction and tissue-resolved proteomics from Hyalomma anatolicum and Rhipicephalus microplus demonstrated that evolutionary stratification is reflected at the protein level. Together, these findings provide an orthogroup-resolved evolutionary framework linking duplication dynamics, molecular evolution, and tissue-level protein deployment. This integrative approach offers a systematic basis for prioritizing conserved and diversified PI lineages for future functional and anti-tick intervention studies.

Animals↗

PubMed2026

Meta-PseU: A meta-classifier for robust prediction of RNA pseudouridine modification sites from long sequences.

BACKGROUND AND OBJECTIVES: Pseudouridine (Ψ) represents one of the most abundant and conserved RNA modifications. Ψ provides an additional hydrogen-bond donor that enhances RNA structural stability and modulates translation. It participates in diverse biological processes, including RNA-protein interactions, splicing, translational control, and stress responses. Aberrant pseudouridylation is implicated in cancer, neurodegenerative disorders, and autoimmune diseases. Despite its biological importance, experimental identification of Ψ sites remains time-consuming and costly, limiting the feasibility of transcriptome-wide profiling. Computational approaches have therefore become essential complements to experimental techniques. However, state-of-the-art machine-learning and deep-learning predictors often suffer from limited generalizability due to small training datasets. To overcome these issues, we aim at constructing new long-sequence datasets and developing a novel Ψ site predictor. METHODS: New long-sequence datasets were constructed as benchmarks for RNA Ψ-site prediction. The Ψ modification sites in RMBase 3.0 were mapped to the reference genomes across three species of human, mouse, and yeast, and the RNA sequences with a length of 201 were generated by extending the upstream and downstream from the mapped, central sites. To eliminate sequence redundancy, the sequences were clustered using CD-HIT with a 70% sequence identity threshold. We developed Meta-PseU, a logistic regression-based meta-classifier that considered 118 machine learning and deep learning classifiers. The datasets and programs are freely accessible at https://github.com/kuratahiroyuki/MetaPseU. RESULTS: By optimizing model configuration, we proposed the Meta-PseU model stacking 32 machine learning and deep learning classifiers out of 118 classifiers. Meta-PseU substantially improved model generalizability, overcoming a key limitation of existing approaches. It greatly outperformed state-of-the-art predictors and achieved increasing accuracy with increasing sequence length. CONCLUSIONS: Long-sequence datasets were newly constructed as benchmarks for RNA Ψ-site prediction. Meta-PseU offers a new framework for robust Ψ-site identification by using long sequences.

Pseudouridine↗

PubMed2026

Transverse testicular ectopia with fused vas deferens: A systematic review.

BACKGROUND: Transverse testicular ectopia (TTE) with fused vas deferens is an extremely rare anomaly, often diagnosed intraoperatively. Current TTE classifications do not address internal ductal variations, limiting surgical guidance. OBJECTIVE: To systematically review cases of TTE with fused vas deferens, summarize presentation, operative strategies, outcomes and identify patterns that highlight the need for classification refinement. METHODS: A PRISMA 2020-compliant systematic review (PROSPERO; CRD420251247785) was performed across PubMed, ScienceDirect and citation of included articles through December 2025. Case reports and series confirming fused vas deferens were included. Data extracted comprised demographics, presentation, imaging, surgical approach, and outcomes. Quality assessment used JBI checklists. RESULTS: 12 studies (16 patients) were included. Most presented with unilateral inguinal hernia (62%) and contralateral undescended testis (68%); 81% were diagnosed intraoperatively. Anatomical patterns included common/proximal fused vas (87%), Y-shaped fusion (6%), and long-loop vas (6%). Trans-septal orchidopexy was the preferred approach, with preservation of vas integrity. Postoperative outcomes were favorable; long-term follow-up was limited. CONCLUSION: TTE with fused vas deferens represents a distinct variant requiring careful intraoperative recognition. We propose a Type IV TTE category for internal ductal fusion to guide surgical planning and classification refinement. Further accumulation of case-based evidence may help clarify its anatomical patterns and operative implications.

Humans↗

PubMed2026

Predicting ACL injury risk in athletes: A systematic review of machine learning-based models.

BACKGROUND: Early ACL injury risk identification in athletes is essential. This systematic review examines machine learning (ML) models for predicting ACL injuries, evaluating their methodological quality, performance, and reliability. METHOD: A comprehensive electronic search was conducted across PubMed, Scopus, Web of Science, and IEEE Xplore databases, supplemented by Google Scholar for grey literature, covering articles published between January 1, 2015, and August 30, 2025. Eligible studies were appraised using the Prediction Model Study Risk of Bias Assessment Tool (PROBAST) for methodological quality and risk of bias, and the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines for quality of evidence. RESULTS: Ten studies were included. PROBAST showed eight studies had moderate risk of bias and two low risk. TRIPOD found only two studies met quality criteria. ML models included logistic regression (n = 5), support vector machines (n = 4), k-nearest neighbor (n = 3), decision trees (n = 3), random forests (n = 5), neural networks (n = 2), linear discriminant analysis (n = 1), and pre-trained CNNs (n = 1). AUC ranged from 0.63 to 0.98. Accuracy (reported in six studies) ranged from 26% to 95%; however, these values should be interpreted with caution due to the absence of confidence intervals, lack of class imbalance handling, and limited external validation across studies. Tree-based ensemble methods such as random forest achieved competitive accuracy (74-86%), while SVM, a non-ensemble classifier, reported accuracy ranging from 71% to 95%; however, the highest values were obtained in studies with notably small sample sizes (n = 12 to n = 39), raising concerns about overfitting and generalizability. CONCLUSION: Current ML algorithms show promise for identifying athletes at high ACL injury risk and detecting relevant risk factors. Although study quality was generally satisfactory, future research should prioritize external validation and model interpretability to support clinical translation.

Humans↗

PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗

PubMed2025

Impact of stromal maturity and proportion on prognosis and immune landscape in colorectal cancer.

BACKGROUND: Tumour microenvironment and cancer cells have constant interaction affecting cancer progression. Tumour-stroma ratio (TSR) in the tumour centre and desmoplastic reaction (DR) classification at the invasive margin are prognostic factors based on stroma evaluation on H&E slides. However, their combined value and immunological associations remain poorly defined. This study examines the prognostic and immunological value of TSR, DR, and their combination in two large colorectal cancer cohorts. METHODS: Two colorectal cancer cohorts (N = 1,876) were analyzed. We introduced a three-tiered Stromal Maturity and Proportion Score (SMAPS) based on the presence of high (>50%) TSR and myxoid stroma (immature DR classification). Alcian blue staining was used to further quantify myxoid stroma. Multiplex immunohistochemistry combined with digital image analyses, was utilized to study immune cell densities associated with SMAPS, TSR, DR, and Alcian blue intensity. RESULTS: In the study cohort (N = 1,100), SMAPS was a stronger predictor of cancer-specific mortality [HR for high (vs. low) SMAPS 2.01 (95% CI 1.47-2.75), p < 0.0001] compared to TSR [HR for stroma-high (vs. stroma-low) 1.49 (95% CI 1.15-1.93), p = 0.003] and DR classification [HR for immature (vs. mature) 1.84 (95% CI 1.39-2.45), p < 0.0001]. High SMAPS, stroma-high TSR, and immature DR correlated with lower densities of CD3+ T cells, B cells, M1-like macrophages, CD66B+ granulocytes, and mast cells. Alcian blue staining was associated with immature DR and corresponding immune cells. The validation cohort (N = 776) confirmed the association of SMAPS with survival and T cell densities. CONCLUSIONS: TSR and DR are independent prognostic factors for cancer-specific survival. SMAPS is a promising prognostic tool that integrates stromal maturity at the invasive margin and stromal proportion in the tumour centre. SMAPS has stronger prognostic value compared to TSR and DR classifications alone. A high stromal proportion and myxoid content are associated with an immunosuppressive microenvironment characterized by lower densities of antitumourigenic immune cells.

Humans↗