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Avian egg incubation period: Revisiting existing allometric relationships via surface area-to-volume ratio of an egg.

The incubation period (I) for bird eggs varies among species and is used in establishing allometric relationships. Research on variations in I shed light on the evolutionary mechanisms that gave rise to the differentiation of embryonic development in distinct taxa of birds. Here, using a sampling of 444 images from 444 avian species, 89 families and 30 orders, we calculated their major geometric dimensions: volume (V) and surface area (S). An assessment of the relationship between I and the measured and calculated egg parameters demonstrated the closest and most significant correlation (R = -0.760) between I and the S/V ratio that was adopted as a conditional indicator and reflects the embryo's metabolic rate. Approximation of the values of these parameters made it possible to derive a power-law dependence for the prediction of I depending on the S/V value of a particular egg (R2 = 0.757). The prediction accuracy was higher (R2 = 0.783) if the eggs of the family Procellariiformes (petrels), whose I value is characterized by a longer time, were removed from the general sampling computation. We conclude that the value of the S/V ratio can characterize both the metabolism of an embryo and the conditional thermal conductivity of an egg, which aids in ensuring the temperature regime of egg incubation.

Animals

Post-weaning social isolation increases reward-seeking behavior in mice.

Social isolation is a growing public health concern. Although isolation at any age is harmful, previous studies have shown that isolation during adolescence, correlating with critical periods of brain development, can impair cognitive function and increase the risk for psychiatric illness later in life. In this study, we utilized a mouse model of social isolation (SI) during adolescence (postnatal day 21-35) and compared performance of isolated and group-housed mice on a touchscreen-based continuous performance test (rCPT) and fixed ratio/progressive ratio (FR/PR) tasks in adulthood. SI improved performance in the rCPT and the improvement in performance was consistent across time bins within the 45-minute testing session. There were no effects of SI on reaction times or reward retrieval latencies. A possible confound for performance in the rCPT would be SI-induced changes in reward-seeking or motivation for the strawberry milk reward. We next compared the SI mice to their group-housed littermate controls on both PR and FR schedules of reinforcement and found that SI mice had higher breakpoints on a PR4 schedule and earned significantly more reinforcers on an FR1 schedule of reinforcement compared to their group-housed littermates, suggesting that high performance in the CPT may be due to increased motivation for food rewards. These data indicate that SI during adolescence has significant effects on reward-seeking behavior in adult mice and may provide a useful behavioral model for studying the link between SI and risk for neuropsychiatric disorders.

Animals

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals

Comparative analyses of olfactory receptor repertoires in Schizothorax fish based on the chromosome-level genomes: Implications for regulatory roles of dietary differentiation and ploidy variation.

The olfactory receptor (OR) genes constitute the molecular basis of fish olfaction, mediating survival behaviors and environmental adaptation while coevolving with habitat-driven evolution. Schizothorax, a cyprinid genus endemic to the Qinghai-Tibetan Plateau, exhibits remarkable dietary divergence and ploidy variation in response to plateau environmental changes, which presumably facilitates the adaptive evolution of OR genes. However, the evolutionary patterns of OR genes associated with trophic divergence and ploidy variation in this genus remain unclear. In this study, three species were selected: the herbivorous diploid S. macropogon, the carnivorous diploid S. lantsangensis, and the herbivorous tetraploid S. curvilabiatus. S. macropogon possessed 142 OR genes (92.25% functional), primarily located on chromosomes 14 and 24, with the fewest sequence clusters. Such compact gene repertoire and highly overlapping chromosomal clusters indicated specialization for a herbivorous olfactory niche. S. lantsangensis contained 127 OR genes (93.70% functional), concentrated on chromosomes 4 and 5, with fewer sequence clusters and a scattered distribution, reflecting evolution of OR genes under carnivorous feeding habits. The herbivorous tetraploid S. curvilabiatus exhibited striking features: 316 OR genes (94.30% functional), the most subfamilies, unique ε and κ OR subfamilies, and species-specific motifs. These characteristics revealed that ploidy, rather than herbivory, dominated OR gene evolution. In conclusion, dietary differentiation and ploidy variation together drove olfactory adaptive evolution in Schizothorax, providing new insights into vertebrate OR gene ecological adaptation.

Animals

Plasma proteomic profiling characterizes candidate biomarkers of perimesencephalic non-aneurysmal subarachnoid hemorrhage.

OBJECT: This study aims to explore the plasma proteomic profiles of angiographically confirmed pmSAH and aSAH, and to identify candidate protein biomarkers for discriminating these subtypes on a biological level. METHODS: The differentially abundant proteins of plasma samples from patients with pmSAH (n = 30) and aSAH (n = 30) were analyzed by data-independent acquisition proteomics, and candidate biomarkers were screened. RESULTS: 291 candidate biomarkers were obtained that could be used to distinguish pmSAH patients from aSAH patients, among which 76 were upregulated and 215 were downregulated in pmSAH. Subsequently, the 10 candidate biomarkers were validated by enzyme-linked immunosorbent assay in a validation cohort of 72 subjects. ORM1, ORM2, HP and NMNAT1 were specifically down-regulated in the pmSAH group, while ANP32A was specifically up-regulated in the pmSAH group. FGL2 was specifically up-regulated in the aSAH group. The combined model of ORM2, HP and ANP32A had the best discriminative power (AUC = 0.880). CONCLUSIONS: This study identified ORM2, HP, and ANP32A as candidate biomarkers reflecting biological differences between pmSAH and aSAH. SIGNIFICANCE: Although some proteomic studies have analyzed aneurysmal subarachnoid hemorrhage, to date, there have been no reports on the circulating proteomic analysis of pmSAH. Comparative analysis of the circulating proteomic differences between pmSAH and aSAH may not only help understand the causes of pmSAH, but also contribute to a deeper understanding of mechanisms showing how pmSAH differs from the formation and rupture mechanisms of intracranial aneurysms.

Humans

Modelling peak microbial pollution events caused by combined sewer overflows in a source-to-sea system.

Predicting peak microbial pollution events in downstream coastal bathing waters caused by combined sewer overflows (CSOs) is essential for protecting public health. In urban areas, wastewater effluents, CSOs, and surface runoff can contribute to elevated microorganism loads to downstream waters. These pressures are likely to be intensified by growing population density and more frequent heavy rainfalls due to climate change. This study developed a process-based model to simulate Escherichia coli (E. coli) emissions, transport, and fate from the initial sources to coastal beaches. A three-year retrospective simulation (2017-2019) shows that E. coli concentrations in CSO discharges varied widely across the catchment (4.6 - 7.3 (log10 CFU 100 ml-1)). 99th percentile E. coli concentrations (4.0 (log10 CFU 100 ml-1)) at the inland water outlet were dominated by local CSO emissions, whereas 90th percentile E. coli concentrations (3.6 (log10 CFU 100 ml-1)) reflected cumulative upstream contributions from both CSO and effluent emissions. With the simulation accuracy of 89%, the model reliably reproduced the E. coli dynamics on the downstream beach and showed strong performance in representing peak concentrations based on Complementary Cumulative Distribution Function (CCDF) analysis. The process-based model enables quantitative tracking of source contributions and identification of pollution hotspots, providing support for mitigation measures. The study lays down a source-to-sea modelling framework for representing pollution transport across the aquatic continuum and provides a transferable tool for microbial pollution forecasting and climate adaptation planning.

Climate projection

Efficacy of current approaches to non-invasive diagnosis of skin cancer and the potential impact of artificial intelligence: A systematic review and meta-analysis.

BACKGROUND: Skin cancer is one of the most prevalent malignancies worldwide, particularly within Caucasian populations. This systematic review and meta-analysis aimed to quantitatively review the current literature on non-invasive diagnosis of skin cancer and evaluate the current evidence to support the use of tools in addition to, or in replacement of clinician face-to-face assessment. METHODS: A literature search was conducted for publications in PubMed, Medline and Embase databases. Articles describing accuracy, sensitivity, specificity and outcomes of their mode of assessment were included. A total of 208 articles met the inclusion criteria. RESULTS AND CONCLUSION: This systematic review and meta-analysis showed that the diagnostic performance of artificial intelligence (AI) in the interpretation of dermatoscopic images was high for melanoma diagnosis, basal cell carcinoma or malignancy, in comparison to dermatoscopic assessment alone by clinicians and experts. Although AI interpretation of images demonstrated higher sensitivity for melanoma diagnosis in comparison to clinical assessment combined with dermatoscopic assessment, it is unclear if this is also the case for basal cell carcinoma and squamous cell carcinoma diagnosis. Reflectance confocal microscopy, a non-invasive high resolution imaging technique, is known to have a high sensitivity for diagnosing cutaneous malignancy, and this may have applications within secondary care. Therefore, AI could help reduce resource burden and aid in clinical assessment, particularly within primary care settings.

Humans

Neurocorrelates of nocturnal enuresis in pre-adolescent children.

INTRODUCTION: Nocturnal enuresis (NE) is a common neurodevelopmental condition, yet its underlying neural mechanisms remain unclear. This study leverages the large-scale Adolescent Brain Cognitive Development (ABCD) dataset to identify structural and functional brain correlates associated with active symptoms and the resolution of bedwetting. METHODS: Using cross-sectional data from 3472 participants aged 9-10 years, children were categorized into three groups: active nocturnal enuresis (ANE, n = 225), history of nocturnal enuresis (HNE, n = 1171), and healthy control groups (CG, n = 2076). Multimodal neuroimaging protocol evaluated macrostructural properties via structural MRI (sMRI), microstructural white matter integrity via diffusion MRI (dMRI), and functional connectivity via resting-state fMRI (fMRI). Group differences were evaluated using linear models within an ANCOVA framework, adjusting for intracranial volume and handedness with False Discovery Rate (FDR) correction. RESULTS: Compared to controls, the ANE group exhibited a significant volume deficit in the right caudate, decreased sulcal depth in the left insula, and lower internal correlation within the Cingulo-Opercular Network (CON). Conversely, the dry HNE group demonstrated significant structural adaptations, including bilaterally larger putamen volumes and increased right caudate volume compared to the ANE group. The HNE group also showed increased microstructural density (decreased mean diffusivity) in the bilateral hippocampus and an increased cortical surface area in the left insula. Both NE groups demonstrated persistently reduced functional coupling within the CON. CONCLUSIONS: Nocturnal enuresis appears to be associated with a potential complex central signaling deficits. Reduced internal correlation within the CON across both active and former bedwetters indicates a potential for impairment in processing internal homeostatic bladder signals during sleep.

Humans

Plasma proteomics: considerations for preanalytical variability; a systematic review with narrative synthesis.

BACKGROUND: The plasma proteome (PP) is a dynamic system subject to pathology-associated changes and a focus for novel disease biomarker discovery. Disease-related PP research assumes protein concentrations in test specimens accurately reflect the in vivo milieu. However, measures to maintain the physicochemical integrity of the proteome before assay are often rudimentary, poorly described, or lacking standardisation in published studies. Contrastingly, in laboratory medicine, there is an expectation that errors in the so-called "preanalytical phase" (PAP) that impact patient results are understood, monitored, and mitigated against, while also being well described in research publications. There is therefore scope for good practice from laboratory medicine to inform PP research workflows. This review considers factors in the PAP which may impact the validity of PP results. CONTENT: A systematic review was conducted per PRISMA guidelines, limited to English-language peer-reviewed studies (2014-2024). Candidate studies were imported, screened, and managed using Covidence systematic review software. SUMMARY: 15 eligible studies were reviewed, covering many relevant processes. 11 studies reported statistically significant differences in PP due to factors in the PAP. Temperature and time-to-processing were the most commonly reported factors affecting the PP, with significant effects reported in 8 studies. OUTLOOK: PAP variability can significantly affect results in PP studies. Careful consideration of the effect of each stage of the PAP is needed when working with the PP. In multicenter studies, pre-defined and research question-specific sample processing workflows are essential for reducing PAP variability, which helps ensure the validity of PP studies.

Humans

ChIP-seq profiling identifies diapause-regulated H3K27me3 targets in the fat body of Culex pipiens.

Culex pipiens, a principal vector of significant arboviruses, survives winter through diapause, a hormonally controlled inactive phase that enhances endurance under severe cold circumstances. Recent data suggests that epigenetic processes, namely histone post-translational modifications (hPTMs), play a crucial role in regulating seasonal dormancy. Prior studies from our laboratory indicated a decrease in the methylation of Histone 3 (H3K27me3) in diapausing fat body tissue, associated with elevated expression of the histone demethylase UTX. Nonetheless, the precise genomic areas impacted by these chromatin alterations remained unidentified. We used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) to delineate the genome-wide distribution of H3K27me3 across fat body chromatin in diapausing (D) and non-diapausing (ND) female Cx. pipiens. Notably, the higher signal at transcription start sites (TSSs) reflects localized redistribution rather than a global decrease, as diapausing fat bodies retain less H3K27me3 overall but concentrate it at promoters. To investigate the functional significance of these chromatin alterations, we confirmed a number of target loci via ChIP-qPCR and assessed gene expression with qRT-PCR. We identified many critical genes that were markedly increased in diapausing mosquitoes, exhibiting an inverse relation to H3K27me3 enrichment. Our data demonstrates different H3K27me3 chromatin landscapes between diapausing and non-diapausing Cx. pipiens, corroborating a hypothesis of selective, locus-specific repression in the non-diapause state and its targeted removal during diapause to permit activation of dormancy-associated genes. These results suggest that chromatin remodeling is a core driver of the diapause switch.

Animals

Examining early-phase symptom trajectories in interpersonal psychotherapy versus antidepressant medication for adults with depression: A dynamic time warp network analysis.

BACKGROUND: Depression is characterized by substantial symptom heterogeneity, which is often concealed when examining total severity scores. Analyzing symptom-level change can improve our understanding of treatment effects and recovery processes. This study, therefore, examined dynamic symptom networks during early-phase interpersonal psychotherapy (IPT) and selective serotonin reuptake inhibitor (SSRI) antidepressant treatment, assessing patterns of symptom change across as well as differences between treatments. METHODS: Using weekly item-level Hamilton Depression Rating Scale (HAM-D) data from a randomized clinical trial comparing IPT and SSRIs for adults with depression, this preregistered study examined symptom trajectories in the first six weeks of treatment with Dynamic Time Warping (DTW). RESULTS: Depressive symptom trajectories and DTW-based symptom networks were largely similar for IPT and SSRI. In both conditions, changes in somatic symptoms of anxiety and middle insomnia tended to precede improvements in depressed mood. CONCLUSIONS: Early symptom change may occur outside the core affective domain, underscoring the importance of monitoring symptoms broadly. Symptom-level patterns may reflect patients' stage of recovery and provide clinically relevant information beyond total severity scores. The absence of differences in improvement patterns between IPT and SSRI suggest few indications for treatment selection based on baseline symptom profiles. Future research should replicate and extend these findings to subsequent treatment phases using more frequent assessments and a broader range of interventions.

Humans

Depression and amyloid-β across CSF, PET, and plasma biomarkers: a systematic review and meta-analysis.

Alzheimer's disease is increasingly defined by biomarker evidence of amyloid-β and tau pathology, sharpening questions about whether late-life depression contributes to, or instead reflects, this pathology. We conducted a systematic review and meta-analysis of studies published between 2000 and 2025 that compared amyloid-β biomarkers in adults with and without depression, with depression defined by validated clinical diagnoses or symptom rating scales. Twenty-four studies were included, spanning three biomarker sources: cerebrospinal fluid, positron emission tomography imaging, and plasma. Across all sources, the pooled difference in amyloid-β burden between depressed and non-depressed individuals was small and clustered near zero, indicating only a weak, statistically non-significant tendency toward higher amyloid in depression. When the three sources were examined separately, each yielded a similar near-null result, although between-study heterogeneity was considerable for cerebrospinal fluid and plasma and moderate for imaging. Importantly, a prespecified subgroup analysis showed that imaging results diverged by quantification method: studies using the simpler standardized uptake value ratio clustered around zero, whereas the smaller group of studies using kinetic distribution volume ratio modelling showed a significant positive association, suggesting that methodological choices critically influence the observed relationship. Taken together, these findings indicate that depression is not consistently accompanied by greater amyloid-β burden across widely used biomarker platforms. The distribution volume ratio signal nonetheless raises the possibility of subtle associations that cruder methods may obscure, and suggests that depression may shape Alzheimer's disease trajectories more by modifying the clinical impact of amyloid than by altering its amount.

Humans

Temporal redistribution of control reveals age-related differences in task switching at the level of preparation.

Task-switching studies often report minimal age-related differences in switch costs, leading to the conclusion that switching-related control processes are relatively preserved in aging. However, this conclusion is based on paradigms that confound preparatory and execution processes. This study examined whether age-related differences in semantic task-set reconfiguration may be underestimated due to this confound. In Experiment 1 (36 young and 30 older adults), participants performed an externally paced task-switching paradigm without control over preparation. In Experiment 2 (28 young and 28 older adults), a self-paced paradigm allowed participants to initiate stimulus onset, enabling measurement of preparation time. Across both experiments, reaction time (RT) and error rate (ER) showed reliable age effects but no interactions between age and condition, whereas switching-related condition effects varied across measures and experiments. The expression of switching-related costs differed across measures and task structures. Local switch costs were expressed in ER in Experiment 1 but in RT in Experiment 2. Global switch costs (all-switch vs. all-repeat) were observed in execution measures only in Experiment 1. In Experiment 2, preparation time showed reliable mixing, local, and global switching effects, with age-related amplification emerging specifically for global switching. These findings indicate that switching-related costs are redistributed across processing stages and behavioral measures. The results suggest that age-related modulation of semantic task-set reconfiguration may emerge more clearly during preparation than task execution, particularly under continuous switching demands. Preparation time is interpreted cautiously as reflecting participant-regulated preparatory processes rather than a pure measure of preparation efficiency.

Humans

From bioactive compounds to volatile profiles: a multidimensional characterization of Indonesian stingless bee honeys.

BACKGROUND: Stingless bee honeys are drawing increasing attention as ingredients for functional foods and health-oriented products because of their distinctive sensory characteristics and bioactive potential. In this study, honeys collected from nine stingless bee species reared in West Sumatra, Indonesia, were comprehensively characterized using physicochemical indices, antioxidant assays [DPPH (i.e. 2,2-diphenyl-1-picrylhydrazyl) and ferric reducing antioxidant power], microbiological screening, volatile profiling [gas chromatography-mass spectrometry (GC-MS)] and Fourier transform infrared (FTIR) fingerprinting. RESULTS: Marked between-sample variability was observed across key quality attributes, including pH (2.80-3.68), Brix (49.83-61.25), viscosity (23.36-175.22 cP) and color parameters. FTIR spectra were consistent with carbohydrate-rich matrices and exhibited carbonyl-related bands. GC-MS profiling identified linalool oxide isomers and junenol among the predominant volatiles. To the best of our knowledge, junenol has not previously been reported in stingless bee honey and may represent a potential regional chemical marker for Indonesian stingless bee honeys. Lactic acid bacteria were detected in selected samples, whereas yeast and mold were not detected. Antioxidant activities were comparatively low, which may reflect local environmental and ecosystem-related factors. CONCLUSION: The results provide a multi-parameter baseline for stingless bee honeys produced within a shared ecosystem in West Sumatra and demonstrate the value of integrating conventional chemical indices with FTIR and volatile fingerprints for quality assessment. This combined approach may also support future authentication and origin-tracing frameworks for Indonesian stingless bee honeys. © 2026 Society of Chemical Industry.

Animals

Lower androgen sulfate metabolites in women with hypermobile Ehlers-Danlos syndrome may be associated with changed metabolism and disposition.

Hypermobile Ehlers-Danlos Syndrome (hEDS), characterized by joint hypermobility and multisystem involvement, is the most common type of EDS. Its comorbidities are wide-ranging, reflecting the involvement of connective tissue and its role in a multitude of processes. hEDS has been hypothesized to have hormonal aspects since the disorder is diagnosed more often in women and symptom changes closely correlate with hormonal shifts. To better understand the etiology and biochemical changes in hEDS and its comorbidities, a multiple-omics study was performed in women, controls (n = 45) and those with hEDS (n = 45), alongside the collection of questionnaires related to symptom severity. Metabolomic evaluation was performed on serum samples and RNA isolated from fibroblasts cultured from skin punches was analyzed for transcriptomics. Samples from hEDS patients had statistically significantly lower levels of multiple androgen sulfate metabolites, compared with controls, driven largely by participants aged 30-49. Changes to other classes of steroid hormones (corticosteroids, progestogens, and estrogens) were largely not significant between hEDS and control groups. Transcriptomics of skin fibroblasts from hEDS patients revealed downregulation of multiple enzymes involved in biosynthesis, metabolism, and disposition of androgens, compared with controls. Multiple steroid hormones correlated with symptoms surveyed in 18-29 year old participants with hEDS. Shifts in steroid hormone metabolites in hEDS compared with controls may be due to changes to metabolism and disposition, but more validation is necessary to be conclusive. This data provides insights into the unclear links between steroid hormones and hEDS and its comorbidities.

Humans

Uncovering molecular regulatory networks of low-temperature stress response in Trachinotus ovatus via integrated transcriptome and metabolome analyses.

Golden pompano (Trachinotus ovatus) is one of the most economically important marine fish species in China. It is susceptible to low-temperature stress, which significantly challenges its production and supply. Nevertheless, study on the regulatory mechanisms underlying low-temperature stress responses in golden pompano remains limited. Here, we firstly performed a time-series transcriptome analysis to reconstruct dynamic response patterns under low-temperature stress in golden pompano. Transcriptome profiling identified common differentially expressed genes (DEGs), including fos, hlf, and hmgb1, as well as condition-specific DEGs across distinct low-temperature stress groups. Based on cluster analysis, all DEGs were classified into five distinct expression patterns, reflecting diversified regulation of expression in golden pompano during low-temperature stress. Furthermore, condition-specific regulatory modules were explored via weighted gene co-expression network analysis (WGCNA), highlighting that the two module hub genes, serbf2 and lipc, might respond to low-temperature stress by regulating the lipid catabolic process. Subsequently, untargeted metabolomic analysis revealed that glycerophospholipid metabolism was a significantly enriched common pathway, highlighting its crucial role in mediating the response to low-temperature stress. Finally, by integrating transcriptomic and metabolomic analyses, a gene-metabolite interaction network associated with glycerophospholipid metabolism under low-temperature stress was established. These findings underscore the significance of multiple candidate genes and glycerophospholipid metabolism in golden pompano's response to low-temperature stress, thereby laying a solid molecular foundation for the development of low-temperature-tolerant fish strains.

Animals

Mindfulness and Sex Education for Sexual Dysfunction in Breast Cancer Survivors: Mediators and Moderators of Treatment Outcome.

Mindfulness-based cognitive therapy (MBCT) and supportive-expressive sex education therapy (STEP) are effective group treatments for sexual dysfunction after breast cancer (BrCa). We explored mediators and moderators of outcomes following the 8-week groups. BrCa survivors (n = 116, mean age = 49.9 ± 9.5) were randomized to group and completed measures before, immediately after, and 6 months after treatment. Mediators assessed were changes in depression, chronic pain acceptance, pain catastrophizing, and trait mindfulness. Potential moderators included age, treatment expectations, baseline mental health, cancer treatment duration, use of chemotherapy, and adjuvant endocrine therapy. Longitudinal mediation and moderation were assessed using linear mixed models. Increases in pain acceptance mediated improvements in sexual desire and reductions in both sexual distress and vaginal pain. Decreases in pain catastrophizing mediated improvements in sexual distress. Higher expectations for treatment led to greater reductions in sexual distress. Those with low baseline anxiety showed greater improvements in desire and distress. Low baseline depression predicted greater improvements in desire, but only in the STEP arm. Older STEP participants improved significantly more than younger STEP participants. Cancer-related treatment variables, and the impact of adjuvant endocrine therapy, had differential effects on outcomes based on the treatment arm of the study. In conclusion, treatments aimed at improving pain acceptance and pain catastrophizing are likely to promote improvements in sexual health among BrCa survivors, and factoring in patients' expectations about treatment improvements, depression and anxiety, age, duration of cancer treatment, chemotherapy, and adjuvant hormonal therapy may help to guide treatment recommendations for sexual dysfunction.

Humans

A machine learning-derived and functionally validated circadian rhythm signature predicts clinical outcomes and in silico drug sensitivity in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) displays considerable heterogeneity in clinical outcomes, highlighting the need for reliable prognostic biomarkers. While the aberrant expression of circadian rhythm-related genes has been implicated in cancer pathogenesis, its comprehensive role in CRC progression and predicted therapeutic vulnerabilities remains inadequately characterized. METHODS: Bulk and single-cell RNA-sequencing data were integrated from multiple CRC cohorts. A circadian rhythm signature (CRS) was developed through machine learning algorithms and validated for prognostic value. Comprehensive analyses of tumor microenvironment, genomic alterations, and drug sensitivity were performed. Furthermore, the biological function of the core gene, BHLHE40, was validated in CRC cell lines through CCK-8, EdU, and wound healing assays. RESULTS: Single-cell analysis demonstrated an elevated expression signature of circadian rhythm-related genes in dendritic cells. The optimized CRS, comprising 14 circadian rhythm-related genes, successfully categorized patients into high- and low-risk groups. Patients with a high CRS showed markedly poorer overall survival and computationally inferred immunosuppressive features, including reduced CD8+ T cell infiltration and increased M2 macrophage polarization. Genomic analysis revealed enhanced mutation burden in TP53 and alterations in RTK-RAS/WNT pathways. Notably, in vitro assays confirmed that BHLHE40 is significantly overexpressed in CRC cells. Knockdown of BHLHE40 markedly inhibited tumor cell proliferation and migration. Drug sensitivity profiling identified bexarotene and SMER-3 as potential therapeutic options for high-CRS patients. A nomogram integrating CRS with clinical parameters demonstrated superior predictive accuracy for 1-, 3-, and 5-year survival. CONCLUSIONS: The CRS represents a promising prognostic biomarker that reflects tumor immune status and genomic features, providing valuable insights for personalized treatment strategies in CRC.

Circadian rhythm