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Matt is an unusually talented scholar, with seminal contributions in many areas (cognitive ability, environmental influences, substance use, etc.). One key theme that undergirds and unites his work is his development of novel research designs and experiments of nature capable of estimating causal inferences with unusual precision. In this contribution to his Festshrift, I illuminate key models and experiments developed by Matt and their contributions to the field. In lieu of new empirical data, I also present a new idiographic behavioral genetic research design - to be called 'narrative non-shared environmental identification' - in which we leverage idiographic, person-specific measurement tools to meaningfully study the effective non-shared environment for the first time.
Accurate measurement is essential for tracking changes in clinical outcomes. Individuals with Smith-Magenis syndrome (SMS) exhibit challenging and unique food-related behaviors. We sought to determine the best tool to capture their unique food-related behaviors. We conducted focus groups with caregivers of individuals with SMS to evaluate two commonly used questionnaires for food-related behaviors- the Food Related Problems Questionnaire (FRPQ) and the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Based on caregiver input and clinical expertise, we adapted these existing measures into a new tool: the SMS-FRPQ. We then validated this instrument for internal consistency and concurrent validity using online responses from 125 caregivers. Caregivers (n = 24) indicated neither the FRPQ or HQ-CT fully captured their child's food-related behaviors; however, the newly developed SMS-FRPQ was deemed comprehensive by a new group of caregivers (n = 19). The SMS-FRPQ demonstrated strong internal consistency, with a Cronbach's alpha of α = 0.87 [0.84-0.90]. Factor analysis indicated a three-factor model was a good fit (comparative fit index (CFI) = 0.9, Tucker-Lewis index (TLI) = 0.88). The three factors each showed good internal consistency: Desire for Food, α = 0.80 [0.74-0.85]; Takes Food, α = 0.87 [0.83-0.90]; Satiety Impairment, α = 0.83 [0.77-0.87]. The SMS-FRPQ showed higher internal reliability than the FRPQ. Concurrent validity was supported through alignment with similar items from the HQ-CT or Behavioral Problems Inventory (BPI-01). The SMS-FRPQ has 14 items across 3 different factors and 5 additional clinically relevant items. This validated tool may be useful for tracking food-related behavior outcomes in clinical trials for this high-risk population. The online version contains supplementary material available at 10.1007/s44162-026-00193-3.
Ovarian cancer (OC) exhibits significant ethnic and geographic disparities, with rising incidence in Asia contrasting global declines. While non-modifiable risk factors (e.g., genetics) are well-established, evidence for the role of modifiable factors like physical activity remains inconsistent, especially in Asian populations. This study systematically evaluates the association between physical activity, sedentary behavior, and OC risk in Asia. We conducted a meta-analysis of seven studies (156,910 participants, 1,585 OC cases) from Japan, Korea, and China. Physical activity and sedentary behavior were assessed via self-reports. Meta-analysis was performed to pool RR estimates together with their 95% CI. Regular physical activity was associated with a 24% lower OC risk (RR = 0.76, 95% CI: 0.64-0.91; P = 0.002), despite high heterogeneity (I2 = 75%). Sedentary behaviour was associated with a 55% higher OC risk (RR = 1.55, 95% CI: 1.23-1.96; P = 0.0002). In Asian populations, physical activity may protect against OC, while sedentary behavior may elevate risk. These findings underscore the need for dual public health strategies: promoting exercise and reducing sedentary time. Future research should standardize exposure assessments and include diverse Asian subpopulations to refine prevention guidelines.
Many cells require cilia to receive environmental signals. Mutations in the ciliary gene fam149b1 result in the ciliopathy Joubert syndrome. The C. elegans homolog of fam149b1 , xbx-4 , is required for normal cilium structure. We found that loss of XBX-4 hinders multiple cilium-mediated behaviors. xbx-4 mutants display mild defects in male mating and nose touch behaviors and dramatic changes in social feeding. Unexpectedly, xbx-4 mutants increased reversal behavior in response to ethanol, a control stimulus used in olfactory assays. Variation in the magnitude of phenotypes for different neurons is consistent with known cell-specific impacts of XBX-4 loss on cilium structure.
Aedes aegypti is widely distributed in the tropics and sub-tropics and is a major vector of several arboviruses, such as dengue and chikungunya viruses. Mapping the behavioral and genetic divergence among the mosquito populations can enhance our understanding of spatiotemporal variation in disease transmission. Cross-sectional surveys were carried out between 2022 and 2023 to investigate egg-laying abundance in ovitraps as well as adult abundance in BG Sentinel traps baited with carbon dioxide. Both trap types were deployed in outdoor environments in two peri-urban areas in the Rift Valley and coastal regions of Kenya. A subset of the adult specimens was screened for arbovirus infections, and the mitochondrial cox-1 gene was analyzed to estimate genetic differences between the populations. Engorged specimens were also typed to determine host feeding sources. Aedes egg density was significantly higher in Marigat in the Rift Valley than in Ukunda at the coast (p = 0.006), despite recording a lower ovitrap positivity rate. By contrast, adult female abundance was twofold greater in Ukunda than in Marigat (p < 0.0001). A higher human blood feeding rate (HBI = 0.68) in Ukunda compared to Marigat (HBI = 0.29) correlated with higher proportional abundance of the domestic than of the forest Ae. aegypti ecotype. Haplotype network analysis revealed a high mitochondrial diversity dominated by population-specific haplotypes. Limited haplotype sharing between Ukunda and Marigat populations suggests a restricted maternal gene flow and localized population structuring. While all the samples tested negative for pathogenic arboviruses, insect-specific viruses (ISVs) in the families Flaviviridae (Cell fusing agent virus and uncharacterized flavivirus-like sequences (Flaviviridae sp.)) and Phenuiviridae (Phasi Charoen-like virus) were detected, which varied between the two ecological environments. We observed geographic differences in egg and adult capture rates of Ae. aegypti, which correlate poorly, providing valuable information for Aedes surveillance and control. Heterogeneity in entomological, genetic and virological factors likely shapes geographic differences in dengue occurrence and spread.
During pregnancy, estrogen levels rise dramatically, but quickly drop to prepartum levels following birth and remain suppressed until ovulation resumes. This "postpartum estrogen withdrawal" state has been linked to changes in the brain and behavior in humans and rodents. Previous research has demonstrated that following a hormone-simulated pseudopregnancy (HSP), an experimental model of postpartum estrogen withdrawal, female mice show increased anxiety-like behaviors and decreased social motivation. Further, these behavioral changes occur concurrently with an increase in ∆FOSB, a transcription factor associated with stable long-term plasticity, in the nucleus accumbens core. To test whether this increase in ∆FOSB is required for these behavioral changes, we used a viral-mediated gene transfer approach to prevent ∆FOSB-mediated transcription in the NAcC during HSP and found that it reduced the high-anxiety behavioral phenotype in estrogen-withdrawn females. However, preventing ∆FOSB-mediated transcription had little effect on social motivation. Together, these results suggest that postpartum estrogen withdrawal increases ∆FOSB in the NAc core to impact anxiety-like behaviors but not social motivation following estrogen withdrawal.
Background/Objectives: Elevated central adiposity (ECA) in childhood is associated with early cardiometabolic risk and hemodynamic alterations. However, evidence in Spanish schoolchildren regarding the relationship between eating behavior traits and central adiposity is limited, particularly across developmental stages. This study aimed to examine the association between Children's Eating Behaviour Questionnaire (CEBQ) subscales and ECA, and to explore potential differences by age group. Methods: A cross-sectional study was conducted in 496 rural schoolchildren aged 6-15 years. ECA was defined using the waist-to-height ratio (WHtR) and sex-specific cut-offs validated for the Spanish pediatric population. Eating behavior was assessed with the CEBQ (Z-scores), and diet quality was measured using the KIDMED index. Multivariable logistic regression models were adjusted for sex, KIDMED score, and maternal education. Analyses were subsequently stratified by age (6-9 and 10-15 years). Results: The prevalence of ECA was 45.90%. In fully adjusted models, higher Food Responsiveness (FR) was associated with increased odds of ECA, while Satiety Responsiveness (SR) acted as a protective factor; sex also showed an independent association. After stratification, sex remained the only significant predictor in children aged 6-9 years. Among those aged 10-15 years, FR was significantly associated with ECA (p = 0.008), while Slowness in Eating (SE) showed a borderline positive association in the adjusted model (p = 0.049) and was therefore interpreted cautiously. SR and Emotional Undereating (EU) showed protective trends near significance (p = 0.081 and p = 0.082, respectively). Conclusions: The association between eating behavior traits and ECA varies by age. In older children, FR showed a robust association with ECA, whereas no behavioral predictors were observed in younger children. The protective role of SR in the global model and the emergence of behavioral predictors in older participants highlight the importance of targeted interventions during late childhood.
Although dietary intake is a leading risk factor for many common diseases, adherence to dietary recommendations remains low. This may partly reflect limited consideration of individual differences in eating behavior that arise from both environmental and genetic factors. While genome-wide association studies (GWAS) of dietary intake have identified hundreds of associated loci, the X chromosome has largely been ignored. To address this gap, we applied multiple X-chromosome-wide association study (X-WAS) models on dietary intake phenotypes to identify novel associations. We performed X-WAS of 46 dietary intake traits from food frequency questionnaires in up to 424,758 European participants from the UK Biobank. Phenotypes included quantitative measures (e.g., fruit intake), binary traits (e.g., decaffeinated vs caffeinated coffee), and principal component-derived food groups. We tested for genetic associations using several models: a traditional sex-combined additive GWAS, additive models stratified by sex, and two joint models accounting for sex-interaction effects and non-additivity. We also conducted X-WAS in five additional genetic ancestry groups and performed a sex-combined multi-ancestry additive GWAS meta-analysis with up to 445,773 individuals. We identified 18 loci associated with 20 dietary intake traits ( P < 5×10 -8 ), including 17 variants without prior associations in the GWAS Catalog. Among these loci, 10 were significant across multiple X-WAS models, and 5 were strongest in a model other than the traditional sex-combined additive GWAS, highlighting the value of approaches that address known complexities of the X chromosome. These results demonstrate that incorporating the X chromosome in GWAS can reveal novel loci, even for complex behavioral traits such as dietary intake. Applying multiple association models further improves discovery by accounting for unique features of the X chromosome. Although diet is a major risk factor for many common diseases, adherence to healthy eating guidelines remains low. One reason is that current recommendations do not account for individual differences in food choice that arise from environmental or genetic factors. Previous genetic studies have identified hundreds of genetic variants associated with dietary behaviors, but most have excluded the X chromosome due to its analytical complexity and differences between males and females. However, accumulating evidence suggests that the X chromosome contains important genetic variation that impacts complex traits.We analyzed data from hundreds of thousands of individuals to identify genetic variants on the X chromosome associated with dietary intake. To address the unique features of the X chromosome, we applied multiple different models that account for sex-differences and non-additive genetic effects. We identified 18 regions in the genome associated with at least one dietary intake trait. These results reveal new insights into the genetics underlying eating behavior and highlight the importance of incorporating the X chromosome in genetic studies of complex traits.
Lifestyle behaviors such as smoking, vaping, and physical activity can induce epigenetic modifications that influence health trajectories and may provide forensic value. DNA methylation signatures linked to these behaviors offer potential for behavioral inference, personalized health assessment, and improved investigative practices. This study aimed to characterize methylation patterns associated with nicotine exposure and exercise using buccal cell DNA profiling, and to evaluate the extent to which these patterns differentiate harmful and protective lifestyle habits. Buccal epithelial DNA was analyzed using the Illumina Infinium MethylationEPIC v2 BeadChip to assess genome-wide methylation. Participants were categorized by smoking status, vaping behavior, and exercise activity. Differentially methylated regions (DMRs) and CpG sites were identified through pairwise comparisons among smokers, vapers, non-smokers/non-vapers, athletes, and sedentary individuals. A threshold of p < 1 × 10-4 was applied for significant differentially methylated CpG sites. Distinct epigenetic profiles were associated with smoking/vaping and physical activity. Five DMRs differentiated smokers from non-smokers/non vapers, while 11 DMRs distinguished vapers from the same reference group. Twenty-eight DMRs displayed divergent methylation patterns between smokers and vapers. Exercise also showed measurable epigenetic influence: control athletes exhibited 26 significantly differentially methylated CpG sites relative to non-athletes, and smoker athletes demonstrated 126 suggestive differential sites compared to sedentary smokers. Additionally, 63 sites differentiated smoker athletes from non-smoker/non-vaper non-athletes, indicating interactions between risk-associated and health-promoting behaviors. Buccal cell DNA methylation profiling effectively captured signatures associated with smoking, vaping, and physical activity. These findings underscore the potential of epigenetic markers for lifestyle assessment in both personalized medicine and forensic investigations.
Mitochondria are central to neuronal bioenergetics, supporting the high metabolic demands required for synaptic signaling and network activity. Yet how neurons adapt their activity to rapid fluctuations in energy supply-and how such adaptations shape behavior-remains poorly understood. We previously showed that acute pharmacological manipulation of mitochondrial complex activity in the nucleus accumbens (NAc) affects motivated behaviors, which led us to hypothesize that medium spiny neurons (MSNs) can rapidly adjust their output in response to bioenergetic levels. To test this hypothesis, we examined how acute mitochondrial inhibition alters MSN function using mouse brain slices. Inhibition of mitochondrial complex I with the selective inhibitor rotenone reduced MSN intrinsic excitability, an effect that was counteracted by intracellular ATP replenishment. We next asked whether ATP-sensitive potassium (K-ATP) channels, canonical regulators of membrane excitability under metabolic stress, contribute to these responses. Histological analyses revealed specific expression of Kir6.2 subunits in both D1- and D2-MSNs, as compared to non-MSNs, and electrophysiological recordings showed that K-ATP channel activation blockade prevented rotenone-induced reductions in MSN excitability. In behavioral assays, complex I inhibition impaired effort-related performance, an effect that was rescued by K-ATP channel blockade. These findings identify K-ATP channels in MSNs as key mediators that sense acute changes in neuronal energy state and translate them into rapid adjustments in NAc excitability and behavior.
To design novel heart valve bioprostheses, it is extremely important to predict leaflet failure and fatigue for 10-20 years, as the aortic valve opens and closes approximately 40 million times per year. Most studies devoted to aortic valve leaflets mechanical tests employ uniaxial or biaxial tests, which do not fully and explicitly describe the time-dependent biomechanical behavior of this tissue. The aim of this study was to evaluate the viscoelastic response of porcine pericardium using biaxial tensile tests. Biaxial creep tests were performed on a biaxial test machine to evaluate the circumferential and axial behavior of the porcine pericardium under creep testing, and biaxial stress relaxation was used to complement creep. The results showed that the creep behavior was the same in both directions after 1 s, 60 s, 300 s, 900 s, and 1800 s. After 30 min of creep, deformation in the circumferential and radial directions was 3303 × 10-6 and 5192.9 × 10-6, respectively. Stress relaxation tests showed the same behavior as creep. At stress relaxation test after 30 min, the pericardium deformation in the circumferential and radial directions was 15.28 kPa and 9.6 kPa, respectively. The Prony series with Levenberg-Marquardt as the optimizer was used to obtain material parameters to use for finite element analysis. The data obtained during such tests can be employed in numerical FSI simulations of novel aortic valve bioprosthesis long-term performance in a patient's body.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive synaptic dysfunction, axonal pathology, and cognitive decline, with the hippocampal circuits showing particular vulnerability during disease progression. However, early-life nutritional interventions may influence long-term synaptic resilience. In this study, we investigated the long-term effects of prenatal and lactational supplementation with choline, UMP, and fish oil in the 5XFAD mouse model. To this end, hippocampal synaptic and axonal pathology was assessed at 3, 6, and 9 months using Western blotting and immunofluorescence to measure synaptophysin, PSD-95, and neurofilament medium chain (NF-M), alongside a multidimensional behavioral battery that evaluated cognitive, affective, motor, and sensory outcomes. Results showed that early-life supplementation did not significantly improve the learning performance decline, increase nociception, or reverse changes in anxiety behavior in transgenic mice. However, it attenuated synaptic decline in transgenic animals by partially preserving synaptophysin and PSD-95 levels and reducing NF-M elevations. These molecular effects were accompanied by selective behavioral modulation, including preserved learning dynamics, altered anxiety-like behavior, and delayed nociceptive hypersensitivity, while late-stage motor impairments remained largely unaffected. Overall, prenatal and lactational supplementation produced modest, age-dependent effects on synaptic markers and partially prevented neurodegenerative progression in the 5XFAD model.
Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.
Biological manipulation via physical stimuli such as light and magnetism has become a central goal in modern biotechnology. Among these modalities, magnetic fields offer unique advantages, including deep tissue penetration and untethered interventions in living systems. An ideal platform for such a magnetogenetic toolkit would be a genetically encodable protein with tunable magnetic features under physiological conditions. However, the development of such tools has been hindered by the lack of robust and stable protein scaffolds with strong intrinsic magnetic properties. Inspired by animal magnetoreception in nature, here, we rationally designed and systematically screened single-chain variants of the magnetoreceptor MagR. Through nine iterative rounds of design and experimental validation, we generated 25 constructs and ultimately identified a stable single-chain-dimer-based-tetramer, SDT-MagR, as the optimal magnetic molecular platform. This engineered protein exhibits exceptional structural stability and state-dependent magnetic behavior, showing ferrimagnetic-like characteristics in the solid state and paramagnetic behavior in solution. With enhanced magnetic susceptibility, purified SDT-MagR can be directly attracted by a magnet in vitro, establishing it as a promising new platform for future biomagnetic manipulation and magnetogenetics applications.
Mutations in SHANK3 are a leading monogenic cause of autism spectrum disorder (ASD), often associated with profound sensory abnormalities. However, the impact of SHANK3 deficiency on olfactory processing and the underlying neural mechanisms remains unclear. Here, we identify a cross-species disruption of olfactory valence perception in individuals with SHANK3 mutations and in Shank3 mutant mice. Patients carrying SHANK3 mutations exhibited impaired valence-oriented sniffing and electroencephalography (EEG) responses, whereas Shank3B-/- mice displayed blunted behavioral responses to both attractive and aversive odors. In mice, these behavioral deficits were associated with attenuated odor-evoked calcium signals and reduced excitatory synaptic transmission in the cortical amygdala (CoA), a key node for olfactory valence processing. Acute CoA-specific Shank3 deletion recapitulated these deficits, whereas targeted restoration of CoA Shank3 expression rescued odor-induced appetitive and aversive behaviors. Our findings reveal a conserved function for SHANK3 in encoding olfactory valence and identify CoA dysfunction as a circuit mechanism in mice.
Background: Chronic unpredictable stress triggers various pathological and metabolic alterations by modulating psychophysiological balance. Valeric acid (VA), a postbiotic material, has been reported to mitigate stress-induced behavioral changes in rodents. Objectives: To investigate the protective effect of valeric acid against chronic unpredictable stress in a rodent model by assessing neuro-physiological alterations along with changes in biochemical parameters to confirm the possible mechanism. Methods: A 14-day chronic unpredictable stress (CUS) model in albino Wistar rats was developed to check the stress-induced changes using forced swim test, tail suspension test and sexual behavior observation. Quantification of IL-6, TNF-α, IL-1β, plasma corticosterone level and oxidative stress parameters were also done. Results: Findings revealed the protective effects of valeric acid against CUS, which reversed the depression caused by a forced swim and tail suspension test in rats. Proinflammatory and oxidative stress markers were significantly (p < 0.05) restored in CUS rats treated with valeric acid as compared with the vehicle control, which was comparable to the standard drug, Panax ginseng. Conclusions: The present study concludes that valeric acid demonstrated significant (p < 0.05) anti-stress effect by modulating both behavioral responses and stress-related biochemical modifications.
Cognitive control develops rapidly during the preschool years, but its multimodal neurophysiological correlates remain incompletely understood. The present study examined age-related differences in neural, facial-expression, and physiological responses during a counteractive motion task in preschool children. Forty-five healthy preschool children were stratified into two age groups (<5 years vs. ≥5 years). During task performance, cerebral hemodynamic responses were recorded using functional near-infrared spectroscopy (fNIRS), while facial expressions and vital signs were simultaneously collected. Group differences were evaluated for behavioral performance, oxygenated haemoglobin (HbO), functional connectivity (FC), facial expressions, and physiological indicators. No significant between-group differences were observed in behavioral performance. However, the younger group showed higher task-related HbO responses in the middle temporal gyrus (MTG), pre-motor and supplementary motor cortex (PM and SMC), and dorsolateral prefrontal cortex (DPC), as well as stronger FC in selected fronto-motor and fronto-somatosensory connections. Significant between-group differences were also observed in specific facial expressions and cardiovascular indicators. Within this narrow age window, similar behavioral performance may be supported by different neural and physiological response patterns. These findings provide preliminary evidence for age-related variation in multimodal neurophysiological processes during a task involving inhibitory demands and broader task-control components in preschool children.
Parkinson's disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology.
Colorectal cancer (CRC) shows consistent sex-related differences in incidence, anatomic distribution, molecular subtype, immune context, and clinical outcome. However, these differences are often discussed through broad parallel themes such as hormones, genetics, or the microbiome, rather than through the biological settings in which sex meaningfully modifies tumor behavior. This review argues that sex is most informative in CRC when treated as a contextual modifier whose relevance emerges only after integrating tumor sidedness, mismatch repair status, oncogenic background, immune ecology, and age at onset. The clearest signals arise from interaction-based contexts, particularly when sex is interpreted together with tumor sidedness and dMMR/MSI-H or BRAF-linked disease states. Current evidence indicates that women are enriched for proximal or right-sided, microsatellite instability-high, mismatch repair-deficient, CpG island methylator phenotype-high, and BRAF-associated CRC, whereas men more often present with distal disease and a higher overall burden. Mechanistic studies further show that sex-related differences extend beyond hormone exposure to include KRAS-STAT4-KDM5D signaling, site-specific immune-checkpoint programs, metabolic phenotypes, epigenetic biomarker variation, and microbiota-hormone crosstalk. These effects are most evident in defined clinical niches, particularly right-sided CRC, mismatch repair-deficient disease, BRAF-mutated metastatic CRC, and early-onset CRC. A sex-aware, subtype-aware, and location-aware framework therefore offers a more clinically useful interpretation of CRC heterogeneity than descriptive male-versus-female comparisons alone.
Achillea fragrantissima (AFG) is known for its medicinal properties, while different Achillea species have shown both beneficial and detrimental impacts on male fertility. This investigation evaluated the effects of AFG oral administration on behavior, steroidogenesis, and immune-related gene expression in Sprague-Dawley male rats. Forty-five mature rats were randomly grouped into: Control, Low-dose group (AFG-L: 500 mg/kg extract), and High-dose group (AFG-H: 1000 mg/kg extract). The AFG extract was orally administered for 30 days. Behavioral, hematological, reproductive, immune, and oxidative stress-related indices were evaluated. The AFG administration at both doses significantly (p < 0.05) modulated the feeding and drinking, hole-board, swimming performance, tube dominance, and modified Y-maze tests outcomes. The AFG-L group displayed significant (p < 0.05) increases in final weight gain, sperm count, motility, and viable sperms %, with significant (p < 0.05) reductions in aberrant and dead sperms %. AFG significantly (p < 0.05) increased phagocytic index (PhI) and phagocytic %. However, erythrogram and leukocyte counts were not significantly altered. The AFG-L group displayed significant (p < 0.05) increases in serum testosterone (TEST), FSH, LH, and Estradiol (E2) hormones. Additionally, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-ɑ) concentrations were significantly decreased (p < 0.05). AFG extract administration significantly improved (p < 0.05) lipid profile, increased the testicular and splenic glutathione peroxidase (GPx), superoxide dismutase (SOD), total antioxidant capacity (TAC) levels, whereas the malondialdehyde (MDA), protein carbonyl (PCO), 8-hydroxy-2-deoxyguanosine (8OH2dG), and testicular lactate dehydrogenase (LDH) levels were significantly reduced (p < 0.05). AFG administration significantly (p < 0.05) upregulated mRNA expression of StAR, CYP11A1, CYP17A1, and HSD17B3 in the testes, as well as CD3, CD4, CD20, and IL-10 in the spleen, but expression levels of CYP19A1 and Caspase-3 in testes, along with CD8 and Caspase-3 in spleen, were significantly (p < 0.05) downregulated. The AFG-L group maintained normal testicular architecture with preserved seminiferous tubules and only mild interstitial edema alongside mild splenic sinusoid dilatation with macrophage infiltration. In contrast, the AFG-H group exhibited significant histopathological alterations, including irregular seminiferous tubules, reduced mature sperm, and increased interstitial edema, while the spleen showed preserved lymphoid follicles with congested vasculature. The findings of the ongoing work demonstrate for the first time that A. fragrantissima extract exerts reproductive and immune-enhancing outcomes in male rats, with the low dose exhibiting greater efficacy than the high dose, indicating a clear dose-dependent response.