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461 papers

Differences in Physical Fitness and Health-Related Variables Between Older Adults With Versus Without Self-Reported Impairments in Activities of Daily Living: A Population-Based Study.

Bergmann M et al. · Jul 1, 2026

Activities of daily living (ADL) are associated with declines in physical fitness and subjective health. However, it remains unclear as to whether ADL impairments are related to specific components of physical fitness and health variables. Therefore, we examined differences between community-dwelling older persons with versus without ADL impairments with regard to various physical fitness components, physical complaints as well as subjective and objective health outcomes. Cross-sectional study among 254 participants aged ≥ 55 years [51% female; 84 with ADL impairments; mean (SD) age 62.1 (6.6) years] enrolled in the population-based "Gesundheit zum Mitmachen" study in Southwestern Germany. ADL, physical complaints and subjective health status were assessed using a self-report questionnaire, physical fitness (cardiorespiratory fitness, strength, gross motor coordination, flexibility, and functional mobility) was assessed using a fitness test battery, and objective health status was derived from health exam performed by a physician. We ran analyses of covariance, adjusted for age, sex, body mass index and education. Participants with ADL impairments had statistically significantly worse subjective (p < 0.001) and objective (p < 0.001) health and reported more physical complaints (p < 0.001) compared to those without ADL impairments. Regarding physical fitness, ADL-impaired participants performed worse in 10 out of 12 variables. The findings provide additional evidence that ADL impairments are related to decreased objective and subjective health and physical fitness in older community-dwelling adults. Future studies employing more comprehensive, preferably objective, ADL assessments and considering cognitive impairments, which may also impact ADL performance, are warranted.

Health Professions

Integrating Functional Consequence Annotation With PAH Allelic Phenotype Values Refines Prediction of Tetrahydrobiopterin Responsiveness.

Himmelreich N et al. · Jul 1, 2026

Tetrahydrobiopterin (BH4; sapropterin) responsiveness in phenylalanine hydroxylase (PAH) deficiency is genotype dependent, yet many patients remain untested. Allelic phenotype values (APV) summarize allele severity, but responsiveness can be heterogeneous within APV strata. We assessed whether integrating functional consequence annotation from Ensembl variant effect predictor (VEP) improves genotype-based prediction of BH4 response. We analyzed 23 640 individuals with biallelic PAH genotypes and BH4 status (RESP, S-RESP, N-RESP, or not tested). Tested individuals were used for model development (responders defined as RESP+S-RESP; nonresponders as N-RESP). APV values were assigned from published APV resources and merged at the variant level. Functional consequence predictors were derived from VEP output and included strict predicted loss-of-function (pLoF) flags, splice-impact scores (SpliceAI maximum delta score), and missense pathogenicity predictions (SIFT and PolyPhen). Genotype predictors were constructed using a milder-versus-severer allele framework, with the milder allele defined as the allele with the higher APV. Models were evaluated using genotype-held-out cross-validation (GroupKFold by genotype). Among 4640 tested individuals, 2044 (44.1%) were BH4 responders. Responder rates were enriched in milder phenotypes and increased monotonically across milder-allele APV bins. In genotype-held-out evaluation, integrating functional consequence predictors with APV improved discrimination modestly overall and more clearly in intermediate APV genotypes. Genotype predicts BH4 responsiveness with high performance under stringent genotype-held-out validation, and VEP-derived functional consequence annotation provides modest complementary value beyond APV, particularly for intermediate-severity genotypes.

Biochemistry, Genetics and Molecular Biology

Pegargiminase Suppresses the Fanconi Anemia Pathway and Promotes Melphalan-Induced DNA Double-Strand Breaks in Uveal Melanoma.

Pavlyk I et al. · Jul 1, 2026

Uveal melanoma is a hard-to-treat arginine-dependent cancer secondary to argininosuccinate synthetase 1 (ASS1) loss with half of patients succumbing to liver-dominant metastases. Arginine deprivation with pegargiminase is a novel antimetabolite strategy for patients with uveal melanoma. We investigated the preclinical rationale for combining pegargiminase with melphalan, an alkylating agent approved recently for the treatment of hepatic-centric disease. Drug sensitivity of ASS1-deficient uveal melanoma cell lines was performed in 2D culture using proliferation and cytotoxicity assays, with analysis of cell death, cell cycle, DNA double-strand breaks, and interrogation of the molecular mechanism of action by RNA-seq. ADI-PEG20 and melphalan suppressed uveal melanoma cell line proliferation and triggered cytotoxicity, effects which were enhanced with the drug combination. ADI-PEG20 downregulated multiple genes of the Fanconi anemia pathway and synergized with melphalan to increase DNA double-strand breaks. Melphalan and pegargiminase is a rational new drug combination that warrants clinical testing in uveal melanoma.

Biochemistry, Genetics and Molecular Biology

A Critical Examination of the Usefulness of Taxonomies for Comparing Cognitive Functions Across Sports.

Will L et al. · Jul 1, 2026

Taxonomies are widely used in sport science to classify disciplines according to structural, cognitive, and physiological demands, yet their robustness in differentiating athletes' cognitive performance remains uncertain. This study examined whether commonly applied sport classification frameworks-open versus closed skills, strategic-static-interceptive, participant classification, and multidimensional team/precision-skill/speed-strength-meaningfully represent cognitive differences within junior and senior national squad athletes. A total of 595 national squad athletes from eight sports (artistic gymnastics, rhythmic gymnastics, trampoline, basketball, volleyball, ice hockey, table tennis, modern pentathlon) completed standardized measures of basic (processing speed, attention) and higher (working memory, inhibition, cognitive flexibility) cognitive functions. Using a model comparison approach, we show that the usefulness of taxonomic contrasts is limited because taxonomy-based models did not improve model fit relative to the null model or the model containing single sport disciplines. For processing speed, single disciplines provided the best fit. Supplementary analyses showed that processing-speed-based norm scores were above population means and moderately related to attention, but only weakly related to working memory and unrelated to executive control measures. Together, these findings suggest that conclusions about cognitive differences among high-performance athletes cannot be reliably made using taxonomic classifications as they lack robustness under realistic sampling conditions. The results underscore the importance of sport-specific and individual-level approaches when investigating cognitive functioning in high-performance sport contexts.

Psychology

Granulosa Cell Tumour in a Spayed Cat With Ovarian Remnant Syndrome and Hyperestrogenaemia Without Estrus Signs.

Shinoda H et al. · Jul 1, 2026

Background Granulosa cell tumour (GCT) is the most common primary ovarian neoplasm in cats and may arise from residual ovarian tissue following incomplete spay procedures. Objectives To describe the surgical management of a GCT identified in the setting of Ovarian Remnant Syndrome (ORS) in a spayed cat with hyperestrogenaemia without estrus signs, and to assess the potential utility of serum estradiol as an adjunct for diagnosis and postoperative monitoring. Methods A 6-year-old female domestic shorthair cat, reportedly spayed, presented with a 2-week history of weight gain and abdominal distension. Diagnostic imaging and cytology suggested a large neuroendocrine tumour occupying the abdominal cavity. Exploratory laparotomy was performed, and the abdominal mass along with one hepatic nodule was resected. Results Histopathology confirmed GCT in the abdominal mass with hepatic metastasis. A preoperative serum sample collected at initial presentation and assayed after receipt of the histopathology report showed markedly increased estradiol. Although clinical signs improved after surgery, the cat re-presented 4 weeks later with abdominal distension and severe anaemia; imaging revealed progression of hepatic lesions, and the patient died 5 weeks after surgery. Conclusions This case highlights that GCT can occur in the setting of ORS without estrus signs, despite marked hyperestrogenaemia. Ovarian remnants may undergo neoplastic transformation and cause life-threatening disease, even in the absence of estrus signs. Serum estradiol may be a valuable marker for diagnosis, treatment response, and recurrence monitoring in feline GCT.

Veterinary

Increasing the Acceptability of Insect-Based Foods as Future Foods: A Comprehensive Review of Barriers, Strategies, and Pathways to Mainstream Adoption.

Suarez JMA et al. · Jul 1, 2026

Edible insects are increasingly recognized for their high nutritional value and favorable environmental profile, yet their acceptance (defined as the continuum from willingness to try and purchase to repeated consumption) in Western and globalized food systems remains limited by cultural, sensory, regulatory, and economic barriers. This narrative review critically synthesizes recent advances in understanding the multidimensional determinants of consumer acceptance of insect-based foods and evaluates the technological, cultural, and policy-driven strategies proposed to overcome them, drawing on interdisciplinary evidence from food science, consumer behavior, and sustainability research. Evidence indicates that processing approaches such as protein hydrolysis, extrusion, fermentation, and encapsulation can significantly improve sensory quality, functionality, and product integration into familiar food matrices. In parallel, targeted marketing, consumer education, and transparent regulatory frameworks emerge as essential to building trust and reducing neophobia. This narrative synthesis provides a comprehensive conceptual framework for advancing the mainstream adoption of insect-based foods. The analysis highlights research gaps related to sensory optimization, traceability, sustainability assessment, and cross-cultural consumer studies, offering evidence-based directions to support the development of safe, acceptable, and nutritionally valuable insect-derived products within contemporary food systems.

Agricultural and Biological Sciences

The role of moral identity in ideological obsession and violent extremism.

Bélanger JJ et al. · Jul 1, 2026

This research examines how ideological passion shapes moral identity and support for political violence, drawing on the Dualistic Model of Passion to distinguish between obsessive (OP) and harmonious passion (HP). Across six studies with diverse ideological groups, OP consistently predicted the adoption of a villainous moral identity, whereas HP predicted a heroic identity. Studies 1A (N = 202; Democrats) and 1B (N = 232; Republicans) showed that OP was associated with villain identity, which mediated support for political violence. Study 2 (N = 315; environmentalists) experimentally manipulated passion, demonstrating that an OP mindset increased villain identification and violent endorsement. Study 3 (N = 179; Black Lives Matter supporters) manipulated moral identity directly, revealing that adopting a villain role amplified support for political violence. Studies 4 (N = 277; U.S. Muslims) and 5 (N = 294; Republicans, preregistered) examined mechanisms of appeal, showing that OP individuals perceived villains as warm, which reinforced villain identification. Finally, Study 6 (N = 236; environmentalists) showed that villain identity was tied to a coherent pattern of moral inversion-villains recast as justified and not harmful, heroes as harmful-which in turn predicted support for political violence.

Neuroscience

Effects of Selective Sphingosine-1-Phosphate Receptor 1 Agonist, TRV045, on Evoked Pain Tests: An Exploratory, Four-Way Cross-Over Study in Healthy Volunteers.

Bakker WA et al. · Jul 1, 2026

Introduction Preclinical evidence suggests that dysregulation of the ceramide-sphingosine-1-phosphate (S1P) axis may have analgesic properties. However, currently approved S1PR1 modulators such as fingolimod are hindered for this indication as they induce lymphopenia. The aim of the current study was to evaluate whether the novel, selective S1PR1 agonist TRV045 has analgesic effects in a validated evoked pain test battery in healthy volunteers. Methods In this randomized, double-blind, double-dummy, placebo-controlled, four-way cross-over study, 25 male or female healthy volunteers were randomized to receive either placebo or TRV045 50, 150 or 300 mg at separate occasions. The primary endpoint was heat pain detection threshold on UVB-induced inflammatory pain. Secondary endpoints included analgesic reduction of capsaicin-induced allodynia and pain detection and tolerance thresholds to evoked cold, electrical, pressure and heat pain. Furthermore, safety, tolerability and pharmacokinetics were monitored throughout the study. Data analyses included a repeated-measures mixed-effects model. Results TRV045 was well tolerated, without serious adverse events. Compared to placebo, TRV045 did not reduce heat pain detection thresholds on UVB-exposed skin, but significantly reduced the secondary area of capsaicin-induced pain for the higher dose levels: 150 mg: -304.10 mm 2 (95% CI: -494.78 to -113.43, p = 0.002); 300 mg: -298.51 mm 2 (-486.83 to -110.20, p = 0.002). No effects on peripheral lymphocyte count were observed. Conclusion TRV045 is a well-tolerated S1PR1 modulator with analgesic properties in healthy volunteers as measured by the capsaicin-induced pain model, which provides initial clinical evidence that selective S1PR1 modulation may be an appropriate novel target for the treatment of neuropathic pain. Significance statement Selective S1PR1 modulation produced analgesic effects in a validated human experimental pain model. This study provides clinical proof-of-concept for S1PR1 as a promising therapeutic target for neuropathic pain.

Biochemistry, Genetics and Molecular Biology

Early Life Stress Affects Human Decision Making by Increasing Expectations of Volatility.

Smith KE et al. · Jul 1, 2026

People learn most effectively when they can flexibly modify strategies to accommodate environmental changes. Here, we explore how chronic early life stress influences the ways individuals weight and prioritize new information when making decisions. To do so, we examined the choices of 11-16-year-old children in a reward learning task. Children varied on their level of stress exposure. We used a Bayesian computational learning model to assess whether differences in children's decision making were driven by difference in their expectations about the task environment. Children with high stress exposure switched their responses rather than maintaining choices that had previously been effective for them when making decisions about rewards. This switching was driven by children with high stress exposure expecting environments to be more volatile. These findings offer insight into how early life experiences can shape the subsequent parameters of human learning. SUMMARY: How experience shapes an individual's ability to flexibly adjust learning strategies when making decisions is not well understood. Using behavioral tasks combined with a novel computational model, we find exposure to high stress environments biases children towards learning strategies optimal to unpredictable environments. Stress in childhood shapes the development of learning parameters in ways that have implications for decision making.

Neuroscience

Covalent grafting of hyaluronic acid on drug nanocrystals for mucosal delivery.

Fuster MG et al. · Jul 1, 2026

Nanocrystals (NCs) represent an advanced drug delivery platform due to their nearly 100% drug loading capacity, enhanced solubility, and improved tissue penetration. The surface-rich structure of NCs enables chemical modifications, with covalent grafting emerging as a superior strategy to impart stability and introduce targeted functional groups. In this study, we explore the development of curcumin nanocrystals (CUR-NCs) covalently grafted with hyaluronic acid (HA). To enhance mucosal targeting and permeation, HA was chemically grafted to chitosan (CS) on the NCs' surface via EDC/NHS-mediated chemistry. This surface conjugation was confirmed through FTIR and 1 H-NMR analyses, validating the successful formation of HA-CS-CUR-NCs. The resulting nanoparticles exhibited an average particle size of 110 nm, remaining within the ideal range for mucosal delivery. Importantly, cytotoxicity assays on THP1 monocytes and NIH/3T3 fibroblasts revealed that the HA-CS-CUR-NCs possessed suitable biocompatibility properties. Ex vivo mucosal deposition studies using neonatal porcine tissue demonstrated significantly improved mucopenetration with HA-functionalized NCs, achieving 37.3 ± 2.6% drug deposition after 24 hours, compared to only 1.81 ± 1% for non-functionalized CUR-NCs. These findings position HA-CS-CUR-NCs as a promising platform for advanced mucosal drug delivery, combining nanoscale precision with bioresponsive surface chemistry to enhance therapeutic outcomes.

Pharmacology, Toxicology and Pharmaceutics