Baaz M et al. · Jul 1, 2026
Variational autoencoders (VAEs) combined with neural ordinary differential equations provide a flexible framework for exploring neural latent-variable models in population pharmacokinetics. In this work, we investigate an empirical Bayes VAE formulation that integrates encoder-decoder architectures with covariate-dependent population priors, enabling correlated latent representations and probabilistic inference. We evaluate the proposed framework using controlled simulation studies and a small clinical benchmark dataset. The simulation experiments assess the ability to recover known population structures and covariate effects, while the clinical study evaluates subject-specific prediction and model diagnostics. In simulation studies with correlated individual parameters, the empirical Bayes VAE consistently captured population-level variability, whereas a fixed-prior VAE baseline exhibited systematic biases. In our experiments, extrapolation beyond the training dosing schedules showed more stable predictive behavior when using the proposed input-response normalization, relative to models trained without normalization, within a limited range. Diagnostic analyses indicated clear relationships between inferred latent variables and true parameters, and estimated observation noise was consistent with simulated values. In the clinical case study, cross-validation experiments suggested predictive performance comparable to previously reported neural ODE-based approaches. Overall, the results illustrate the feasibility of combining empirical Bayes inference with neural ODE-based decoders for population modeling. The proposed framework should be viewed as a methodological proof-of-concept, highlighting both the potential and the current limitations of variational neural approaches in pharmacometric applications.
Mathematics
Worku M et al. · Jul 1, 2026
Ethiopia has one of the highest rates of undernutrition among children under five (U5) and women of reproductive age (WRA) globally, alongside rising overweight/obesity, particularly in urban areas. Poor diet is a shared driver of multiple forms of malnutrition. We used a participatory photography (Photovoice) approach to explore the lived experiences of WRA and their children U5 in adopting healthy diets across lower- and higher- socio-economic status (SES) groups in Addis Ababa. Women took photographs illustrating challenges to healthy diets, and five focus groups (n = 31 women) were conducted to discuss challenges and solutions, with separate sessions held for different SES groups. A hybrid thematic analysis, combining deductive and inductive approaches, identified themes/subthemes, with comparisons across SES groups. Financial and physical barriers to accessing healthy foods, time constraints and perceived poor food safety were major contributors to poor diets. In lower SES groups, women also reported limited knowledge about healthy diets, inadequate family support and poor home food environments. In higher SES groups, unhealthy food preferences coupled with easy access to and aggressive promotion of unhealthy foods were key challenges. Proposed government-level solutions included job creation, nutrition education, affordable healthy food, investment in household infrastructure, expanded childcare and restrictions on unhealthy food availability and promotion. Societal-level solutions included gender equality, strengthened community-based loan schemes and support for urban agriculture. These findings highlight that women recognise their needs and who should support them, and emphasise the importance of including women's voices in decision-making processes. Findings also underscore the need for integrated interventions targeting individual, food environment and socio-economic drivers to improve diets among women and children in urban Ethiopia.
Nursing
Rajamaki B et al. · Jul 1, 2026
Purpose Prevalence of breast cancer (BC) increases with age, but the external validity of data obtained from pivotal trials of medicinal products remains a concern due to the underrepresentation of frail and older adults. Cyclin-dependent kinase inhibitors (CDKi), palbociclib, abemaciclib, and ribociclib are considered an essential part of the standard-of-care in the management of advanced/metastatic breast cancer. We investigated age, comorbidities, and survival in a nationwide real-world cohort of CDKi users. Methods Data from the Finnish Cancer Registry, reimbursed dispensed prescriptions, Electronic Prescription Database, Care Register for Health Care (CRHC), and Causes of Death Register were combined and analysed. Results Altogether 1921 women with BC initiated CDKi treatment in 2018-2022. The median age at initiation was 66.9 years, with 43.2% of the study cohort being Conclusions Real-world CDKi users are older than women included in the pivotal trials, and the survival differences between age groups imply challenges in the generalisability of data from pivotal trials. The real-world CDKi user population is characterised by a low prevalence of major comorbidities.
Medicine
Wang Y et al. · Jul 1, 2026
Sema3c is specifically expressed in the cardiac outflow tract (OFT) of the developing mouse heart and has been implicated in OFT polarization and great artery formation. However, the regulatory basis underlying its spatially restricted expression remains unclear. To investigate the mechanisms underlying OFT-specific Sema3c expression, we utilized chromatin accessibility data from distinct segments of the developing heart and identified a differentially accessible region as an OFT-specific Sema3c enhancer candidate. Unlike previously characterized Sema3c enhancers, this region is located distal to the transcription start site. Reporter analysis using transgenic mouse embryos demonstrated that this region exhibits transcriptional activity from E8.5 onward and remains specifically active in the OFT myocardium throughout heart development. We further defined a minimal 603 bp enhancer whose activity depends on GATA binding sites. This enhancer provides insight into the mechanisms underlying spatially restricted Sema3c expression involved in OFT development.
Biochemistry, Genetics and Molecular Biology
Pardo Larrabeiti I et al. · Jul 1, 2026
Cellulosomes are multi-enzyme assemblies whose catalytic efficiency depends on the spatial organization of their components. However, their pronounced conformational flexibility has precluded quantitative characterization of inter-enzyme distances and overall topology. Here, we present a methodological framework to tailor and analyze the architecture of constrained multi-enzyme complexes composed of two endoglucanases AtCel8A and AtCel9R and one xylanase AtXyn11A by fixing enzyme positions using the Jo-In scaffold. This approach enables generation of defined assemblies structurally characterized by small-angle X-ray scattering (SAXS) and/or atomic force microscopy (AFM). SAXS analysis of the two-glucanase complexes reveals distinct scattering profiles corresponding to different degrees of compaction depending on the enzyme spatial arrangement. Complementary AFM imaging of bifunctional assemblies supports SAXS derived models at the single-particle level, reinforcing the robustness of the proposed workflow. The three-enzyme assemblies' SAXS measurements distinguish different constructions while showing relatively homogeneous radii of gyration (53 ± 2 Å) and maximum dimensions of 180 to 200 Å. Atomistic modeling using two independent approaches, DADIMODO and BILBO-MD, converges toward consistent average spatial organizations with constrained interdomain distance ranges, and consistent quantitative parameters validating the structural models. Altogether, the results establish a quantitative framework for designing tailored multi-enzyme assemblies. Jo-In scaffold provides a versatile tool for structural analysis of modular, dynamic protein complexes, advancing our understanding of structure-function relationship in multi-enzyme systems.
Agricultural and Biological Sciences
Ettefaghdoost M et al. · Jul 1, 2026
Background Natural carotenoids have gained considerable attention in aquaculture due to their potential to enhance growth performance, physiological status, and product quality in crustaceans. However, limited information is available regarding the dietary effects of norbixin on Macrobrachium nipponense. Objectives This study evaluated the effects of dietary norbixin supplementation on growth performance, haemato-biochemical indices, immune responses, antioxidant status, digestive enzyme activity, intestinal microbiota, carotenoid accumulation, and body composition in M. nipponense. Methods A 56-day feeding trial was conducted using juvenile prawns (initial weight: 1.48 ± 0.07 g) fed diets supplemented with 0.00, 0.05, 0.10, 0.15, and 0.20 g/kg norbixin. Growth indices, biochemical and immunological parameters, antioxidant capacity, digestive enzyme activities, intestinal bacterial populations, tissue carotenoid deposition, and proximate body composition were subsequently assessed. Results Dietary norbixin significantly improved growth performance, feed conversion ratio, hepatosomatic index, and survival rate, with the most pronounced effects observed at 0.15 g/kg (p 0.05). Norbixin supplementation further enhanced digestive enzyme activities, increased lactic acid bacteria abundance, reduced total bacterial counts, and promoted carotenoid accumulation in muscle, shell, and hepatopancreas (p Conclusions Dietary supplementation with 0.15 g/kg norbixin effectively enhanced growth, immunocompetence, antioxidant defence, intestinal microbial balance, carotenoid deposition, and nutritional quality in M. nipponense, suggesting its potential as a functional feed additive in freshwater prawn aquaculture.
Immunology and Microbiology
Sharma L et al. · Jul 1, 2026
Maintaining mitochondrial integrity and function is fundamental to cellular homeostasis. Cells rely on coordinated protein quality control (QC) systems-including intricate chaperone-protease networks, the ubiquitin-proteasome system, and cytosolic surveillance pathways-that together form a dynamic, cell-wide mitostasis network governing the import, folding, synthesis, and degradation of mitochondrial proteins. Disruption of mitochondrial homeostasis, for example, by impairing mitochondrial protein import, induces proteotoxic stress and contributes to human disease. Mass spectrometry (MS)-based proteomics has established itself as an indispensable method to dissect mitostasis at unprecedented depth by enabling systematic quantitative analysis of protein abundance, localization, interactions, stability, and dynamics. In this review, we highlight state-of-the-art MS technologies and multifaceted proteomics approaches used to study mitostasis on a proteome-wide level. These functional analysis approaches build on quantitative MS methods employing label-free, metabolic, and chemical labeling strategies, which allow precise tracking of proteome dynamics in response to different cellular conditions including stress. Spatial and interaction-based approaches, such as affinity purification-MS, proximity labeling, and complexome profiling, provide detailed insight into the organization and regulation of the complex mitochondrial organizing system, chaperone networks, and protein QC pathways. Furthermore, we discuss advanced methodologies such as nascent chain and dynamic proteomics strategies, which offer a proteome-wide comprehension of early stress responses and fast regulation. The skillful integration of temporal, spatial subcellular, interaction, nascent, and dynamic proteomics approaches now enables a systems-level assessment of mitostasis, paving the way for a holistic while nuanced understanding of this essential cellular process and the underlying molecular mechanisms.
Chemistry
Wolfschlag M et al. · Jul 1, 2026
Dopaminergic medication used in disorders like Parkinson's disease (PD) and restless legs syndrome can cause impulsive-compulsive behaviour (ICB), often with strong negative effects on patients' quality of life. This narrative review presents translational evidence on iatrogenic ICB, taking findings from epidemiological, clinical, neuroimaging and preclinical studies into consideration. Epidemiological and clinical studies find dopamine agonists with high D2/3-selectivity to be most strongly linked to ICB. Their effect on ICB has often been shown to be dose-dependent, but the impact of combining different dopaminergic drugs or applying extended-release formulations is less clear. Intervention studies support tapering or replacing dopamine agonists for ICB reduction, whereas no efficacious pharmacotherapy has been identified for ICB treatment specifically. Adequate animal models for mimicking different types of ICB are available, and point, in line with human neuroimaging studies, towards an involvement of striatum and prefrontal cortex in iatrogenic ICB. Overall, complementary research designs have led to profound evidence regarding the occurrence of ICB in PD and establishing methods transferable to other, less-studied patient populations. A combined approach integrating insights from human studies and animal models could contribute to developing dopaminergic drugs with lower ICB risk but also specific pharmacotherapies for impulsivity or compulsivity in the future.
Medicine
Nardelli D et al. · Jul 1, 2026
Introduction Simonetta Vespucci is the model for the world-renowned Venus painted by Sandro Botticelli at the end of the XV Century. Her unexpected death at the age of 23 remained a mystery for more than 500 years, until we proposed in 2019 that she probably suffered from a pituitary adenoma. Methods We now hypothesize with further evidence from historical descriptions of her last days that an expansion of the adenoma was the cause of her premature death, aged twenty-three. Results Our hypothesis is supported by three elements: (1) tumour characteristics; (2) symptoms presented during her last days; and (3) the historical records of two potential precipitating events. Conclusions We conclude that Simonetta Vespucci, the Venus by Botticelli, died as a consequence of a rapidly expanding pituitary adenoma causing tumour apoplexy, thereby making this endocrine emergency the likeliest cause of her death.
Arts and Humanities
Bahman F et al. · Jul 1, 2026
Background The aryl hydrocarbon receptor (AhR) is linked to inflammation, but its plasma agonist activity and association with metabolic and inflammatory markers in obesity remain unclear. This cross-sectional study aimed to determine the level of plasma AhR agonistic activity and its association with systemic inflammation and metabolic dysregulation in obesity. Methods Plasma samples were collected from 80 non-diabetic (39-obese, 23-overweight, and 18-normal/healthy weight) individuals. AhR agonist activity was assessed using a cell-based luciferase reporter assay. Plasma AhR was quantified by ELISA. Inflammatory markers were assessed using a multiplex Luminex platform. Results Our findings indicate that plasma AhR agonist activity is elevated in obese (92.77 ± 4.002 fold activation) compared with normal/healthy weight (51.39 ± 2.335) and overweight participants (67.54 ± 5.24 fold activation). Moreover, the AhR protein was also elevated in obese (94.88 ± 7.62 pg/ml) compared to normal/healthy weight (65.88 ± 6.78 pg/ml) and overweight participants (67.54 ± 5.24 pg/ml), which was positively correlated with AhR activity (r = 0.441, p Conclusions Our findings demonstrate that elevated plasma AhR agonist activity is associated with obesity, systemic inflammation, and metabolic dysregulation. These results highlight AhR activity as a biomarker of interest and support further studies to clarify its mechanistic role and potential clinical relevance in metabolic disorders.
Environmental Science