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461 papers

An Outflow Tract Myocardium-Specific Enhancer at the Sema3c Locus During Heart Development.

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

Integrative SAXS and AFM analysis of engineered carbohydrate-active enzyme assemblies with tunable spatial organization.

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

Effects of Norbixin on Growth Performance, Immunomodulation, Antioxidant Systems, and Metabolic Alterations in the Oriental River Prawn (Macrobrachium nipponense): An Integrative Analysis.

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

Mass spectrometry proteomics for studying mitostasis.

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

The Effect of Dopaminergic Medication on Impulse Control and Compulsive Behaviour: A Translational Perspective.

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

Pituitary Tumour Apoplexy as Cause of Death of Simonetta Vespucci, the Venus by Botticelli.

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

Oxidative Stress-Induced Expression Levels of PXDN and NF-κB in Type 2 Diabetic Patients With Nephropathy.

Hanin Z et al. · Jul 1, 2026

Background Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in patients with diabetes mellitus (DM). Early detection remains difficult, but essential for timely management. In this study, we assessed Peroxidasin (PXDN) gene expression as a biomarker for early detection of DN and for reflection of oxidative stress status. We also compared PXDN and Nuclear factor-κB (NF-κB) expression levels in DN patients, aiming to identify a reliable diagnostic biomarker. Methods This prospective cross-sectional study included 40 patients with T2DM with and without nephropathy, and 20 matched healthy controls. PXDN mRNA expression was quantified by real-time polymerase chain reaction (qRT-PCR). Biochemical analyses of malondialdehyde (MDA) and total antioxidant capacity (TAC) were also done to assess the oxidative stress status. Laboratory parameters, including glycated haemoglobin, urinary albumin-to-creatinine ratio, estimated glomerular filtration rate, and microalbuminuria, were measured and correlated with gene expression levels and the oxidative stress status. Results PXDN mRNA expression was significantly upregulated in patients with DN compared to diabetic cases without nephropathy and control subjects. MDA levels were significantly elevated in both diabetic groups relative to controls, but no significant difference was found between DN and DM without renal impairment. TAC was significantly lower in DN cases compared to DM and controls. The NF-κB gene was upregulated in both diabetic groups compared to control subjects, but no significant difference was found between DN and DM without nephropathy. Furthermore, PXDN expression did not correlate with MDA, TAC, or NF-κB levels. Receiver operating characteristic (ROC) analysis identified PXDN as a highly specific and sensitive marker for DN, outperforming conventional oxidative stress biomarkers in distinguishing DN from both diabetic and healthy individuals. Conclusion PXDN is significantly upregulated in DN and may serve as a sensitive and specific molecular marker for early detection of nephropathy compared to NF-κB.

Medicine

Fusion protein condensate formation via coiled-coil domains.

Narayan OP et al. · Jul 1, 2026

While recent research shows that biomolecular condensates play important roles in normal cellular processes and diseases, the driving forces in condensate formation are not well understood, especially regarding the role of structured self-associative protein domains. In this work, we study the contribution of a model structured domain, coiled-coil domain, in promoting condensate formation of fusion proteins (FPs). Starting from a large set of ~50,000 FPs, we systematically narrowed down to investigate 14 FPs and their corresponding 18 coiled-coil domains. We showed that all 14 FPs are capable of assembling condensates with high potency. When isolated from the rest of the protein contexts, 11 of the 18 coiled-coil domains can induce condensation on their own, despite their short length compared to their full-length counterparts. To understand the differences between coiled-coils that can drive condensate formation and those that cannot, we developed a "triad-extension" model and found the condensate-sufficient coiled-coil domains have a higher propensity to extend beyond perfectly end-to-end matched dimer/oligomer to promote condensate formation.

Biochemistry, Genetics and Molecular Biology

Liver Transplantation for HBV-Related Disease in France: NUC Type Before LT Is Associated With Patient Survival.

Bienvenue I et al. · Jul 1, 2026

Background & aims Liver transplantation (LT) is indicated for liver complications related to hepatitis B virus (HBV) infection: acute liver failure (ALF), decompensated cirrhosis or hepatocellular carcinoma (HCC). The present study aimed to describe and evaluate patient survival after LT for HBV-related disease in France and identify the factors influencing survival. Methods The present retrospective cohort study based on medical record information included all adult patients transplanted with positive HBsAg (+/- coinfection with Hepatitis D virus (HDV)) between January 1, 2005 and December 31, 2023 in all French LT centres. Results The study population consisted of 1083 patients, the majority of whom were men (81.5%) with a median [IQR] age at LT listing of 52.8 [42.5-59.8] years. Indications for LT were HBV-related HCC (47.2%), HBV-related cirrhosis (28.5%), HDV-related cirrhosis (11.2%), HBV-related ALF (10.5%), HDV-related HCC (1.4%) and other (0.7%). Median [IQR] post-LT follow-up was 6.0 [2.2-11.1] years. Patient survival at 1, 5, 10 and 15 years after LT was 91.6%, 80.1%, 71.8% and 63.6% respectively. Multivariate analysis showed that independent significant prognostic factors were age at LT (HR: 1.030; 95CI: 1.019-1.042; p Conclusions Survival after LT for HBV-related liver disease is good. NUC type prior to LT seems to be associated with patient survival.

Medicine

Formulation of Peptide-Based Nanoparticles Using a Microfluidic Device.

Hammoum T et al. · Jul 1, 2026

Peptide-based nanoparticles (PBN) have emerged as a promising alternative to lipid nanoparticles (LNP) for nucleic acid delivery and efficient cellular uptake. In this study, we evaluated the formulation of WRAP5 (W- and R-rich amphipathic peptide 5)-based PBN using a microfluidic device and assessed the impact of key process parameters, flow rate ratio (FRR), total flow rate (TFR), and mixing channel design, on nanoparticle characteristics. Across 72 formulations encapsulating small interfering RNA (siRNA) or plasmid DNA (pDNA), dynamic light scattering revealed consistent mean sizes ranging from 50 to 70 nm, with a low polydispersity index (PdI < 0.22), independent of FRR, TFR, or mixer type. Stability studies demonstrated that siRNA-loaded PBN exhibited moderate size increases during storage at 4°C, whereas pDNA-loaded PBN remained highly stable for up to 70 days. Biological assays confirmed robust activity: WRAP5:siRNA PBN achieved approximately 50% CDK4 silencing in GIST-T1 cells, and WRAP5:pDNA PBN mediated efficient mCHERRY expression in HeLa cells, regardless of formulation method or storage duration. These findings highlight the robustness and scalability of WRAP5-based PBN, contrasting with LNP systems that require stringent control of FRR and TFR, and partially underscore their potential for nucleic acid delivery applications.

Biochemistry, Genetics and Molecular Biology