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63 papers

Prevalence, Disease Onset and Clinical Outcome in Arginase 1 Deficiency: Cross-Border Surveillance in Germany, Austria, and Switzerland.

Scharre S et al. · Jul 1, 2026

Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by progressive spastic paraplegia, developmental delay, epilepsy, and episodic hyperammonemia. Evidence on prevalence and clinical presentation is scarce. Therefore, epidemiology and the phenotypical spectrum were assessed in Germany, Austria, and Switzerland (DACH region). We conducted a questionnaire-based, cross-sectional study of confirmed ARG1-D patients in the DACH region. Patients were stratified into early-diagnosed (newborn screening [NBS] or high-risk family screening [HR]) and diagnosed after symptom onset. We evaluated clinical, biochemical, and therapeutic characteristics of individuals with confirmed ARG1-D. Epidemiological prevalence estimates were derived using national population data. A total of 20 patients were identified (Germany: 12, Austria: 7, Switzerland: 1). Eight were diagnosed early (NBS: 4, HR: 4) and 12 after symptom onset. Symptomatically diagnosed patients (median age 11 years) presented with a broad range of clinical manifestations, specifically progressive spastic paraplegia (67%), epilepsy (58%), dystonia (46%), developmental delay (58%), and hepatopathy (50%). Median age at diagnosis was 35 months in symptomatic patients versus 1 month in early-diagnosed patients (p = 0.03). Estimated pediatric prevalence was 1:1042080 in the DACH region, with high regional differences. Hyperammonemia was reported in 72%. Enzyme therapy had been initiated in 21%; 2 patients underwent liver transplantation. ARG1-D is a rare disease with a prevalence of approximately 1:1000000 individuals, and a complex and progressive clinical phenotype. Detection via NBS or HR allows early diagnosis and treatment initiation, potentially altering the clinical outcome.

Biochemistry, Genetics and Molecular Biology

Integrating Serological and Molecular Data to Characterize Fowl Adenovirus Associated With Inclusion Body Hepatitis in Broiler Chickens From Malaysia.

Bhuiyan MSA et al. · Jul 1, 2026

Background Inclusion body hepatitis (IBH), caused by fowl adenoviruses (FAdVs), is an emerging disease of commercial broilers associated with significant economic losses. In Malaysia, molecular epidemiological data on circulating FAdV serotypes have largely been restricted to Peninsular regions, with limited information available from East Malaysia (Sabah), despite its rapidly expanding poultry industry and distinct production systems. This regional knowledge gap limits comprehensive understanding of FAdV transmission dynamics at the national level. Objectives This study aimed to detect FAdV infection in broiler flocks with IBH-compatible lesions in Sabah, Malaysia, and to characterize circulating serotypes and their phylogenetic relationships. Methods Thirty pooled tissue samples (liver and gizzard) and 60 serum samples were collected from three broiler farms (YAN, KON, and NIS). FAdV detection was performed using polymerase chain reaction (PCR) targeting the hexon gene. Serological responses were assessed using enzyme-linked immunosorbent assay (ELISA). Positive PCR products were sequenced, and phylogenetic analysis was conducted to determine serotype distribution and genetic relatedness. Results FAdV DNA was detected in 33.3% (10/30; 95% CI: 17.3-52.8) of pooled tissue samples, with detection rates of 70% (95% CI: 44.4-97.5), 20% (95% CI: 2.5-55.6) and 10% (95% CI: 0.3-44.5) in the YAN, KON and NIS farms, respectively. Although descriptive differences were observed among farms, these variations were not statistically significant (p > 0.05). All positive samples yielded the expected 897 bp hexon gene amplicon. ELISA revealed high seropositivity in unvaccinated flocks, with the highest mean antibody titre observed in the YAN farm (24,716.5 ± 4516.1). Molecular characterization identified FAdV-8b (species E) and FAdV-11 (species D), indicating co-circulation. Phylogenetic analysis showed close relatedness to strains from Korea, Belgium, China and Australia. Conclusions The co-circulation of FAdV-8b and FAdV-11 in Sabah broiler farms underscores the need for continuous molecular surveillance, enhanced biosecurity and breeder-level vaccination strategies using locally circulating FAdV strains to control IBH in Malaysia.

Biochemistry, Genetics and Molecular Biology

Intestinal microbiota profile and inflammation in patients undergoing hemodialysis: a comparison between the Southern and Southeastern regions of Brazil.

Paiva BR et al. · Jul 1, 2026

Introduction Exogenous lifestyle factors, such as different cultures, diets, and geo-graphic location, can alter the microbiota in patients with chronic kidney disease (CKD), which is closely related to inflammation. However, few studies have examined how these factors influence the composition of the microbiota. Thus, the objective of this study was to characterize and compare the intestinal microbiota profile and inflammation in CKD patients undergoing hemodialysis (HD) in the Southern and Southeastern regions of Brazil. Methods Blood and stool samples were obtained from two groups of HD patients: one from the city of Blumenau (Southern region) and the other from the city of Rio de Janeiro (Southeastern region). Fecal DNA was extracted, and the V4 region of the bacterial 16S ribosomal RNA gene was sequenced. The fecal microbiome was analyzed using bioinformatic tools. Plasma concentrations of IL-6 and TNF-α were evaluated by ELISA. Results Thirty patients were included in the study, with 14 individuals residing in the Southern region (group S) [50% male, 58 (13.5) years of age] and 16 individuals residing in the Southeastern region (group SE) [47.1% male, 57 (19) years of age]. The α- and β-diversity indices of the intestinal microbiota did not differ significantly between the groups. However, patients from the Southern region had higher plasma TNF-α (p = 0.008) and IL-6 (p = 0.003) levels than those from the Southeastern region. Conclusion Although HD patients with CKD residing in the Southern and Southeastern regions present similar intestinal microbial patterns, patients from the Southern region had higher concentrations of inflammatory markers.

Biochemistry, Genetics and Molecular Biology

Wild Pedigree exploreR (wpeR): Streamlined Analysis and Visualization of Wild Pedigrees in Time and Space.

Simčič G et al. · Jul 1, 2026

Advances in non-invasive genetic sampling and long-term genetic monitoring programmes have enabled collection of large individual genotype datasets for many wildlife populations, often accompanied by rich field metadata that place the genotyped individuals in time and space. These datasets allow reconstruction of multigenerational pedigrees and have the potential to provide valuable insights into population demography, reproduction, dispersal, social structure and genetic processes. But while the tools for construction of pedigrees keep improving, their interpretation remains challenging. Integrating multigenerational pedigree data with field metadata creates significant complexity, yet specialized tools to facilitate the interpretation of such datasets remain scarce. Here we introduce wild pedigree exploreR (wpeR), an R package designed to simplify exploration, organization and interpretation of complex pedigrees. The package enables users to link reconstructed pedigrees with genetic sample metadata, enabling evaluation of biological plausibility of inferred relationships, but also allowing exploration of other characteristics of individuals and populations in spatial and temporal contexts. wpeR implements a linear workflow through which the pedigree data is imported, formatted, organized into families and integrated with field metadata. The resulting dataset can be visualized through temporal plots that track individuals and families over time, as well as with spatial outputs representing parent-offspring relationships and individual movement patterns as geographic features that can be either directly visualized on maps within R, or exported to be further explored with common GIS tools. wpeR allows exploration of lineage relationships within their ecological context, bridging the gap between statistically reconstructed pedigrees and their biological interpretation. It provides a scalable and flexible framework for analyzing these complex data, providing a practical tool for researchers and managers working with genetic monitoring datasets.

Biochemistry, Genetics and Molecular Biology

Differential effects of lipid composition on the thermal and functional properties of membrane associated CYP2J2.

Das R et al. · Jul 1, 2026

CYP2J2 is a membrane-bound cytochrome P450 that is expressed in cardiomyocytes, where it is known to metabolize arachidonic acid into cardioprotective epoxyeicosatrienoic acids (EETs). It consists of transmembrane domains embedded in the hydrophobic segments of the cell membrane and surrounded by various lipids. Currently, we lack a detailed understanding of the role of specific lipids in mediating the physicochemical properties of CYP2J2 and the factors that govern this phenomenon. In this study, CYP2J2 was reconstituted into nanodiscs with different lipid compositions, selected to reflect those of the endoplasmic reticulum (ER) membrane, where the enzyme is expressed. Using a combination of Nano-Differential Scanning Fluorimetry (nano-DSF) and UV-Visible Spectroscopy, we demonstrate that CYP2J2 undergoes a transition in its unfolding behavior between the detergent micelle and the nanodisc environment, with the first melting transition corresponding to heme perturbation. Furthermore, we show that altering the lipid environment causes shifts of up to 3-4°C and 8-9°C in the first and second melting transition temperatures, respectively, with sphingomyelin- and POPS (1-palmitoyl-2-oleoyl-glycero-3-phosphoserine) containing nanodiscs exhibiting the highest and lowest thermal stabilities, respectively. Lipid composition was found to have no effect on substrate (ebastine) binding affinities. However, NADPH-oxidation rates showed that lipid composition directly affects CYP2J2 function in nanodiscs by altering the rate of electron transfer between the CYP and its redox partner, Cytochrome P450 Reductase (CPR). Fluorescence anisotropy measurements with DPH (1,6-Diphenyl-1,3,5-hexatriene) were also used to characterize the membrane fluidity of cholesterol- and sphingomyelin-containing nanodiscs. Together, the results show that lipid composition directly modulates the thermal stability and functional properties of CYP2J2 in nanodiscs and underscore the importance of the charge of the lipid headgroup and membrane fluidity in our understanding of the mechanism by which lipid composition exerts these effects.

Biochemistry, Genetics and Molecular Biology

From extracellular entry to intracellular release: A water-assisted transport cycle for creatine in SLC6A8.

Poudel P et al. · Jul 1, 2026

The creatine transporter (CRT/SLC6A8) plays a key role in cellular energy homeostasis, yet the molecular mechanism underlying creatine transport remains poorly understood. Here, we reconstruct the complete transport cycle of human CRT using a hybrid simulation strategy that combines constant-force steered molecular dynamics (cf-sMD) with targeted molecular dynamics (tMD). This approach captures continuous progression through the outward-open, outward-occluded, inward-occluded, and inward-open states and reveals a water-assisted, sequential intracellular release of Na2, creatine, and Na1. Hydration analysis shows that progressive water penetration into the binding pocket weakens protein-substrate and protein-ion interactions and destabilizes the bound state before release. Residue-level contact analysis identifies residues that interact with creatine along the transport pathway, while dynamic network analysis reveals a TM1-TM6 communication backbone that mediates long-range coupling during transport. Together, these results provide a molecular framework for creatine transport and establish an approach for investigating transport mechanisms across the broader solute carrier family.

Biochemistry, Genetics and Molecular Biology

Photocross-linking activity-based probes to capture the dynamics of ubiquitin RING E3 ligase interactions.

Chandler SF et al. · Jul 1, 2026

Almost all cellular processes are influenced by ubiquitination. A large family of enzymes known as E3 ligases provides the specificity for ubiquitination, with the largest class among them, the Really Interesting New Gene (RING) E3s, comprising over 600 members in humans. RING E3s facilitate transfer of ubiquitin (Ub) to substrates by constraining the highly dynamic E2-Ub thioester linkage to be primed for attack from the substrate nucleophile. We have established a workflow that uses an N-maleimido diazirine (NMD) photoactivatable cross-linker attached to ubiquitin that, once stably linked to the active site of an E2, creates an activity-based probe (ABP) to monitor interactions with E3 ligases. Cross-linking mass spectrometry using the NMD-Ub-E2 ABP identified regions of interaction between ubiquitin and a selection of different RING E3s, which not only agreed with existing crystal structures, but was also used to evaluate in silico structural models of complexes yet to be resolved by conventional means. The cross-linking data also provided insight into domains of conformational flexibility which likely adopt multiple configurations in solution and which are challenging to monitor by other methods. NMD-Ub-E2 ABPs offer great potential to explore the ensemble conformations of E2-E3 complexes in solution and have scope for applications beyond the ubiquitin system.

Biochemistry, Genetics and Molecular Biology

Redox signals and oxidative stress in the control of mitochondrial protein import.

Hasberg L et al. · Jul 1, 2026

Mitochondrial protein import is essential for organelle biogenesis and cellular homeostasis. It operates in an environment that is intrinsically shaped by redox chemistry. Mitochondria are major sources of reactive oxygen species (ROS), which arise as by-products of oxidative phosphorylation. Cells therefore maintain sophisticated ROS-handling systems, including compartmentalized antioxidant networks, to balance redox signaling with protection from oxidative stress. Increasing evidence indicates that these redox conditions directly influence mitochondrial protein import at multiple levels. In this review, we provide an overview of ROS production, ROS signaling, and oxidative stress in relation to mitochondrial protein import. We outline the major mitochondrial protein import pathways, and discuss how their activity is modulated by redox-dependent mechanisms. A particular focus is placed on the mitochondrial disulfide relay system of the intermembrane space, which directly couples protein import to redox chemistry through oxidative folding, and how it is influenced by the local redox environment. Collectively, we propose that mitochondrial protein import is partially governed by redox-dependent mechanisms, enabling integration of metabolic state, stress responses, and signaling pathways.

Biochemistry, Genetics and Molecular Biology

Efficacy of Metformin in Prevention of Glucocorticoid-Induced Hyperglycemia in Patients Without Diabetes: A Meta-Analysis.

Murtaza S et al. · Jul 1, 2026

Purpose The glucocorticoids are increasingly being used in the management of different autoimmune conditions and cancers. Our meta-analysis aims to leverage metformin's potential to reverse the metabolic complications of glucocorticoids by activating AMP-activated protein kinase (AMPK), while sparing their anti-inflammatory benefits. Methods PubMed, Cochrane Library, trial registries and Google Scholar were searched from inception to June 2025 for Randomized Controlled Trials (RCTs) and observational studies comparing metformin and placebo to prevent metabolic side effects of glucocorticoid therapy in non-diabetic patients. After screening by two independent reviewers according to PRISMA guidelines, four studies involving 187 patients were analysed using the random-effects model in RevMan 5.4.1, and mean differences (MD) were calculated. Results Preventive metformin administration during glucocorticoid treatment is superior to placebo with respect to glycaemic control as shown by statistically significant reduction in fasting blood glucose [MD = -0.60 (95% CI: -0.86 to -0.34)], HOMA index of insulin resistance [MD = -0.53 (95% CI: -0.97 to -0.08)], LDL levels [MD = -0.20 (95% CI: -0.40 to -0.00)] and total cholesterol [MD = -0.27 (95% CI: -0.54 to -0.01)]. However, our study failed to show significant improvement in area under the curve glucose (mmol/L × min) after challenge [MD = -176.66 (95% CI: -415.42, 62.11)], basal metabolic rate (BMR) [MD = 51.99 (95% CI: -53.08, 157.07)], HDL [MD = -0.04 (95% CI: -0.13, 0.05)], insulin levels [MD = -2.26 (95% CI: -5.90, 1.38)], triglycerides [MD = -0.15 (95% CI: -0.42, 0.13)] and body weight [MD = -0.93 (95% CI: -2.29 to 0.44)]. Conclusion While glucocorticoids remain essential in various clinical contexts, their detrimental effects on glucose metabolism are well documented. This study supports metformin as a promising preventive treatment in non-diabetic patients receiving systemic glucocorticoid therapy. Improvement in insulin sensitivity and resulting fasting glucose levels may offset glucocorticoid-exacerbated inflammation. Further studies are needed to address long-term outcomes, including adiposity, bone metabolism, appetite, liver function and muscle wasting, as well as to identify possible predictors of therapeutic response. Trial registration International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD420251104082.

Biochemistry, Genetics and Molecular Biology

Three-dimensional approaches to measuring primary cilia in hippocampal neurons: A comparative analysis.

Rasmusson S et al. · Jul 1, 2026

Primary cilia are non-motile sensory organelles that detect extracellular signals; disruptions in their functions are linked to neurodevelopmental disorders. Because cilia lengths can rapidly change in response to stressors, they are important for both plasticity and brain homeostasis. Accurate measurement of ciliary length is therefore essential but the absence of standardized methods and the variability introduced by different techniques can compromise measurement reliability and precision. To address this challenge, our study employed two distinct methods to estimate the length of primary cilia in hippocampal subregions in mice. We compared stereology-based 3D quantification, which is considered a methodological gold standard due to its unbiased sampling design and correction for tissue shrinkage, with 3D reconstruction to measure primary cilia length. 3D reconstruction imaging used a 100× oil-immersion objective. With neuronal cilia typically ∼2-10 µm long in hippocampus, a 1-µm z-step provided multiple optical sections per cilium thereby ensuring full structural visualization. Our findings show that both methods allow simple and equally precise measurements of neuronal primary cilia length in hippocampal subregions. Their strong agreement provides researchers with reliable tools for studying primary cilia on immunohistochemically stained sections and supports a consistent methodological framework for investigating cilia dynamics.

Biochemistry, Genetics and Molecular Biology