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63 papers

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

Lean, Non-Autoimmune Young-Onset Diabetes in Bangladesh: A Metabolically Obese Phenotype With Disproportionate Insulin Secretory Defect.

Hasan M et al. · Jul 1, 2026

Background Young-onset diabetes in South Asians frequently manifests in lean individuals, but the metabolic drivers of this phenotype remain poorlycharacterised. Objective This study aimed to evaluate the clinical, biochemical, and insulin-related indices of lean, non-autoimmune young-onset diabetes mellitus (DM) among Bangladeshi young adults. Methods This comparative cross-sectional study (2023-2024) enrolled 373 participants (aged 18-34 years) categorised into four groups based on glycemic status and body mass index (BMI): Lean DM (n = 53), obese DM (n = 125), lean non-DM (n = 78), and obese non-DM (n = 117) from the Young-diabetes Clinic of the Department of Endocrinology, Bangladesh Medical University, Dhaka after excluding those with positive islet autoantibodies, low C-peptide, pancreatic pathology, and monogenic variants. β-cell function (HOMA2-B) and insulin resistance (HOMA2-IR) were quantified using the HOMA2 C-peptide calculator. Results Lean DM participants were comparable to other groups in age, sex, and family history, though smoking was more prevalent than in lean controls (p Conclusion Lean young-onset diabetes in Bangladesh appears to be a phenotype of disproportionate insulin secretory defect with only modest insulin resistance and metabolic dysfunction. These features highlight the need for targeted screening and individualised management.

Biochemistry, Genetics and Molecular Biology

Polygenic Risk Scores for Incident Dementia in the Multi-Ethnic Study of Atherosclerosis.

Xue D et al. · Jul 1, 2026

Over 75 Alzheimer's disease (AD) and dementia-associated variants have been identified through genome-wide association studies, but the utility of polygenic risk scores (PRS) for predicting AD and dementia in diverse and admixed populations remains unclear. We compared how PRS approaches differing in p-value thresholds, variant weights, and source ancestry perform in predicting dementia in 6338 African American, Chinese, Hispanic, and White individuals from the Multi-Ethnic Study of Atherosclerosis. We tested clumping and thresholding (C+T) methods with varying parameters against Bayesian approaches (PRS-CS, PRS-CSx). We compared the ability of each method to predict incident dementia in all participants and in groups stratified by self-reported race/ethnicity. We additionally analyzed performance across groups stratified by estimated proportion of non-Finnish European (NFE)-like ancestry. Including more variants does not improve performance. We found comparable associations between dementia and PRS when comparing a C+T method with only 15 SNPs and PRS derived from Bayesian models that include > 800,000 SNPs (HR 5e-08 = 1.18, 95% CI: 1.08-1.28; HR CSx = 1.17, 95% CI: 1.07-1.27). The p lowNFE _ 5e-08 = 1.27, 95% CI: 1.08-1.50; HR lowNFE _ CSx = 1.12, 95% CI: 0.94-1.33). More selective PRS models using genome-wide significant SNPs may be preferable for dementia prediction in diverse populations.

Biochemistry, Genetics and Molecular Biology

Airway secretory cells contain both a perinuclear Golgi ribbon and dispersed Golgi satellites.

Hoang ON et al. · Jul 1, 2026

Rationale Finely tuned production and secretion of the polymeric mucins MUC5AC and MUCB are required for lung health, but knowledge of many details between their translation and their packaging into secretory granules is lacking. Objectives To analyze the structure and function of the Golgi apparatus, a key site of mucin glycosylation, folding, polymerization, and packaging, in airway epithelial secretory cells. Methods Lung tissue was obtained from mice stimulated or not with IL-13 to upregulate mucin production and from normal human lungs. Golgi elements in mouse and human tissue were imaged by high-resolution immunofluorescence microscopy and electron microscopy. Tissue from mice with deletion of both polymeric mucins was also examined. Measurements and main results By immunofluorescence microscopy, both mouse and human airway secretory cells contained approximately 100 dispersed puncta labeled by markers of medial and trans-Golgi cisternae and the trans-Golgi network (TGN), but only a few perinuclear puncta were labeled by markers of cis-Golgi cisternae. By electron microscopy, secretory cells contained both a perinuclear Golgi ribbon and numerous dispersed Golgi stacks, termed satellites. In mucous metaplastic cells, satellites were concentrated among immature mucin granules. Increasing mucin production by cytokine stimulation did not increase the number of TGN puncta, nor did preventing polymeric mucin production by gene deletion reduce TGN puncta. Conclusions Mucin-producing airway secretory cells express an unusual Golgi structure consisting of a conventional perinuclear ribbon as well as dispersed satellites. While the Golgi satellites are likely an adaptation for mucin production and packaging, their presence is specified developmentally, independent of mucin production.

Biochemistry, Genetics and Molecular Biology

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

Magel2 deficiency promotes cardiac remodeling and increases arrhythmogenic susceptibility in a mouse model relevant to Prader-Willi and Schaaf-Yang syndromes.

Dötsch L et al. · Jul 1, 2026

Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) share overlapping phenotypic features, but potential cardiac involvement in both conditions remains poorly understood. Here, we investigated cardiac function in Magel2 knockout (KO) mice, a model relevant to PWS and SYS, to assess the impact of Magel2 deficiency on the heart. Echocardiographic analysis of 20-week-old Magel2-KO mice revealed concentric remodeling of the left ventricle together with reduced left ventricular end-diastolic volume and stroke volume, as well as a modest but significant reduction in ejection fraction. Electrophysiological studies identified sex-dependent alterations, particularly in males, characterized by shortened action potential duration and increased atrial potassium currents. Surface electrocardiography recordings showed no overt arrhythmias and visual inspection confirmed sinus rhythm during the monitoring period; however, the observed cellular alterations indicate increased arrhythmogenic susceptibility. In addition, aged Magel2-KO mice developed adult-onset obesity and exhibited elevated HbA1c levels consistent with impaired glycemic control. Given the minimal expression of Magel2 in cardiac tissue, these findings suggest that systemic and metabolic alterations may contribute to the observed cardiac phenotype. Together, these results demonstrate structural cardiac remodeling and electrophysiological changes consistent with increased arrhythmogenic susceptibility in Magel2-deficient mice, suggesting clinically relevant cardiac involvement in SYS and PWS. Our findings support consideration of structured cardiovascular monitoring to mitigate potential secondary cardiac complications in affected individuals.

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

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

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