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63 papers

Creating molecular complexity in the chemoenzymatic synthesis of chlorothricin analogues using tandem Diels-Alderases.

Devine AJ et al. · Jul 8, 2026

Chlorothricin is a polyketide-derived natural product isolated from Streptomyces antibioticus . It possesses an elaborate pentacyclic aglycone core which incorporates a spirotetronic acid moiety, linked to a trans -decalin system, embedded within a macrocycle. Using synthetic substrate analogues and purified recombinant proteins, here we demonstrate that assembly of this scaffold proceeds via sequential biocatalytic Diels-Alder reactions, promoted by the enzymes ChlE3 and ChlL. Both Diels-Alderases exhibit sufficiently relaxed substrate selectivity to facilitate access to non-natural chlorothricin analogues via biotransformations. The X-ray crystal structure of ChlE3 reveals the molecular basis of decalin formation by this enzyme. Harnessing this enzymatic cascade in biocatalysis could provide a valuable biomimetic route to both natural and non-natural spirotetronates, and the work described herein lays the foundation for application of these enzymes in chemoenzymatic syntheses of complex products.

Biochemistry, Genetics and Molecular Biology

Machine-learning prediction of affinity and epistasis in the bovine pancreatic trypsin inhibitor-chymotrypsin complex.

Tzuri N et al. · Jul 1, 2026

Protein-protein interactions (PPIs) are shaped by evolutionary pressures that fine-tune binding affinities and drive the epistatic relationships that support functional outcomes. Here, we used the complex of bovine pancreatic trypsin inhibitor (BPTI) and chymotrypsin as a model system to study how mutations at one or two positions affect binding affinity and epistasis. To predict the binding affinity landscape of the BPTI-chymotrypsin complex, we combined deep sequencing data, obtained from a saturation scanning mutagenesis BPTI library, with a machine-learning (ML) model. Using this ML model, which was trained on a subset of experimental binding data, we predicted the binding affinities and epistatic interactions across thousands of single and double BPTI mutants, including those not observed in the library. Our predictive approach completed missing data points and enabled us to reveal global trends in affinity changes and mutation couplings within specific binding interface positions. Our analysis revealed that different mutations in the same position may have different effects on affinity, with most double mutations leading to increased epistasis, particularly at hotspot positions, thereby indicating a cooperative binding effect. In most cases, affinity and epistasis were inversely correlated, with affinity enhancement of double-mutant variants being associated with negative epistasis. Our approach can be readily generalized to predict mutation effects in larger combinatorial libraries and in proteins for which structural information is lacking.

Biochemistry, Genetics and Molecular Biology

Interaction Between Rec8 and Mis4 Is Required for Axis-Loop Chromatin Formation and Homologous Chromosome Recombination During Meiosis.

Sakuno T et al. · Jul 1, 2026

The Rec8 cohesin complex is required for the pairing and recombination of homologous chromosomes during meiosis, as well as for the cohesion of sister chromatids. In the fission yeast Schizosaccharomyces pombe, we previously identified a rec8-F204S mutant that lost the ability to assemble the axis-loop chromatin structure without losing sister chromatid cohesion. This mutant showed reduced meiotic recombination, indicating that pairing and recombination of homologous chromosomes require the formation of the axis-loop chromatin structure mediated by the Rec8 cohesin complex. Loading of the Rec8 cohesin complex onto chromatin is mediated by Mis4 (NIPBL in humans; Scc2 in yeast). In this study, to elucidate the functions of Mis4, we identified a mis4-LR mutant (L1150S and R1159G) that reproduced the phenotypes of the rec8-F204S mutant, which is defective in chromatin axis formation and homologous recombination while retaining sister chromatid cohesion. These mutation sites (Mis4-L1150, Mis4-R1159, and Rec8-F204) are all localized at the interaction surface between Mis4 and Rec8. Biochemical analysis revealed that the Mis4-LR mutant protein exhibited reduced Rec8-binding activity. Considering that the mis4-LR mutant phenocopied the rec8-F204S mutant, our results demonstrate that the Mis4-Rec8 interaction is required for proper formation of Rec8-dependent meiotic chromosome axis.

Biochemistry, Genetics and Molecular Biology

Expansion of the Phenotypic and Genotypic Spectrum of MED13L-Associated Neurodevelopmental Disorder: A Case Report and Literature Review.

Wang Z et al. · Jul 1, 2026

Background Pathogenic variants in MED13L, including copy-number changes and sequence variants, cause MED13L syndrome. This rare neurodevelopmental disorder is characterized by global developmental delay, intellectual disability (ID), distinctive facial dysmorphism, hypotonia, and variable congenital heart defects. The phenotypic heterogeneity of MED13L syndrome underscores the significance of genotype-phenotype correlation analysis for improving clinical diagnosis and precise phenotypic characterization of affected individuals. Methods Venous blood samples anticoagulated with EDTA were collected from the patient and family members, followed by whole-exome sequencing analysis and subsequent validation using fluorescent quantitative PCR. Concurrently, a systematic search of the PubMed database was performed to summarize previously reported cases harboring MED13L copy number Variations (CNVs). Results Whole-exome sequencing revealed a de novo heterozygous single-copy duplication of a ~19-kb region within the MED13L gene (exons 8-16) in the proband. The patient presents phenotypic features consistent with MED13L syndrome and represents the first reported case exhibiting cleft lip. A literature review indicates that vision impairment, developmental delay, and congenital heart disease are widely observed phenotypes, while other less frequent manifestations vary between patients with duplications and deletions. Conclusion This study, integrating a case report and a literature review, provides important reference evidence for the clinical genetic counseling of MED13L syndrome.

Biochemistry, Genetics and Molecular Biology

A Ten-Country Study on Public Perceptions of 5G EMF Emissions: Who Feels Exposed, and Why?

Link SC et al. · Jul 1, 2026

Formal risk assessment considers characteristics such as proximity, dose, and vulnerability. However, public risk perception may also be influenced by other-possibly less relevant-factors such as visibility and novelty. The introduction of 5G and its associated infrastructure and radiofrequency electromagnetic fields (RF-EMF) may therefore change perceptions of RF-EMF from mobile communications in general. To explore this, we conducted an online survey in 10 European countries (n = 10,358) using a picture-based approach. Respondents perceived daily RF-EMF exposures as moderate but expected them to increase with 5G. A mobile phone at the ear was generally associated with higher perceived exposure than multiple base stations. Overall, distance to the RF-EMF source most strongly influenced perceived exposure, followed by the number of sources. 5G reception was linked to higher exposure perception than 4G or Wi-Fi reception. These patterns were consistent across most countries. We conclude that when assessing RF-EMF exposure, people rely on heuristics (e.g., more sources imply more exposure) that often guide them correctly. Understanding when and why people feel particularly exposed can help develop more effective communication about true levels of exposure and risk.

Biochemistry, Genetics and Molecular Biology

Exercise-Induced Extracellular Vesicles as Mediators of Mitochondrial Biogenesis and Insulin Sensitivity in Metabolic Adaptation.

Wang J et al. · Jul 1, 2026

Background Metabolic diseases like type 2 diabetes and obesity share insulin resistance as a common feature, driven partly by mitochondrial dysfunction. Exercise-induced extracellular vesicles (EVs) have emerged as mediators of inter-organ communication in metabolic regulation. Objective To synthesize evidence on exercise-induced EVs in mitochondrial adaptation and insulin sensitivity, and propose an integrative framework linking EV-mediated communication to systemic metabolic benefits: METHODS: Narrative synthesis of mechanistic, animal, EV transfer/inhibition, translational, and human studies. Results Exercise alters EV abundance and cargo, including mitochondrial proteins, metabolic enzymes, and microRNAs. These cargoes may activate energy-sensing, NAD + -dependent, transcriptional, and post-transcriptional pathways to enhance mitochondrial biogenesis and oxidative metabolism. By improving substrate utilization and reducing lipotoxicity, mitochondrial ROS, ER stress, and inflammation, EV-mediated mitochondrial adaptation may boost insulin sensitivity and insulin signaling. EV transfer/inhibition studies support a contributory role for exercise-induced EVs in glucose homeostasis, though evidence remains context-dependent. Conclusions Exercise-induced EVs may link exercise stimuli to mitochondrial adaptation and systemic insulin sensitivity. The proposed "exercise-EV-mitochondrial adaptation-insulin sensitivity" framework offers a conceptual basis for understanding systemic metabolic adaptation and highlights translational potential for metabolic diseases. Future work should clarify causality, tissue specificity, pharmacokinetics, and standardization.

Biochemistry, Genetics and Molecular Biology

Renal expression of Bach1 and oxidative stress in chronic kidney disease: evidence from a preclinical model.

Cruz BOD et al. · Jul 1, 2026

Introduction The transcription factor BTB and CNC homology 1 (Bach1) represses the nuclear factor erythroid 2-related factor 2 (Nrf2), which controls antioxidant gene expression, and its role in chronic kidney disease (CKD) remains unclear. Methods CKD was induced by 5/6 nephrectomy in rats. Kidney fibrosis and oxidative stress markers were measured. The gene expression of Nrf2, Bach1, and nuclear factor kappa B (NF-κB) was assessed. Results CKD increased oxidative stress markers in plasma, kidney, and heart, as well as promoted kidney fibrosis. Moreover, CKD reduced cardiac Nrf2 expression. However, Bach1, Nrf2, and NF-κB remained unchanged in the kidney. Conclusion CKD did not modulate Bach1 mRNA levels in the kidneys of 5/6 nephrectomized rats.

Biochemistry, Genetics and Molecular Biology

UPLC-QTOF-MS/MS and Antifungal Activity of a Fraction Enriched in Saponins From Sarcomphalus joazeiro Against Candida spp.

da Silva ARP et al. · Jul 1, 2026

The development of antifungal resistance is a complex process that involves the interaction between hosts, drugs, and microbial factors, all of which contribute to therapeutic ineffectiveness. For this reason, studies on natural products as possible therapeutic alternatives are increasingly necessary in order to gain a better understanding of plant compounds that may be more effective in treating infections caused by fungal pathogens. In this context, this study aimed to investigate the antifungal potential of the saponin-enriched fraction of the Sarcomphalus joazeiro species against the Candida albicans, Candida tropicalis, and Candida krusei strains. The selection of this species for study is due to its rich phytochemical composition and the vast traditional knowledge of its medicinal properties. The fraction obtained from the stem bark of S. joazeiro was analyzed by UPLC-QTOF-MS/MS, in which compounds such as triterpenoids, flavonoids, acids, and saponins were identified. Therefore, the results obtained in this study contribute to understanding the antifungal potential of the S. joazeiro species fraction against fungal infections, especially those caused by Candida spp.

Biochemistry, Genetics and Molecular Biology

Ectonucleotidases CD39 and CD73 expression levels are independent and inverse predictors of survival in muscle-invasive bladder cancer.

Ledderose S et al. · Jul 1, 2026

Bladder cancer is one of the leading causes of cancer-related mortality worldwide. Long-term survival is particularly poor in patients with muscle-invasive bladder cancer (MIBC). Modulation of purinergic signaling through the ectonucleotidases CD39 and CD73 has emerged as a promising therapeutic strategy in cancer medicine. Altered expression patterns of these molecules have been linked to prognosis in various malignancies. In this study, we assessed the value of CD39 and CD73 expression as prognostic markers and potential therapeutic targets in MIBC. CD39 and CD73 expression was determined by immunohistochemistry using tissue microarrays from 180 patients with MIBC. Associations between tumoral and stromal expression and clinicopathological variables, including overall survival (OS), tumor-specific survival (TSS) and disease-free survival (DFS), were analyzed. Tumor cells did not express CD39. High stromal CD39 expression was significantly associated with a lower T category and UICC stage as well as prolonged median OS, TSS, and DFS. High CD73 expression by tumor cells was significantly associated with poorer OS and TSS. Stromal CD73 expression was not significantly correlated with survival outcomes. Our findings indicate distinct and compartment-specific roles for CD39 and CD73 in MIBC. They suggest that high CD73 expression in tumor cells and low CD39 expression in stromal cells are negative prognostic indicators and potential therapeutic targets in MIBC.

Biochemistry, Genetics and Molecular Biology

Cellular Heterogeneity During Arterial Aging.

Xu H et al. · Jul 1, 2026

Arterial aging is a major risk factor for cardiovascular disease and is associated with progressive changes in vascular structure and function, including arterial stiffening, reduced elasticity, extracellular matrix remodeling, chronic low-grade inflammation, and accumulation of senescence-associated cell states. Recent advances in single-cell RNA sequencing (scRNA-seq) have provided new opportunities to resolve the cellular heterogeneity underlying these age-related alterations in the arterial wall. In this review, we summarize current single-cell studies of arterial aging by focusing first on key phenotypic programs, including cellular senescence, extracellular matrix remodeling, inflammaging, and altered intercellular communication, and then discuss how these programs are reflected in endothelial cells, smooth muscle cells, fibroblasts, and immune cells. Across studies, aging is recurrently associated with endothelial dysfunction, smooth muscle cell phenotypic modulation, fibroblast-related matrix remodeling, and immune activation, although the degree of conservation varies depending on species, vascular bed, sex, and disease context. We further discuss emerging evidence that vascular aging involves not only cell-intrinsic transcriptional changes but also alterations in communication networks across the arterial wall. Although current single-cell studies have substantially improved our understanding of arterial aging, important limitations remain, including inconsistent cell-state annotation across studies, incomplete functional validation, and limited spatial and epigenetic resolution. Future integration of cross-species analyses with spatial transcriptomics, single-cell epigenomic approaches, and functional studies will help refine the cellular framework of arterial aging and improve its translational relevance.

Biochemistry, Genetics and Molecular Biology