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
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
Parchuri P et al. · Jul 1, 2026
Triacylglycerols are the major energy storage lipids in plants, animals, and microorganisms, and are predominantly produced by acyl-CoA:diacylglycerol (DAG) acyltransferases (DGATs). Two enantiomers of the DAG substrate, sn-1,2 and sn-2,3, can be produced by different biological mechanisms; however, little is known about which species produce each enantiomer, the selectivity of DGAT isoforms for either enantiomer, or whether DGAT enantiomer selectivity varies across organisms. Here, DAG enantiomer selectivity of DGAT1 and DGAT2 was measured from eight seed plants, two mammals, one oleaginous yeast, and one photosynthetic microalga using enantiomer-specific in vitro DGAT assays. Across most plants, DGAT1 favored sn-1,2-DAG, whereas DGAT2 preferentially utilized sn-2,3-DAG. However, there were several exceptions. Mammalian DGAT1, DGAT2, and microbial DGAT1s efficiently used both DAG enantiomers, while microbial DGAT2s had unique selectivity. The selectivity of several DGATs for combined acyl-CoA and DAG enantiomer molecular species were also evaluated for biotechnical applications. Therefore, DGAT DAG enantiomer selectivity is common yet strongly dependent on lineage and isoform and likely shaped in part by species-specific metabolic context of triacylglycerol synthesis, turnover, and remodeling. This work expands our understanding of DGAT function and establishes a foundation for leveraging enantiomer-selective acyltransferases in metabolic engineering of tailored lipid products.
Biochemistry, Genetics and Molecular Biology
Shahparvari MR et al. · Jul 1, 2026
Background Pancreatic steatosis (PS) is a metabolic condition associated with obesity, insulin resistance, and fatty liver disease. Advanced Glycation End Products (AGEs), abundant in processed and high-temperature-cooked foods, have been linked to several metabolic disorders; however, their relationship with PS has not been previously examined. Methods In this case-control study, 278 individuals with gallstones, aged 55.7 ± 15.1 years, were classified as cases (with PS, n = 89) or controls (without PS, n = 189). PS was defined based on increased echogenicity of the pancreatic parenchyma relative to surrounding structures. Dietary intake was assessed using a food frequency questionnaire. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for PS across quartiles of dietary AGE intake. The fully adjusted model included age, sex, total energy intake, body mass index, smoking status, and alcohol consumption. Results Higher dietary AGE intake was significantly associated with an increased likelihood of PS. In the crude model, odds of PS did not differ significantly across quartiles of dietary AGE intake compared with the lowest quartile. After adjustment for age and sex, individuals in the highest quartile had higher odds of PS (OR = 3.56; CI: 1.1-11.6; p = 0.040). In the fully adjusted model, significant associations were observed for the third (OR = 2.76; CI: 1.69-11.1) and fourth (OR = 3.3; CI: 1.79-13.7) quartiles of dietary AGE intake compared with the lowest quartile. A significant positive trend in the odds of PS was observed across increasing quartiles of dietary AGE intake (p for trend = 0.024). Conclusion Our findings suggest a potential role of dietary AGEs in pancreatic fat accumulation; however, causality cannot be inferred. Larger prospective and interventional studies are needed to confirm these associations and to determine whether reducing dietary AGE exposure can beneficially influence pancreatic fat.
Biochemistry, Genetics and Molecular Biology
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
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
Huang H et al. · Jul 1, 2026
Elastin-collagen nanoparticles (ECnPs) have been shown in our previous studies to self-assemble into different morphologies, including nanoplates and nanovesicles, by manipulating the sequence length of the elastin-like peptide (ELPs) and collagen-like peptide (CLPs) of a given conjugate. In this work, we demonstrate that the morphologies of ECnPs can also be modulated, for a given ECnP sequence, with variations in solution pH and/or the amount of encapsulated drug. Specifically, the peptide (VPGYG) 6 -(GPO) 8 preferentially formed nanovesicles under basic conditions but assembled into nanoplates under acidic conditions. Another sequence, (VPGWG) 2 (VPGFG) 2 -(GPO) 8 , produced nanovesicles when loaded with a high concentration of dexamethasone-carboxyfluorescein (Dex-CF), but transitioned to nanoplates at lower drug loading. Furthermore, in addition to the different morphologies observed for a given set of initial solution conditions, our studies also illustrate the possibility of triggering vesicle-to-plate transformations for a given ECnP with release of Dex-CF over time. These results highlight multiple avenues for controlling ECnP morphology, expanding their applicability as a flexible and efficient drug delivery platform.
Biochemistry, Genetics and Molecular Biology
Khan MA et al. · Jul 1, 2026
Background and objective Cutaneous leishmaniasis (CL) remains a significant public health concern in endemic regions of Pakistan, particularly in ecologically diverse and resource-limited areas. This study aimed to investigate the epidemiology, risk factors, lesion characteristics, seasonal trends and spatial distribution of CL in District Bajaur, Khyber Pakhtunkhwa, Pakistan. Methods A cross-sectional observational study was conducted in 2022, including clinically suspected and laboratory-confirmed CL cases from all nine tehsils of District Bajaur. Demographic information, lesion characteristics (site, type and number), season of presentation and regional distribution were collected using a structured questionnaire. Statistical analyses included univariate and multivariate logistic regression, multinomial regression, Poisson regression, stratified analyses and interaction modelling. Spatial clustering was evaluated using Z-scores, Moran's I statistics and GIS-based risk mapping. Results CL prevalence was significantly higher among males, younger individuals, unmarried participants and during the summer season. Lesions were predominantly located on exposed body parts, especially the hands and face, with dry lesions and single-lesion presentations being most common. Multivariate analysis identified male gender, younger age, unmarried status, summer season, dry lesion type and single lesions as independent risk factors. Stratified and interaction analyses indicated an elevated risk among young males during the summer. Spatial analysis revealed significant clustering of cases, with Khar, Loe Mamund and Salarzai identified as high-risk tehsils. A clinician-friendly risk scoring system was developed to estimate individual infection probability. Conclusion CL in District Bajaur is influenced by a complex interaction of demographic, clinical, seasonal and spatial factors. These findings emphasize the importance of targeted surveillance, vector control strategies and risk-based interventions to reduce disease burden in endemic regions.
Medicine
Li C et al. · Jul 1, 2026
Diabetic nephropathy (DN), a major complication of diabetes mellitus (DM), is characterized by severe clinical manifestations, impaired quality of life, and a high risk of progression to end-stage renal disease, underscoring the urgent need for effective therapeutic interventions. Mesenchymal stromal cell-derived exosomes (MSC-Exo) have emerged as promising candidates for mitigating inflammatory injury in DN due to their immunomodulatory properties, and exosomes derived from MSCs pretreated with inflammatory factors such as TNF-α and IFN-γ may possess enhanced therapeutic potential. In this study, exosomes isolated from human umbilical cord MSCs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Their therapeutic effects were evaluated in diabetic mice, focusing on renal inflammation and macrophage polarization. Both normal MSC-Exo (Norm-Exo) and TNF-α&IFN-γ-pretreated MSC-Exo (TNF-α&IFN-γ-Exo) effectively ameliorated kidney injury and promoted M2 macrophage polarization, with TNF-α&IFN-γ-Exo showing superior efficacy. High-glucose-stimulated RAW264.7 cells were used to explore the underlying mechanisms, and high-throughput RNA sequencing identified inhibitor of DNA binding 3 (ID3) as a molecule involved in MSC-Exo-regulated macrophage polarization. Loss-of-function experiments confirmed that ID3 knockdown alone recapitulated the effects of exosomes, promoting M2 polarization and suppressing M1 markers. Conversely, ID3 overexpression attenuated exosome efficacy. Mechanistically, ID3 partially mediated exosome-induced inhibition of the NF-κB pathway. The translational relevance of these findings was further validated in PMA-differentiated THP-1 human macrophages. Collectively, these findings demonstrate that MSC-Exo-particularly TNF-α&IFN-γ-Exo-attenuate diabetic renal injury by modulating macrophage polarization through ID3 regulation, highlighting a novel cell-free immunomodulatory approach for DN therapy.
Biochemistry, Genetics and Molecular Biology
Snel LIP et al. · Jul 1, 2026
Introduction The use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the perioperative setting may lead to SGLT2i-associated postoperative ketoacidosis (SAPKA) in patients with type 2 diabetes (T2D). Therefore, cessation of this drug is recommended before surgery. We aimed to study reported cases to assess the causality of SGLT2i, identify common characteristics, potential risk factors, treatment and outcomes of SAPKA. Methods We conducted a systematic literature search to identify case reports of patients with metabolic acidosis and the presence of ketones who used SGLT2i in the perioperative setting. Case reports were summarised for common characteristics, assessed for quality and distributed to a panel of diabetes experts, who evaluated the likelihood of SAPKA using a questionnaire. Results Ninety-three papers containing 128 case reports fulfilled the inclusion criteria. The expert panel found SAPKA to be 'likely' in 53 (41%), 'possible' in 38 (30%) and 'unlikely' in 27 (21%) cases; 10 cases (8%) could not be validated due to insufficient data or implausible timing. SAPKA was therefore considered likely or possible in 71% (91/128) of cases. Common factors identified in the SAPKA reports included a diagnosis of T2D mellitus (n = 115), impaired perioperative intake (n = 30) and insufficient insulin supplementation (n = 10). Treatment with insulin was effective, and ketoacidosis resolved in all surviving patients, although significant morbidity, including ICU admission, was reported in a substantial proportion of cases. Discussion Confirming a SAPKA diagnosis is challenging due to the variable reporting quality and numerous confounding factors present during the perioperative period. Clinicians should remain aware of SAPKA given the increasing prevalence of SGLT2i use. Focusing on early recognition and treatment represents a potential alternative strategy to routine preoperative SGLT2i discontinuation, though this requires further prospective evaluation. Editorial comment This systematic review presents an overview and discussion of the many, to date, case reports of ketoacidosis thought to be associated with perioperative SGLT2 inhibitor treatment.
Medicine