The comprehensive annotation of human genomic variants is crucial for the biological interpretation and association of these variants with disease phenotypes. Various tools have been developed to annotate variants using established reference databases. In addition to the significant advancements in open-source genomics, parallel initiatives have been undertaken within the industry to facilitate variant identification and annotation. evaiutilities enhances these capabilities by offering a scalable solution for population-level analysis through a command line, a web interface, and a desktop interface.
Zinc dyshomeostasis has been associated with neurodegenerative processes, but molecular-level models of Zn(II) recognition by guanidino- and biguanide-containing molecules must account for protonation, conformational flexibility, and competition with the first hydration shell. Here, a hierarchical density functional theory strategy was applied to guanidine, galegine, metformin, and L-arginine. Neutral ligands, relevant protonated forms, and simplified [Zn(L)]2+ adducts were examined using the Becke three-parameter Lee–Yang–Parr (B3LYP) functional with the 6-311+G(d,p) basis set and integral equation formalism polarizable continuum model (IEFPCM) water solvation (Set I), whereas [Zn(H2O)6]2+ and explicitly hydrated [Zn(L)(H2O)5]2+ first-shell substitution models were evaluated using B3LYP with Grimme D3 dispersion and Becke–Johnson damping [D3(BJ)]/def2-SVP/IEFPCM(water) (Set II). Harmonic-frequency analyses supported the reported stationary structures as local minima within the corresponding computational models. Within Set I, the simplified [Zn(L)]2+ adducts display Zn-N distances of 1.924–1.935 Å. Within the separate Set II hydrated coordination models, direct Zn-N coordination is retained with Zn-N distances of 2.007–2.028 Å. Protonation shifts the molecular electrostatic potential toward positive values around guanidino/biguanide fragments, reducing electrostatic donor accessibility. Targeted torsional checks further show that flexible-ligand descriptors are conformer-dependent; for neutral L-arginine, the A6 carboxylic-OH rotamer adopted for the final analysis has a frontier-orbital separation of 6.214 eV, compared with 5.984 eV for the initial pre-A6 conformer. These results define a preliminary descriptor-based electronic-structure and first-shell coordination framework rather than a prediction of binding affinity, predominant physiological speciation, or pharmacological activity.
Amyloidosis such as Alzheimer’s disease is characterized by the deposition of amyloid fibrils in organs. Amyloid fibrils show polymorphism, where the same protein forms fibrils with distinct morphologies. However, it remains unknown what structural differences in monomers result in polymorphic amyloid fibrils. Here, using small-angle X-ray scattering (SAXS) on hen egg white lysozyme, a model protein for amyloid research, monomer structures were investigated at pH 2.7 and pH 6.0, where two kinds of polymorphic amyloid fibrils are formed. It was found that the monomer takes on a highly extended conformation in the buffer to form fibrils at pH 2.7 whereas it takes on a less extended conformation in the buffer to form fibrils at pH 6.0. The resultant fibrils were found to be represented by a long cylinder with different sizes of cross-sections, suggesting polymorphic fibrillar structures. Wide-angle X-ray scattering (WAXS) measurements on the fibrils showed that both fibrils possess an inter-β-strand distance of 4.8 Å while only those at pH 6.0 possess an additional inter-β-strand distances of 4.7 Å, indicating diverse structures for this polymorph. The present results suggest that monomers with a less extended conformation hamper the formation of stable β-sheet structures, leading to diverse conformations of fibrils.
The Mycobacterium tuberculosis enzyme EthA (Rv3854c) impacts the survival of mycobacterial cells by converting inactive precursors of second-line anti-tubercular drugs like ethionamide (ETH) to an active form. This potentially inhibits cell wall mycolic acid biosynthesis. An Alphafold2-computed structural model of EthA reflects that it is a Class B Baeyer–Villiger Monooxygenase (BVMO) with two Rossmann fold motifs. Motif 1 is a FAD-binding motif which spans His4-Trp45 and Motif 2 is an overlapping FAD/NADP that spans between Asp174 and Gln215. We identified 4-Amino-3-methylnaphthol as the top-ranked structural alternative substrate candidate from the DrugBank library and 4-(1H-1,3-benzodiazole-2-yl)quinoline from the Maybridge library. Steady-state kinetic studies on the NADPH-dependent oxidation of EthA—using its lead natural substrate ETH and 4-methoxyphenylacetone—revealed that 4-methoxyphenylacetone is a promising structural alternative substrate. The molecular interactions and stability of ligands like ETH, DB15664, JFD03535 and 4-MPA with EthA model were analyzed using molecular dynamic simulations carried out over a 500-nanosecond time scale. Furthermore, the biophysical characterization of EthA was carried out through Dynamic Light Scattering, Differential Scanning Calorimetry, Circular Dichroism, Fluorescence and Fourier-Transform Infrared Spectroscopic methods.
MicroRNAs (miRNAs) are small (19–24 nucleotide), non-coding RNAs that regulate post-transcriptional gene expression and play fundamental roles in maintaining cellular homeostasis and human health. Their disease-specific expression profiles have established them as promising biomarkers for the diagnosis, prognosis, and therapeutic monitoring of cancers, infectious diseases, cardiovascular disorders, neurological diseases, and metabolic conditions. More recently, miRNAs have been identified in diverse plant, animal, and microbial-derived foods, raising interest in their potential roles as bioactive dietary molecules capable of modulating human physiology following oral consumption. This review summarises current knowledge on food-derived miRNAs, their biological functions, cross-kingdom regulatory activities, and therapeutic potential. To achieve this, a literature search was undertaken across PubMed, Web of Science, and Scopus for articles published between January 2000 and May 2026. Keywords related to food-derived miRNAs, cross-kingdom regulation, stability mechanisms, and advanced biosensing platforms were utilised for article retrieval with a focus on peer-reviewed experimental and clinical studies. Beyond the biological roles of miRNAs, the review highlights the structural and biophysical determinants governing miRNA stability, including secondary structure, thermodynamic properties, Argonaute (AGO) interactions, extracellular vesicle encapsulation, and biomolecular assemblies that influence their persistence, transport, bioavailability, and regulatory activity. Recent advances in nanomaterial-enabled biosensors, electrochemical sensing, CRISPR-based diagnostics, super-resolution imaging, and microfluidic analytical platforms for miRNA detection and quantification are also discussed. Despite growing evidence supporting the biological relevance of dietary miRNAs, important challenges remain regarding their stability during food processing and gastrointestinal digestion, absorption, systemic transport, and definitive demonstration of bioactivity in humans. Collectively, this review highlights the potential of food-derived miRNAs in precision nutrition, biomarker discovery, functional food development, and RNA-based therapeutics while emphasizing the need for standardized analytical methodologies, mechanistic validation, and rigorous clinical investigation to facilitate future translational applications.
