Variation in protein 3D structures reflects genetic variation and contributes to phenotypic diversity, yet its underlying genetic mechanisms remain unclear. To investigate the relationship between protein 3D structure and phenotype, we predict the 3D structures of 795,649 proteins from 26 maize (Zea mays L.) inbred lines using AlphaFold2. Population genetics analysis of these protein 3D structures reveal that buried residues held greater genomic evolutionary rate profiling (GERP) scores than exposed residues, indicating that buried residues are under stronger purifying selection. The design of the maize nested association mapping population makes it possible to utilize haplotype information and protein 3D structural variation to reveal the molecular mechanisms linking genetic diversity and phenotypic variation for a population with about 5000 individuals. Associating protein 3D structure variation with phenotypes (structure-based proteome-wide association study [PWAS]) identifies 14.2% more (96 vs. 84) significant proteins compared with associating protein sequence with phenotypes (sequence-based PWAS) using 32 agronomic traits. Moreover, structure-based PWAS identifies 24 additional significant proteins unique to predicted structures, whereas sequence-based PWAS identifies 12 additional significant proteins. Structure-based proteome-wide predictions (PWPs) improve genomic prediction accuracy by an average of 3.8% compared with sequence-based PWPs. In general, predicted protein 3D structures represent a powerful approach for understanding the natural diversity of protein haplotypes.

Objective.β-emitting radionuclides, such as90Sr90Y, are widely used in clinical settings for the treatment of both benign and malignant lesions, particularly as surface applicators. Despite their clinical relevance, the three-dimensional dose distributions delivered by these applicators remain inadequately characterized using Monte Carlo simulations, the current gold standard for dose calculation. This study aims to address these limitations by characterizing the three-dimensional dose distribution of a commonly used90Sr90Y Pterygium applicator. The goals include generating accurate percent-depth-dose (PDD) curves and validating a custom irradiation setup using radiochromic film and Monte Carlo simulations to enable accessible, reproducible, and highly precise radiobiology experiments.Approach. A Monte Carlo dose calculation software based on Geant4 10.02.p02 was developed, and the Amersham SIA 20 Pterygium applicator, a stacked film setup with 30 EBT-XD GafChromic®films, and a film-cell irradiation setup (a film layer, cell monolayer, and growth media) were modeled. The dose rate was averaged over the 8.2 mm diameter active area on the surface in water in both the stacked film setup and the film-cell setup. The spectrum of the source was also calculated. An experimental PDD was generated by irradiating stacked films and was compared to the Monte Carlo simulations.Main results. The measured and computed PDDs agreed within 2% within 2.6 mm of depth. The dose rates were 28.30, 26.48, 21.23, and 22.76 cGy s-1on the surface in water, in the film active layer, in the cell monolayer, and in the growth media, respectively, compared to the manufacturer's nominal value of 27 cGy s-1.Significance. A Monte Carlo-validated PDD curve of the source was generated in a stacked film setup using EBT-XD GafChromic®film. A custom film-cell irradiation setup was characterized for future radiobiology experiments.

DNA literacy is becoming increasingly essential for navigating healthcare, understanding pandemics, and engaging with biotechnology-yet genomics education remains limited at the secondary level of education. We present a modular, hands-on curriculum designed for high school and early undergraduate students (ages 14-21) that introduces key genomics concepts through an experiment on fermentation, a process that is key to food preservation and medicine. Students follow a complete scientific process: exploring what DNA is and how microbial succession works, analyzing real DNA sequencing data, and writing a formal scientific report. The course integrates molecular biology, bioinformatics, and data analysis obtained from portable nanopore sequencing technology (Oxford Nanopore MinION), giving students access to authentic data sets. Activities such as microbial species identification using taxonomic IDs foster skills in observation, experimental design, and quantitative reasoning. The curriculum aligns with Next Generation Science Standards (NGSS) and Vision and Change (V&C) frameworks, supporting interdisciplinary learning and scientific literacy. By making molecular biology visible and relatable, this curriculum equips diverse learners with the tools to engage meaningfully in a genomics-driven world.

Human milk exhibits dynamic diurnal variations in bioactive components that are conducive to the consolidation of the biological clock in early life, particularly in the establishment of the sleep-wake cycle in infants. The objectives of the present study are to evaluate the circadian rhythm of amino acids and melatonin in human milk and elucidate their potential sleep-wake regulatory mechanism. Amino acids and melatonin were analyzed in 80 human milk samples collected every 6 hours over a 24-hour period from 20 healthy nursing mothers around 30 days postpartum. Different doses of rhythmic components in human milk were administered to normal mice via oral gavage for 7 days. The comprehensive lab monitoring system (CLAMS) and pentobarbital sodium-induced sleep test (PST) were used to evaluate the sleep-inducing and wake-promoting effects. Liquid chromatography-tandem mass spectrometry and enzyme-linked immunosorbent assay were used to detect the levels of neurotransmitters and hormones to identify the underlying mechanisms. Histidine, phenylalanine, tyrosine, tryptophan and melatonin in human milk exhibit circadian variation with higher levels of histidine, phenylalanine and tyrosine during the daytime and higher contents of tryptophan and melatonin at night. High-dose histidine increased total activity levels in the x-direction and sleep latency and decreased sleep duration through the increased level of histamine and decreased level of gamma-aminobutyric acid (GABA) in the hippocampus and hypothalamus of normal mice. In contrast, high doses of tryptophan and melatonin decreased oxygen consumption rate, x-direction total activity levels and sleep latency and increased sleep duration through different neurotransmitter pathways where high-dose tryptophan increased the 5-hydroxytryptamine level while high doses of melatonin increased melatonin and GABA in the hippocampus and hypothalamus of normal mice. In conclusion, the circadian variation of specific amino acids and melatonin in human milk might contribute to the establishment of the sleep-wake cycle in infants.

ABSTRACT Introduction The combination of MEK and BRAF inhibitors is effective in melanomas and other tumors with BRAF V600E mutations. MEK inhibitors enhance efficacy and delay the development of resistance to BRAF inhibitors. Recently, MEK inhibitors have demonstrated activity in plexiform neurofibromas in patients with type 1 neurofibromatosis and in histiocytic neoplasms. In the preclinical setting, MEK inhibitors are effective in tumors with RAS or receptor tyrosine kinase mutations. However, after the inhibition of MEK, regulatory feedback determines the rebound activation of ERK, thereby limiting the effect of the MEK blockade. In early clinical trials, MEK inhibitor monotherapy has shown limited efficacy in RAS-mutated tumors, whereas trials combining MEK and RAS inhibitors are still ongoing. Areas covered Clinical trials have been selected from clinicaltrials.gov searching for ‘MEK inhibitors,’ and their results have been searched in PubMed and meeting abstracts. Preclinical studies have been searched in PubMed using the names of the MEK inhibitors. This is a descriptive review. Expert opinion While MEK inhibitors in combination with BRAF inhibitors obtained one of the first tumor-agnostic FDA approvals for BRAF V600E/K mutated tumors, additional indications for MEK inhibitors alone have been received in very selected diseases for which molecular characterization is crucial.

Octopamine (OA), the insect analog of noradrenaline, plays important roles in diverse behavioral and physiological processes, from modulating fight-or-flight behavior to regulating post-mating ovulation. In Drosophila, six OA receptors have been identified: Oamb, Octα2R, Octβ1R, Octβ2R, Octβ3R, and Oct-TyrR, and they have been linked to different behavioral and physiological processes. Here, we investigated the evolutionary characteristics of these receptors across Drosophila species. We found that OA receptors are generally found as single-copy genes. Notably, Octβ2R and Octβ3R exhibit positive selection within the melanogaster group, though in different structural regions from one another. The positively selected sites in Octβ2R are exclusively located in regions important for ligand binding, whereas those in Octβ3R are predominantly found in regions crucial for signal transduction. Interestingly, Octβ2R remains highly conserved outside the melanogaster group, so the detection of positive selection in its ligand-binding related domains within this clade raises the possibility that it has evolved an additional, melanogaster-specific ligand interaction(s), among other potential reasons. These findings highlight the evolutionary flexibility of aminergic signaling and suggest lineage-specific adaptations of OA receptor function in Drosophila, likely shaped by lineage-specific selective pressures.

Enolate carboxylation by CO2 is essential to applications ranging from polymer synthesis to CO2 capture, yet the CO2-reactivity of stabilized enolates, such as β-dicarbonyl enolates, remains understudied. Combining detailed NMR and DFT studies, we report the reactivity of diverse potassium β-diketonates and β-diketiminates towards CO2. Our findings reveal the critical role of β′-substituents on β-diketiminates and an unexpected CO2-concentration-dependent reactivity switch, offer-ing structural insights for designing materials with tunable CO2 reactivity.