Potassium channels exhibit high selectivity and conductance, yet the atomic details of ion permeation, particularly the involvement of water molecules, remain debated. Two main conduction mechanisms have been proposed: the hard knock-on, in which ions traverse the selectivity filter in direct contact, and the soft knock-on, which involves co-permeation of water molecules. Using microsecond molecular […]

Background: Antidepressant prescribing and autism diagnoses have both increased in recent years, however antidepressant prescribing patterns for autistic adults are not well understood. Aims: (1) To describe antidepressant trends in autistic and non-autistic adults in the UK from 1997 to 2023. (2) To compare trends between autistic adults and age- and sex-matched non-autistic adults. (3) […]

Machine learning holds great promise for accelerating enzyme optimization, but its power is fundamentally constrained by the limited availability of sequence-fitness data. Here, we introduce MillionFull, a low-cost method that enables high-throughput full-length sequence-fitness mapping for enzymes of arbitrary length. Each run yields on the order of 10^5 – 10^7; data points, capturing sequence-function relationships […]

Methionine adenosyltransferase synthesizes S-adenosylmethionine (SAM), the universal methyl donor. Its ubiquitous isozyme MAT2 is present in the nucleus and regulates gene expression through histone methylation. However, the physiological significance of its nuclear enzymatic activity remains unclear. Here, we investigate the role of nuclear MAT2 in antibody class switch recombination (CSR), a crucial process in adaptive […]

Type III CRISPR systems generate cyclic oligoadenylate (cOA, 3 to 6 AMPs) messengers upon detecting viral RNA, activating downstream effectors to defend against viral infection. Although cOA-activated effectors have been extensively characterized, the cA5-specific effectors remained unexplored despite cA5 being among the most abundant cOA species produced during phage infection. Here, we report that Actinomyces […]

Cells rely on precise metabolic control to adapt to environmental cues. The mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, with amino acids serving as key signals. Lysosomes, which act as nutrient recycling centers, maintain amino acid homeostasis by breaking down macromolecules and releasing amino acids for cellular use. SLC38A9, a lysosomal amino […]

Heterotrophic bacteria exhibit remarkable taxonomic and metabolic diversity. Experimental phenotyping of individual strains is often impractical due to the diversity of metabolic strategies, highlighting the need for predictive approaches based on biochemical principles. Here, we demonstrate that bacteria preferentially catabolize amino acids that are energetically inexpensive to synthesize and require shorter degradation pathways. Our results […]

The human-specific bacterial pathogen Group A Streptococcus (GAS) is a significant cause of morbidity and mortality due to its ability to cause severe invasive infection. Although macrophages are important for controlling GAS infection, we and others have demonstrated that GAS can persist in macrophages by perforating the phagolysosome using the pore-forming toxin streptolysin O (SLO). […]