eLife

Adaptive behavior under threat requires deciding when to act and when to withhold action to avoid harm, often under conditions where movement, arousal, and task demand covary. Medial prefrontal cortex (mPFC) activity is widely associated with such control, yet it remains unclear whether this activity reflects causal action generation or broader evaluative processes shaped by behavioral state. Her…

The ryanodine receptor (RYR) genes encode evolutionarily conserved calcium release channels involved in a wide range of calcium-dependent biological processes. Here we show that the sole Drosophila RYR gene (dRyR) functions in differentiated somatic and cardiac muscle as well as in developing embryonic myotubes. In the larval body wall muscles, dRyR protein localizes at the SR membranes and dRyR …

Missense variants in the O-GlcNAc transferase (OGT) gene have recently been shown to segregate with a syndromic form of intellectual disability (OGT-ID), underscoring the importance of protein O-GlcNAcylation in brain function. However, the underlying pathophysiological mechanisms linking ID to potential OGT malfunction—whether developmental, neurophysiological, or both—remain unclear. Here, we p…

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from infection globally, yet the contribution of non-classical T-cell pathways to human immunity remains poorly defined. CD1c-autoreactive T-cells, which recognise self-lipids presented by the antigen-presenting molecule CD1c, are frequent in human blood, but their role during infection is unclear. H…

Translation failure, in which promising animal study results can not be reproduced in human trials, is a challenge in biomedical research. Metrics for replication success are widely used to evaluate reproducibility, i.e., the extent to which the results of a study agree with those of replication studies. The relevance of these metrics in assessing animal-to-human translation success (or faillure)…

Effective emotional processing, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA) and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, the functional specialization of the mPFC→BLA and mPFC→NAc pathways in representing affective states remai…

Lenacapavir (LEN) is the first HIV-1 capsid inhibitor approved for clinical use. It inhibits multiple steps of the viral life cycle; however, the molecular details of the effect of LEN on capsid structure and the mechanistic steps of the inhibition are not understood. Recent studies show that intact cone-shaped capsids and capsids with LEN-induced breaks can dock at nuclear pore complexes (NPC), …

Ciliogenesis is a highly ordered process that requires membrane trafficking, fusion, and maturation. In this study, we investigated EXOC6A, a component of the exocyst complex known for secretory vesicle trafficking and fusion, and found that it interacts with myosin-Va (Myo-Va) during ciliogenesis. EXOC6A colocalizes with Myo-Va at various stages of ciliogenesis, including preciliary vesicles, ci…

Mitochondria are essential organelles in eukaryotic cells, enclosed by two membranes with distinct compositions and functions. In addition to the endoplasmic reticulum, mitochondria are major sites of cellular lipid production. Cardiolipin, for example, is exclusively synthesized in the mitochondrial inner membrane. This requires the precursor lipid phosphatidic acid to be imported from the endop…

The immune and sensory nervous systems, having evolved in parallel, communicate through shared receptors and transmitters to maintain homeostasis and respond to both external and internal disruptions. Although neural responses often confer protective benefits, they can also exacerbate inflammation during allergic reactions such as asthma. In our study, we modeled pollution-exacerbated asthma by e…

Tagging all proteins encoded by an animal genome with a fluorescent tag would open many windows to the discovery of unexpected patterns of protein expression and localization. To scale such an approach, it would be beneficial to introduce multiple, spectrally distinct fluorophore tags in parallel. As a first step in this direction, we undertook a pilot study in the nematode C. elegans, in which w…

Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPR^MT)…

Bidirectional cargo transport by kinesin and dynein is essential for cell viability and defects are linked to neurodegenerative diseases. Computational modeling suggests that the load-dependent off-rate is the strongest determinant of which motor ‘wins’ a kinesin-dynein tug-of-war, and optical tweezer experiments find family-dependent differences in the sensitivity of detachment to load, with kin…

CRISPR–Cas9 nucleases have transformed genome engineering, yet their application is often constrained by protospacer-adjacent motif (PAM) requirements. Staphylococcus aureus Cas9 (SaCas9) is particularly attractive for in vivo applications due to its compact size; however, its NNGRRT PAM limits targetable genomic sites. Here, we report KRH, a SaCas9 variant designed entirely from the wild-type en…

Muscle stem cells (MuSCs) are parenchymal cells in skeletal muscle regeneration and maintenance. With aging, MuSCs experience a decline in their regenerative function and reduction in their number. However, recent evidence points to substantial heterogeneity within the aged MuSC population, raising questions about the underlying mechanisms of age-associated dysfunction. Here, we used Pax7CreERT2;…

We have previously shown that the slender form of Trypanosoma (T.) brucei is able to infect teneral tsetse flies, develop to the first fly form, which is the procyclic form, and complete the life cycle in the insect vector (Schuster et al., 2021). Further, analysis of the transmission index (TI; defined as the number of salivary gland infections relative to the number of midgut infections) reveal…

Double-strand breaks (DSBs) are the most deleterious lesions experienced by our genome. Yet, DSBs are intentionally induced during gamete formation to promote the exchange of genetic material between homologous chromosomes. While the conserved topoisomerase-like enzyme Spo11 catalyzes DSBs, additional regulatory proteins—referred to as ‘Spo11 accessory factors’—regulate the number, timing, and pl…

APOE4, the major genetic risk factor for Alzheimer’s disease (AD), and ABCA1, required for lipidation of APOE are gene products of the liver X receptor (LXR) receptor. LXR agonists have been validated in animal models as therapeutics for AD, atherosclerosis, and many other diseases. Clinical progress has been thwarted by unwanted hepatic lipogenesis. Structurally diverse LXR ligands were profiled…

Although it is well-established that stem cells maintain tissue homeostasis while tumors disrupt it, the mechanisms by which tumors influence the development of nearby stem cells remain poorly understood. Using Drosophila ovaries as a model system, here we discovered that bam or bgcn mutant germline tumors inhibit the differentiation of neighboring wild-type germline stem cells (GSCs). Mechanisti…

Pseudouridine (Ψ) modifications are the most abundant RNA modifications; however, their distribution and functional significance in bacteria remain largely unexplored compared to eukaryotic systems. In this study, we present the first transcriptome-wide and quantitative mapping of Ψ modifications across five diverse bacterial species (Bacillus cereus, Escherichia coli, Klebsiella pneumoniae, Pseu…