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Most vertebrate genes are split up into exons and introns, with exons being spliced together to make mRNA. Many of the proteins involved in splicing, called splicing factors, exert concentration-dependent effects on gene expression through post-transcriptional modification of mRNAs. These include the serine/arginine-enriched (SR) proteins that have essential roles in normal development and physiology. All SR proteins (and many other splicing factors) regulate their own expression levels, often using negative feedback pathways involving alternative splicing of “poison exons” (PEs), which lead to mRNA degradation. The PEs within SR protein genes are encoded by ultra-conserved genome sequences, suggesting they have been under extreme selective pressure despite not encoding protein sequences. Here, we discuss the hypothesis that PEs enable rapid switches in SR protein concentrations, yet prevent these splicing regulators from increasing to toxic levels that cause cell death or interfere with cell function. This hypothesis is based on analysis of an ultra-conserved PE in the TRA2B gene during male meiosis. Distinct roles for this TRA2B PE in different tissues further predict cell type-specific effects on development and physiology that will need to be experimentally detected using animal models.

TDP-43 is a ubiquitously expressed RNA-binding protein that aggregates in the brains of patients suffering from neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease. Aggregated TDP-43 in these diseases is hyperphosphorylated in its C-terminal intrinsically disordered region, while physiological TDP-43 is normally unphosphorylated. Whether TDP-43 phosphorylation is a pathological driver, or rather a protective antagonist of TDP-43 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP-43 phosphorylation in disease and the kinases and phosphatases that regulate this post-translational modification. We discuss how TDP-43 phosphorylation is thought to shape TDP-43's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP-43 phase separation and aggregation, and speculate about a potential role of condensates in TDP-43 phosphorylation.

The allosteric mechanism of G-protein-coupled receptors (GPCRs) involves a population shift from inactive to active receptor conformations in response to the binding of ligand agonists. Two possible kinetic mechanisms for this population shift are induced fit and conformational selection. In the induced-fit mechanism, ligands bind to inactive receptor conformations prior to the conformational transition of the receptor. In the conformational-selection mechanism, ligands bind to active conformations after the conformational transition. For the peptide-activated neurotensin receptor 1, stopped-flow mixing experiments that probe the chemical relaxation into binding equilibrium and conformational transition rates measured with NMR experiments indicate an induced-fit mechanism. For the small-molecule-activated $�{\beta }_2$-adrenergic receptor, an induced-fit mechanism has been inferred from a decrease of ligand association rates after stabilization of the active receptor conformation. A structural explanation for the induced-fit mechanism of the $�{\beta }_2$-adrenergic receptor is a closed lid over the binding site that blocks ligand entry in the active conformation. Since constriction and closing of the ligand-binding site in the active conformation is rather common for small-molecule-activated and peptide-activated GPCRs, induced fit is likely shared as allosteric mechanism by these GPCRs.

Zebrafish (Danio rerio) have become a versatile model in precision medicine, bridging fundamental biology with translational applications. Their optical transparency, rapid development, and high genetic conservation with humans enable real-time imaging and cost-efficient high-throughput screening. Advances in CRISPR/Cas9, prime editing, and morpholino approaches have expanded their utility for modeling diverse human diseases. In addition to well-established roles in cardiovascular, neurological, metabolic, oncological, and infectious disease research, emerging applications include non-invasive larval urine assays, functional validation of rare human variants, host–microbiome interactions, and automated behavioral profiling for neuropsychiatric conditions. Limitations such as species-specific lipid metabolism and limited antibody availability remain, yet recent integration of single-cell transcriptomics, computational modeling, and machine learning is enhancing translational relevance. Collectively, these innovations position zebrafish as a scalable and powerful platform for disease modeling and personalized therapeutic strategies, underscoring their growing impact in the evolving landscape of precision medicine.

The clonal evolution model provides a framework for understanding the evolution of cancer cells. According to this model, cancer cells accumulate genetic mutations over time, and these mutations are passed down to their descendants, leading to genetic diversity within the tumor. Some of these mutations confer selective advantages, causing certain lineages of cancer cells (clones) to dominate and expand. However, this model is rooted in certain conceptual assumptions, which we propose to revisit by considering the potential involvement of retrotransposons in cancer initiation and progression. In recent years, it has become evident that transposable elements, particularly retrotransposons, play a significant role in driving cancer transformation and progression. We first review how current knowledge about retrotransposon activity aligns with the clonal evolution model by highlighting its ability to modulate cancer cell fitness. We then take a forward-looking perspective to explore additional ways retrotransposons may also influence clonal dynamics beyond the current model.

Astrocytes are emerging as critical regulators of the sleep–wake cycle, actively contributing to both sleep homeostasis and circadian rheostasis. This dual role challenges neuron-centric frameworks that have dominated sleep and circadian biology and highlights astrocytes as potential integrators of internal temporal information. Experimental evidence shows that astrocytic calcium dynamics correlate with sleep state and that manipulating astrocytes can alter sleep architecture and homeostasis. In parallel, key aspects of circadian timekeeping can be autonomously driven by astrocytic clocks, with pulses of rhythmic GABA and glutamate able to synchronize circadian circuits and support circadian patterns of behavior. These findings are coherent with the idea that astrocytes can act as context-dependent integrators to convey environmental cues and internal states to neuronal circuitries and promote adaptive behavior. Incorporating astrocytes into conceptual models of the sleep–wake cycle may help reconcile contradictory findings and offer new frameworks to better understand how salient internal temporal representations are encoded within the brain.