BioEssays

Brancaccio, Marco

doi: 10.1002/bies.70077pmid: 41025155

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.

Lee, Chang‐Seok; Hwang, Cheol‐Sang

doi: 10.1002/bies.70074pmid: 41017204

Formyl peptides, exemplified by the synthetic tripeptide formyl‐Met‐Leu‐Phe (fMLF), are well‐established ligands for formyl peptide receptors (FPRs), central to neutrophil chemotaxis, and innate immune signaling. Traditionally attributed to bacterial and mitochondrial origins, these peptides are now proposed to arise from an additional, stress‐inducible source within the eukaryotic cytosol. Recent findings suggest that under specific stress conditions, eukaryotic translation can initiate with formylmethionine (fMet), producing fMet‐bearing nascent chains that are processed by the fMet/N‐degron and fMet‐mediated ribosome quality control (fMet‐RQC) pathways. These proteostatic mechanisms may generate short, structurally diverse formyl peptides with the potential to function as endogenous FPR ligands. By introducing cytosolic proteostasis as a hypothetical source of formyl peptides, this perspective expands the landscape of formyl peptide biology and opens new directions for investigating their roles in immune regulation under stress and disease.

Siddiqui, Sundus; Siddiqui, Hiba; Riguene, Emna; Nomikos, Michail

doi: 10.1002/bies.70080pmid: 41108536

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.

Asadollahi, Kazem; Gooley, Paul R.; Weikl, Thomas R.

doi: 10.1002/bies.70082pmid: 41108533

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 β2$\ubeta_2$‐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 β2$\ubeta_2$‐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.

Badell‐Grau, Rafael A.; Schlachetzki, Johannes C. M.

doi: 10.1002/bies.70083pmid: 41108524

Lysosomal storage disorders (LSDs) such as Sanfilippo syndrome (Mucopolysaccharidosis type III) are characterized by impaired lysosomal degradation due to inherited in lysosomal proteins. This dysfunction leads to the accumulation of undegraded substrates, such as heparan sulfate, ultimately leading to progressive neuroinflammation and neurodegeneration. Despite well‐defined genetic causes, no disease‐modifying therapies exist for Sanfilippo syndrome. While microglia, the brain's resident immune cells, can play both protective and pathogenic roles, the contribution of neuroinflammation to LSD pathology remains underexplored. This review examines the contribution of neuroinflammation to Sanfilippo syndrome, emphasizing emerging mechanisms involving TLR4 signaling, inflammasome activation, the cGAS‐STING pathway, and lysosomal biogenesis regulators such as TFE family transcription factors. We also discuss the potential of cellular therapies to modulate neuroimmune responses and offer new therapeutic avenues. By integrating insights from neuroimmunology and lysosomal biology, we aim to identify shared mechanisms and therapeutic targets across Sanfilippo syndrome and related LSDs.

Lamoureux, Anaïs; Elvira‐Matelot, Emilie; Porteu, Françoise; Laplane, Lucie

doi: 10.1002/bies.70078pmid: 41065417

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.

Rajalekshmi, Sailasree; Sathyan, Kizhakke Mattada

doi: 10.1002/bies.70075pmid: 41047505

Conditional degron approaches for acute and reversible protein depletion have become standard tools for studying gene function in cells and model organisms. Traditional gene perturbation methods have advanced gene function studies but are limited by slow kinetics, potential irreversibility, and lethality when targeting essential genes. To overcome these limitations, tag‐based and antibody‐based direct protein degradation technologies have been developed. These direct protein degradation systems utilize endogenous protein degradation pathways to achieve rapid and reversible protein depletion. When combined with genome editing, these systems provide precise temporal—and in some cases, spatial—control over endogenous protein expression. In this review, we will discuss the current status of tag‐based and antibody‐based direct protein degron technologies. We aim to provide a comprehensive guide for selecting these tools, highlighting their context‐dependent applications and potential improvements to enhance efficiency and reliability.

Dalgliesh, Caroline; Ghorbani, Farimah; Wollman, Adam J. M.; Elliott, David J.

doi: 10.1002/bies.70081pmid: 41178187

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.

Keydar, Ifat

doi: 10.1002/bies.70076pmid: 41133970

Genome organization is reproducible and linked to gene expression, but the forces shaping it remain poorly understood. This hypothesis proposes that chromatin positioning is directed by a weak radial electric field generated by the nuclear membrane potential. Although classical models predict rapid charge screening, the confined and viscous nuclear interior, regulated by ion pumps, limits this process and allows a residual field to persist. This field biases the movement of charged macromolecules within the gel‐like nucleoplasm, similar to electrophoresis. DNA is uniformly negative, but chromatin charge varies. GC‐rich regions bind more nucleosomes and are less negative, drawing them inward with positively charged nuclear speckles, hubs of gene expression. Epigenetic modifications further modulate chromatin charge, producing a self‐organized, dynamic radial architecture that regulates transcription. This framework connects the noncoding genome to expression and helps explain variable disease penetrance. Its testable predictions open new avenues for deciphering the logic of genome regulation.

doi: 10.1002/bies.70089pmid: N/A