Open Biology最新文献

Multicellularity emerges from the ability of cells to undergo functional differentiation. One of the key mechanisms that enables this coordination is cellular signalling-a series of molecular interactions within or between cells that induce changes in cell behaviour or gene expression. As the body plan of multicellular organisms becomes more complex, so does the sophistication of their signalling systems. The Wnt and Notch pathways are central to regulating cell fate, tissue development and maintenance in all studied metazoa. Affecting overlapping biological processes, often within short developmental time windows, these molecular systems appear to be functionally interconnected, leading to the proposal of a 'Wntch' signalling concept. This concept implies that Wnt and Notch modules do not operate as isolated linear pathways but form a coherent network that integrates signals to ensure precise control of developmental and physiological outcomes. In this review, we synthesize both past and recent insights into the direct crosstalk of Wnt and Notch signalling molecules, examine crosstalk within the context of recently developed assays such as single-cell RNA sequencing and proximity labelling, and discuss the broader implications of this interplay in development and disease.

Ionizing radiation (IR) is used to treat more than half of cancer patients because it induces DNA double-strand breaks and triggers apoptosis. IR also damages other nucleic acids, lipids, proteins and cellular organelles, initiating additional complex cellular responses. Some of these responses are transient, while others can become permanent and lead to changes in cellular identity. This review focuses on cell fate plasticity, defined as the conversion of one cell type into another, during recovery after IR-induced damage. We recognize that this process likely occurs along a continuum and may be reversible. We will distinguish cell fate plasticity from molecular or phenotypic plasticity, such as epigenetic modifications, transcriptomic shifts, altered signalling, morphological changes or acquisition of migratory behaviour, all of which are clinically relevant but do not constitute a change in cell type for the purposes of this review. Importantly, cell fate plasticity can enable cancer cells to acquire stem-like properties, which has major implications for tumour progression and therapy resistance.

Characterizing the effect of pesticides on pollinators is essential in the strive to protect biodiversity while maintaining efficient food production. Metabolomics offers detailed insight into the physiological response to pesticides. The impact of pre-dissection and dissection methodology on the metabolic response remains largely unknown, as does their possible effect on the measured metabolic response to pesticide exposure. Three different pre-dissection treatments were evaluated in Eristalis tenax: carbon dioxide, ice or no anaesthesia. Brain dissections were conducted at room temperature or on ice. Flies were also orally exposed to a high dose of the neonicotinoid insecticide acetamiprid (4 μg per fly) in sucrose or sucrose alone. Brains were homogenized, and metabolites extracted and analysed by gas chromatography/mass spectrometry. Pre-dissection and dissection conditions affected metabolites linked to oxidative stress, energy production and cold response. Acetamiprid exposure elicited consistent metabolic responses across all immobilization methods, including significant alterations in glutamate metabolism. Alterations in brain metabolism in response to acetamiprid were largely conserved across various pre-dissection methods, allowing for flexibility in methodology to address experimental constraints. Whether the subtle differences observed would compromise studies of lower doses of acetamiprid or other pesticides requires further validation.

SACK1G (aka FAM83G, PAWS1) plays a central role in activating canonical WNT signalling through interaction with the Ser/Thr kinase CK1α. The loss of CK1α binding and WNT signalling underlies the pathogenesis of palmoplantar keratoderma (PPK) caused by several reported mutations in the SACK1G gene. We modelled the scaffold anchor of CK1 (SACK1) domain of SACK1G and used fragment-bound structures of the SACK1B (FAM83B) dimer to guide our analysis. This allowed us to computationally predict several key residues near the fragment-binding site in SACK1G that may be important for its function. We mutated these residues, introduced them into SACK1G-/- DLD-1 colorectal cancer cells and investigated their ability to bind endogenous CK1α. We uncovered two SACK1G mutations, namely Y204A and I206A, that abolish interaction with CK1α similarly to the PPK pathogenic mutant A34E. Consistent with this loss of SACK1G-CK1α interaction, the molecular glue degrader of CK1α, DEG-77, fails to co-degrade the Y204A and I206A mutants while it still co-degrades native SACK1G. Our findings demonstrate the utility of our computational methods to uncover functional residues on proteins based on fragment-binding sites.

Trinucleotide repeat instability has been implicated in the pathogenesis of numerous neurodegenerative disorders. While germline expansions destabilize trinucleotide repeats to cause disease anticipation, somatic cell trinucleotide repeat instability drives earlier onset of symptoms and further disease progression. However, the drivers behind these repeat length changes remain unclear. Current models suggest that DNA replication slippage events and the action of genome instability pathways, such as DNA repair, cause trinucleotide repeat mutagenesis. Whether mutagenic polymerases from the translesion synthesis pathway result in trinucleotide repeat instability is unclear. Translesion synthesis polymerases are best at bypassing difficult-to-replicate DNA regions due to bulky lesions or gaps in DNA. While some effects of translesion synthesis polymerases on trinucleotide repeat instability have been explored in lower organisms, evidence in human cells is lacking. Using a quantitative green fluorescent protein (GFP) reporter with expanded CAG repeats, we show that inhibition of the translesion synthesis polymerase REV1 by its inhibitor, JH-RE-06, or siRNA knockdown increases trinucleotide repeat instability and the underlying mutability. These results suggest that REV1 protects trinucleotide repeat length mutagenesis through potential continuous DNA synthesis when replicative polymerases stall ahead of repeat secondary structures. Collectively, we present evidence of the translesion synthesis pathway's role in trinucleotide repeat instability, with potential implications for understanding mutability mechanisms, disease biology and therapeutic targeting.

Bioelectrical signalling is fundamental for regulating biological processes in all forms of life. Ion channels and transporters generate and propagate electrical currents by selectively allowing ions to flow across membranes in response to voltage changes. Although recent breakthroughs in structural determination methods, such as cryogenic electron microscopy, have provided novel insights into the structure-function relationships of ion channels and scaffolding proteins, their precise roles in bioelectrical signal generation and propagation within and across different cells and tissues remain unresolved. This article examines the biochemical and ultrastructural features of the three most studied modes of bioelectrical conduction in human tissues-electrotonic, saltatory and ephaptic conduction-and how biophysical constraints set by membranes and proteins give rise to bioelectricity. Notably, ion channel clustering and scaffolding proteins that define intermembrane distances are common key features among all forms of bioelectrical signalling. Techniques like cryogenic electron tomography offer promising avenues for exploring ion channels and their regulatory protein interactions in situ. The central question is: 'How does the spatial organization of ions, molecules and tissues give rise to bioelectricity?' These insights may inform novel therapeutic approaches for various diseases, while also potentially offering new perspectives on life, evolution and consciousness.

Synaptonemal complex (SC) is a structurally conserved, supramolecular assembly that forms at the interface of aligned chromosome axes during meiosis, where it provides a physical context for crossover recombination intermediates. In yeast, the SC is composed of Zip1 transverse filaments and central element proteins Ecm11 and Gmc2. Here, we identify a biochemically stable constitutive complex between Ecm11 and Gmc2, which is mediated by their α-helical coiled-coil regions formed of amino acids 230-302 and 59-188, respectively. We find that the Ecm11-Gmc2 is a 2 : 2 hetero-oligomer, which has an architecture and dimensions similar to the mammalian SC central element complex SYCE2-TEX12. Through targeted mutagenesis in yeast, we show that 2 : 2 Ecm11-Gmc2 complex formation is essential for SC assembly in vivo. Further, we identify key additional residues, particularly in Ecm11, that are dispensable for heterocomplex formation in vitro but critical for stability of the complex in vivo.

The SWI/SNF family of chromatin remodelling complexes, comprising BAF, PBAF and ncBAF, is known for their critical roles in regulating chromatin accessibility and gene expression in mammalian cells. Recent advances have shed light on a function for SWI/SNF complexes, particularly PBAF, at centromeres. In this review, we explore the emerging roles of SWI/SNF complexes in safeguarding centromere stability and discuss how disruption of PBAF leads to centromere fragility. We propose that PBAF contributes to the establishment and maintenance of boundaries between heterochromatin and euchromatin regions within centromeres and pericentromeres, thus contributing to their overall architecture. By preserving these boundaries, PBAF ensures the functional integrity of centromeres, which is essential for faithful chromosome segregation.

Chronic pain-the persistence of pain-delineates a huge challenge to the healthcare system. During the process of pain chronification, when acute pain transitions into chronic pain, processing and pathways associated with nociceptive impulse progressively undergo diverse anatomical and physiological alterations in a process known as sensitization. Pain sensitization, which occurs in both the peripheral and central nervous system, entails intricate neurobiological mechanisms that can lead to a cascade of effects, including reduced pain threshold, augmented excitability of pain pathways and heightened sensitivity to painful stimuli. Due to the complex interplay of these neurobiological mechanisms, optimal treatment for chronic pain remains elusive. Elucidating these mechanisms further is essential to devise targeted interventions for preventing or managing chronic pain, particularly following surgical procedures. This review explores the key neurobiological mechanisms involved in the transmission of nociceptive signalling, an in-depth mechanism contributing to pain chronification, with a special focus on peripheral and central sensitization, neuroimmune interactions and neuroplastic changes within the central nervous system. It also encompasses a comprehensive overview of various therapeutic interventions, which is crucial for enhancing therapeutic strategies and patient outcomes in chronic pain management.