Bioscience Reports最新文献

Proteome, the molecular product of regulatory diktat of the cellular machinery, predicts the behaviour and progression of cancers. Designing effective molecular therapies based on proteins with comprehensive patient stratification remains the mainstay of every translational research. Research on the proteome involves a) identification of biomarkers that, with utmost sensitivity and specificity, reveal significant insights into the disease state and b) understanding the mechanistic underpinnings and rewiring of cellular signaling pathways that drive a particular cancerous pathology. In this review, we give a comprehensive description of the evolution of mass spectrometer-based methods, including labeling strategies available to study the proteome and post-translational modifications in response to various perturbations. We summarize their utility in understanding complex processes of cancers, advance research on cancer therapy by decoding novel biomarkers, identify therapy resistance drivers, and enhance spatial attributes of tumor microenvironment by single-cell proteomics. Finally, some of the challenges in the currently used methods have been discussed.

Targeting AXL receptor kinase with a highly selective antibody presents a promising approach for inhibiting AXL and potentially improving cancer treatment. An essential step in antibody optimisation is the mapping of paratope residues to epitope residues. In the present study, we identify the residues of tilvestamab, a function-blocking anti-AXL monoclonal antibody, that are essential for its binding to the extracellular domain of AXL. A single-chain variable fragment (scFv) fused to osmotically inducible protein Y (osmY) was designed to enable the secretion of soluble scFv-osmY mutants, which could be directly subjected to high-throughput biolayer interferometry screening for binding to the AXL Ig1 domain. Each complementarity-determining region residue of scFv was mutated to Ala, while additional mutations were made on the basis of predicted contribution to binding. We generated AlphaFold3 predictions for the scFv (tilvestamab)-AXL Ig1 complex to gain insights into the molecular interactions of the essential residues, as determined by the experimental data. Our study reveals that tilvestamab binds to the Ig1 domain of AXL, with twelve residues on scFv (tilvestamab) contributing most to binding, likely being situated at the binding interface. Glu2 near the N-terminus of AXL is essential for binding. The data give a structural view into the AXL-tilvestamab complex and allow for further optimisation of the binding interface.

Brain-expressed voltage-gated sodium (Nav) and potassium (Kv) channels are essential for maintaining the balance of neuronal excitability, each having opposing effects on membrane potential and neuronal firing. Genetic alterations in these channels can disrupt this balance, leading to epilepsy and/or developmental impairments through gain-of-function (GoF) or loss-of-function (LoF) mechanisms. This review catalogs 48 transgenic mouse models involving sodium channels (SCN1A, SCN2A, SCN3A, SCN8A) and potassium channels (KCNQ2, KCNQ3, KCNT1, KCNA1, KCNB1, KCND2), detailing the effects of genetic alterations in terms of channel function, affected cell types, and phenotypic manifestations. Mechanistic insights from these models reveal that initial channel dysfunction triggers cascading pathological processes including glutamate excitotoxicity, oxidative stress, gliosis, neuroinflammation, and blood-brain barrier disruption. Therapeutic approaches include antisense oligonucleotides to enhance functional allele expression or reduce pathogenic channel expression, viral-mediated gene therapy, gene editing, and small molecule modulators that target persistent sodium currents or that stabilize channel inactivation. The timing of intervention appears to be critical, with early treatment showing greater efficacy in preventing pathological cascades. Strain-specific background effects and compensatory ion channel expression affect phenotypic severity and treatment response, complicating translation of model results. Importantly, transgenic models offer opportunities to better understand mechanisms underlying comorbidities commonly suffered by patients, including behavioral disorders, motor impairments, and sleep disturbances. The integration of these findings suggests that effective treatment strategies may require combinations of channel-directed therapies and interventions targeting downstream pathological processes, particularly for established disease. This comprehensive examination of channelopathy models provides a framework for developing transformative therapeutics for genetic epilepsies.

Ever since its discovery more than 70 years ago, the enzyme polynucleotide phosphorylase (PNPase) has been the subject of intensive research that has highlighted its key functional roles. The enzyme was first described in 1955 for its ability to synthesise RNA from nucleoside diphosphates. This discovery led to a Nobel Prize in Physiology or Medicine in 1959 for using PNPase to synthesise artificial RNA. However, it soon became evident that the primary function of this enzyme, conserved across diverse species, is 3'-5' RNA phosphorolysis rather than polymerisation. Remarkably, over 60 years later, it was discovered that PNPase has an even broader range of functions as it was shown to act as a conditional RNA chaperone in bacteria. In humans, PNPase (hPNPase) is located in mitochondria, where it plays a role in mitochondrial RNA (mtRNA) metabolism, thereby regulating mitochondrial function and the overall cell fitness. In this review, we present the current scope of knowledge of hPNPase, including its structure, subcellular localisation, metabolic activity, roles in mtRNA transport, processing and degradation, and its involvement in apoptosis.