Ribosome Newsletter: Navigating the Convergence of Proteomics, AI, Synthetic Biology, and Translational Medicine
Welcome to this week's edition of the Ribosome Newsletter. In this issue, we explore breakthroughs in proteomics, including the SpiDe-Sr Network for advanced imaging, DIP-MS for protein complex analysis, and SUM-PAINT for detailed neuronal mapping. We also highlight new therapeutic approaches, such as proteomic triage for acute myeloid leukemia, SpiderMass for real-time tumor assessment, and WH244 for targeting cancer proteins. Additionally, we delve into the μ-opioid receptor's role in pain management, tanycytes' function in appetite regulation, personalized treatment in multiple sclerosis, dual inhibition of EGFR by PhosTACs, and the expanding landscape of protein modification. Join us as we navigate these exciting developments in healthcare.
Proteomics Innovations
This study introduced SpiDe-Sr, a super-resolution network combined with a denoising module, specifically designed for Imaging Mass Cytometry (IMC) in spatial proteomics. This innovative approach enhances spatial resolution by four times while effectively resisting noise, leading to significant improvements in peak signal-to-noise ratio and cell extraction accuracy across various samples, including cells, mouse, and human tissues. The application of SpiDe-Sr to a clinical breast cancer cohort revealed correlations between bacterial invasion and cancer markers, providing new insights into the tumor microenvironment. Additionally, SpiDe-Sr's compatibility with fluorescence microscopy imaging suggests its potential as a versatile tool for microscopy image super-resolution.
This study introduced Deep Interactome Profiling by Mass Spectrometry (DIP-MS), a novel method combining affinity purification with blue-native-PAGE separation and deep-learning-based signal processing to resolve complex isoforms sharing the same bait protein in a single experiment. DIP-MS was applied to probe the human prefoldin family of complexes, successfully resolving distinct prefoldin holo- and subcomplex variants, complex–complex interactions, and complex isoforms with new subunits. This method demonstrated the ability to reveal proteome modularity at unprecedented depth and resolution, offering a powerful tool for analyzing the organization of protein complexes.
This study unveiled SUM-PAINT, a high-throughput imaging technique offering resolutions finer than 15 nm, enabling multiplexing without limits. Utilizing this method, researchers constructed a 30-plex, 3D neuron atlas at single-protein resolution, facilitating an in-depth exploration of synaptic heterogeneity. The study revealed a unique synapse type marked by the coexistence of VGlut1 and Gephyrin, indicating a previously unrecognized synaptic subtype. SUM-PAINT marks a significant breakthrough in spatial proteomics, providing intricate insights into neuronal architecture and synaptic diversity.
Therapeutic Applications
This study developed a proteomic-based strategy to optimize therapy selection between venetoclax plus hypomethylating agents (VH) and conventional chemotherapy (CC) for acute myeloid leukemia (AML) patients. Using reverse-phase protein arrays, researchers analyzed the expression of 411 proteins in 810 newly diagnosed adult AML patients. They identified 109 prognostic proteins, which were used to create a protein classifier system that accurately recommended therapy for 87.3% of patients. The study found that applying this proteomic triage could lead to a 43% improvement in overall survival, potentially resulting in 2,600 more AML cures per year in the United States. Additionally, the research highlighted potential therapeutic targets for patients who might not benefit from VH or CC, offering new avenues for treatment development.
This study demonstrated the application of SpiderMass, an ambient ionization mass spectrometry technology, combined with artificial intelligence (AI) for real-time assessment of glioblastoma, a highly aggressive brain cancer. The technology achieved over 90% accuracy in diagnosis and prognosis by identifying 99 lipid markers related to the tumor microenvironment and immune cell infiltration. An immunoscore based on SpiderMass data was developed to predict patient outcomes, highlighting the technology's potential to enhance surgical precision and inform treatment strategies. This approach represents a significant advance in glioblastoma management, offering a non-invasive tool for real-time tumor assessment and personalized patient care.
领英推荐
This study introduced WH244, a second-generation dual degrader targeting BCL-2 and BCL-xL proteins, key regulators of cellular apoptosis often overexpressed in cancer. Utilizing structural insights from previous degrader 753b, WH244 was designed with a more rigid linker and a bridged morpholine group, resulting in enhanced potency and tighter ternary complex formation. Crystal structures of VHL/WH244/BCL-2 and VHL/753b/BCL-xL complexes revealed distinct architectures and interaction networks, guiding the rational design of WH244. Functional assays confirmed WH244's superior ability to degrade BCL-2 and BCL-xL in cancer cells, offering a promising therapeutic strategy for BCL-2/BCL-xL-dependent malignancies.
This study developed a proteomics and computational approach to profile the proximal proteome of the activated μ-opioid receptor (μOR), a key target in pain management and addiction. This method allowed for the systematic exploration of the μOR's interaction network, revealing how different opioid agonists influence the receptor's proximal proteome through endocytosis and endosomal sorting. The research identified two novel components of the μOR network, EYA4 and KCTD12, which are recruited based on G-protein activation triggered by the receptor. These findings suggest a previously unrecognized buffering system for G-protein activity that could broadly modulate cellular GPCR signaling.
This study uncovered a neuronal circuit involving tanycytes, specialized cells in the hypothalamus, that reduces food intake upon heat exposure. The circuit originates from thermosensing glutamatergic neurons in the parabrachial nucleus (PBN) of the brainstem, which directly innervate tanycytes. Upon activation by heat, tanycytes produce and release vascular endothelial growth factor A (VEGFA), which targets nearby neurons in the arcuate nucleus of the hypothalamus, increasing their spike threshold and thereby suppressing appetite. This research elucidates a novel mechanism by which the brain integrates thermal and metabolic signals to regulate feeding behavior in response to environmental temperature changes.
This study involving 309 early multiple sclerosis (MS) patients identified three distinct immunological endophenotypes in peripheral blood through high-dimensional flow cytometry and serum proteomics. These endophenotypes, validated in an independent cohort of 232 patients, were associated with specific disease trajectories, such as inflammation versus early structural damage. The efficacy of interferon-β treatment varied across endophenotypes, with limited effect on endophenotype 3, which exhibited higher disease progression and MRI activity over four years. The findings suggest that blood immune signatures could guide personalized treatment decisions in MS, tailoring therapy based on individual immunobiological profiles.
This study introduced a new heterobifunctional approach, called phosphorylation targeting chimeras (PhosTACs), to achieve targeted protein dephosphorylation by combining the inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) with active dephosphorylation by phosphatases. Researchers developed and analyzed an epidermal growth factor receptor (EGFR) targeting PhosTAC, revealing its effective dephosphorylation of EGFR and differential influence on signaling pathways compared to the TKI, gefitinib. Furthermore, a covalent PhosTAC selective for mutated EGFR showed inhibitory potential for dysregulated EGFR. The study demonstrated that PhosTACs induced apoptosis and inhibited cancer cell viability during prolonged treatment, showcasing their potential for modulating RTK activity and expanding the utility of bifunctional molecules.
This study revealed a family of E2-conjugating enzymes (E2s) capable of noncanonical ubiquitylation, attaching ubiquitin to serine, threonine, and other biomolecules, expanding the understanding of ubiquitin modifications. Using Mass Spectrometry, the researchers identified these E2s and characterized their ability to ubiquitylate beyond the traditional lysine target. Structural modeling and mutational analysis pinpointed key determinants for their noncanonical activity. This discovery of noncanonical E2s underscores the adaptability of ubiquitin modifications and their potential impact on cellular processes.?
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Experimental Medicine , Faculty of Medicine, UBC, Vancouver | Medical Content Writing
1 个月Exciting newsletter! How do you see the synergy of proteomics, AI, and synthetic biology shaping the future of biotech research? https://lnkd.in/guWiXGVC