A5065010623- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA modifications and cancer
- Axon Guidance and Neuronal Signaling
- Cellular transport and secretion
- Heat shock proteins research
- Advanced Fluorescence Microscopy Techniques
- Neurogenetic and Muscular Disorders Research
- Amyotrophic Lateral Sclerosis Research
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- RNA regulation and disease
- Protein Degradation and Inhibitors
- Bacteriophages and microbial interactions
- Advanced Biosensing Techniques and Applications
- Lung Cancer Diagnosis and Treatment
- Radiomics and Machine Learning in Medical Imaging
- Chronic Myeloid Leukemia Treatments
- Autism Spectrum Disorder Research
- Genetics and Neurodevelopmental Disorders
- ATP Synthase and ATPases Research
- Neurogenesis and neuroplasticity mechanisms
- Cell Image Analysis Techniques
- Quinazolinone synthesis and applications
- Retinal Development and Disorders
University of Cambridge
2015-2024
UK Dementia Research Institute
2019-2024
King's College London
2022-2024
Hong Kong University of Science and Technology
2024
University of Hong Kong
2024
The University of Texas MD Anderson Cancer Center
2024
United States Department of Agriculture
2011-2012
Agricultural Research Service
2012
Children's Nutrition Research Center at Baylor College of Medicine
2012
Baylor College of Medicine
2011
The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS FTD remain controversial. We propose a model low-complexity (LC) domains of drive its physiologically reversible assembly into membrane-free, liquid droplet hydrogel-like structures. ALS/FTD LC or non-LC induce further phase transition poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary sufficient for neurotoxicity C. elegans FUS-dependent neurodegeneration....
Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles is, part, driven by intrinsically disordered low-complexity (LC) domain FUS. Here, we report that cooperative cation-π interactions between tyrosines LC arginines structured C-terminal domains also contribute to separation. These are modulated post-translational arginine methylation, wherein hypomethylation strongly promotes gelation. Indeed, significant hypomethylation,...
Local mRNA translation mediates the adaptive responses of axons to extrinsic signals, but direct evidence that it occurs in mammalian CNS vivo is scant. We developed an axon-TRAP-RiboTag approach mouse allows deep-sequencing analysis ribosome-bound mRNAs retinal ganglion cell developing and adult retinotectal projection vivo. The embryonic-to-postnatal axonal translatome comprises evolving subset enriched genes with axon-specific roles, suggesting distinct steps axon wiring, such as...
Local translation regulates the axonal proteome, playing an important role in neuronal wiring and axon maintenance. How mRNAs are localized to specific subcellular sites for translation, however, is not understood. Here we report that RNA granules associate with endosomes along axons of retinal ganglion cells. RNA-bearing Rab7a late also ribosomes, real-time imaging reveals they local protein synthesis. We show often pause on mitochondria encoding proteins mitochondrial function translated...
Abstract While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), independent contribution quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study 394 NSCLC patients, utilize pre-treatment computed tomography (CT) 18 F-fluorodeoxyglucose positron emission (FDG-PET) establish a habitat imaging framework for assessing regional heterogeneity within individual...
Nascent proteins can be positioned rapidly at precise subcellular locations by local protein synthesis (LPS) to facilitate localized growth responses. Axon arbor architecture, a major determinant of synaptic connectivity, is shaped responses, but it unknown whether LPS influences these responses in vivo. Using high-resolution live imaging, we examined the spatiotemporal dynamics RNA and retinal axons during arborization Endogenous tracking reveals that granules dock sites branch emergence...
Ribosome assembly occurs mainly in the nucleolus, yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) axons, far away from neuronal cell bodies. Here, we report a physical functional interaction between locally synthesized RPs ribosomes axon. We show that axonal RP is regulated through sequence motif, CUIC, forms an RNA-loop structure region immediately upstream initiation codon. Using imaging subcellular proteomics techniques,...
Global environmental temperature changes threaten innumerable plant species. Although various signaling networks regulate responses to fluctuations, the mechanisms unifying these diverse processes are largely unknown. Here, we demonstrate that an Arabidopsis monothiol glutaredoxin, AtGRXS17 (At4g04950), plays a critical role in redox homeostasis and hormone perception mediate temperature-dependent postembryonic growth. expression was induced by elevated temperatures. Lines altered were...
Lysosomes, important centers of metabolic sensing and material recycling, play a key role in the dynamic reshaping ER.
Summary While various signalling networks regulate plant responses to heat stress, the mechanisms regulating and unifying these diverse biological processes are largely unknown. Our previous studies indicate that Arabidopsis monothiol glutaredoxin, AtGRXS17, is crucial for temperature‐dependent postembryonic growth in . In present study, we further demonstrate AtGRXS17 has conserved functions anti‐oxidative stress thermotolerance both yeast plants. yeast, co‐localized with ScGrx3 nucleus...
Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling ribosomes to receptors has been proposed as a mechanism linking signals but it is not known how broadly this operates, nor whether can selectively regulate mRNA translation. We report that receptor-ribosome employed by multiple guidance cue and interaction mRNA-dependent. find different associate with distinct sets RNA-binding proteins. Cue stimulation
[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) and computed (CT) are indispensable components in modern medicine. Although PET can provide additional diagnostic value, it is costly not universally accessible, particularly low-income countries. To bridge this gap, we have developed a conditional generative adversarial network pipeline that produce FDG-PET from CT scans based on multi-center multi-modal lung cancer datasets (n = 1,478). Synthetic images validated across...
Abstract Enhanced expression of the cold‐shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and vivo . Whilst upstream signalling pathways leading to RBM3 have been described, precise molecular mechanism cold induction remains elusive. To identify temperature‐dependent modulators RBM3, we performed a genome‐wide CRISPR‐Cas9 knockout screen using RBM3‐reporter human iPSC‐derived neurons. We found that mRNA levels are robustly regulated by several splicing...
Local mRNA translation occurs in growing axons enabling precise control of the proteome response to signals. To measure quantitatively spatiotemporal dynamics protein synthesis growth cones, we further developed a technique for single molecule imaging (SMTI). We report that Netrin-1 triggers burst β-actin at multiple non-repetitive sites, particularly periphery. The is remarkably rapid starting within 20 seconds cue application.
The transcript encoding translationally controlled tumor protein (Tctp), a molecule correlated with aggressive breast cancers, was identified among the most abundant in genome-wide screens of axons, suggesting that Tctp is important neurons. Here, we tested role retinal axon development Xenopus laevis. We report deficiency results stunted and splayed retinotectal projections fail to innervate optic tectum at normal developmental time due impaired extension. Tctp-deficient axons exhibit...
Guidance cues trigger fast responses in axonal growth cones such as directional turning and collapse that require local protein synthesis. An attractive cue-gradient, Netrin-1, triggers de novo synthesis of β-actin localized to the near-side compartment cone promotes F-actin assembly steering. How this precise spatial asymmetry mRNA translation arises across small expanse is poorly understood. Pre-localized mRNAs vicinity activated receptors could be selectively translated and/or new...
Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from commercial hit. The exploration of this led to the selection NVP-HSP990 as development candidate.
Abstract Large fields of view (FOVs) in total internal reflection fluorescence microscopy (TIRFM) via waveguides have been shown to be highly beneficial for single molecule localisation on fixed cells [1,2] and also demonstrated short‐term live‐imaging robust cell types [3‐5], but not yet delicate primary neurons nor over extended periods time. Here, we present a waveguide‐based TIRFM set‐up live‐cell imaging demanding samples. Using the developed microscope, referred as ChipScope ,...
SUMMARY Ribosomes are known to be assembled in the nucleolus, yet recent studies have revealed robust enrichment and translation of mRNAs encoding ribosomal proteins (RPs) axons, far away from neuronal cell bodies. Using subcellular proteomics live-imaging, we show that locally synthesized RPs incorporate into axonal ribosomes a nucleolus-independent fashion. We RP is regulated through novel sequence motif, CUIC, forms RNA-loop structure region immediately upstream initiation codon....
Aberrant condensation and localization of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur variants amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD). Changes RBP function are commonly associated with changes axonal cytoskeletal organization branching neurodevelopmental disorders. Here, we asked whether defects also vivo a model FUS-associated disease. We use two reported Xenopus models ALS/FTD (of either sex), ALS-associated mutant FUS(P525L) mimic hypomethylated...
Abstract The endoplasmic reticulum (ER) comprises morphologically and functionally distinct domains, sheets interconnected tubules. These domains undergo dynamic reshaping, in response to changes the cellular environment. However, mechanisms behind this rapid remodeling within minutes are largely unknown. Here, we report that ER is actively driven by lysosomes, following lysosome repositioning nutritional status. anchorage of lysosomes growth tips critical for tubule elongation connection....