Biology subjects

Yeo, J.

Publications and source records attributed to Yeo, J..

5 recordsLinked to original sources

bioRxiv2023

Clustering predicted structures at the scale of the known protein universe

Proteins are key to all cellular processes and their structure is important in understanding their function and evolution. Sequence-based predictions of protein structures have increased in accuracy with over 214 million predicted structures available in the AlphaFold database (AFDB). However, studying protein structures at this scale requires highly efficient methods. Here, we developed a structural-alignment based clustering algorithm - Foldseek cluster - that can cluster hundreds of millions of structures. Using this method we have clustered all structures in AFDB, identifying 2.27M non-singleton structural clusters, of which 31% lack annotations representing likely novel structures. Clusters without annotation tend to have few representatives covering only 4% of all proteins in the AFDB. Evolutionary analysis suggests that most clusters are ancient in origin but 4% seem species specific, representing lower quality predictions or examples of de-novo gene birth. Additionally, we show how structural comparisons can be used to predict domain families and their relationships, identifying examples of remote homology. Based on these analyses we identify several examples of human immune related proteins with remote homology in prokaryotic species which illustrates the value of this resource for studying protein function and evolution across the tree of life. AvailabilityMethods and data are available at cluster.foldseek.com

bioinformatics↗

bioRxiv2023

The fingering patterns in the epithelial layer control the gap closure rate via curvature-mediated force

Closing gaps in cellular monolayers is a fundamental aspect of both morphogenesis and wound healing. This closure can be achieved through leader cell crawling or actomyosin-based contraction, depending on the size of the gap. Here, we focus on wounds whose closure is driven by interfacial instabilities, featuring both leader cell-driven fingers and actin-mediated contraction. Our proposed model predicts a positive correlation between the frequency of fingering and the overall speed of boundary closure. This fingering frequency is precisely regulated through the orchestration of cell density-driven pressure, cell-cell repulsions, and the initial curvature of the wound boundary. Our findings demonstrate an inverse correlation between fingering frequency and boundary curvatures, indicating a "self-control" mechanism for closure rates independent of the initial curvatures of the wound periphery. Notably, changes in curvature caused by fingering formation generate force that aids in the healing process.

biophysics↗

bioRxiv2023

Coarse-grained Modeling and Experimental Investigation of the Viscoelasticity of Human Gut Mucus and Nanoparticle Dynamics

A thick layer of mucus covering the gastrointestinal tract acts as an innate barrier guarding the epithelial surface. The high molecular weight and cross-linked glycoproteins (mucins), the major building blocks of mucus, can effectively obstruct or trap invading noxious substances, such as detrimental bacteria and virus. The mucus layer as well as any trapped material can be regularly removed by the friction force from food flow and gastrointestinal peristalsis, the process of which primarily relies on the viscoelastic and shear-thinning properties. Conversely, the process by which beneficial substances, such as drug nanoparticles, cross the mucus layer and contact the epithelium is also influenced by the chemical and rheological properties of the mucus layer. Gastrointestinal disorders, most notably colitis, are often accompanied by changes to the mucosal structure. In this study, we experimentally characterized the viscoelasticity and dynamic viscosity of mucus collected from human intestinal cells. In addition, we developed a bi-component mesoscopic-scale mucus model that contained Muc2, the dominant mucin secreted in healthy individuals, and Muc5AC, which is secreted by intestinal goblet cells in certain intestinal disorders. This model enabled us to study the effects of cross-linking and mucin concentration on rheological properties of mucus. Furthermore, we quantified changes in the diffusion dynamics of nanoparticles in mucus networks caused by factors such as the size of nanoparticles, nanoparticle-mucin interactions, and the degree of mucin cross-linking.

biophysics↗

bioRxiv2022

Comprehensive multi-omics characterization of gut microbiome extracellular vesicles reveals a connection to gut-brain axis signaling

Microbiota-gut-brain axis is an evident pathway of host-microbiota crosstalk that is linked to multiple brain disorders. Microbiota released extracellular vesicles (MEVs) has emerged as a key player in intercellular signaling in host microbiome communications. However, their role in gutbrain axis signaling is poorly investigated. Here, we performed a deep multi-omics profiling of MEVs content generated ex vivo and from stool samples in order to get some insights on their role in gut-brain-axis signaling. Metabolomics profiling identified a wide array of metabolites embedded in MEVs, including lipids, carbohydrates, amino acids, vitamins, and organic acids. Interestingly, many neurotransmitter-related compounds were detected inside MEVs, including arachidonyl-dopamine (NADA), gabapentin, glutamate and N-acylethanolamines. Next, we aimed to identify commensal microbes with psychobiotic activity. We isolated 58 Bacteroides strains assigned to four genera, 11 species, and 4 new species based on 16S rDNA sequencing. We performed whole genome sequencing of 18 representative isolates, followed by a comparative analysis of the structure of polysaccharide utilization loci (PUL) and glutamate decarboxylase (GAD), a genetic system involved in GABA production. Quantifying GABA was done using competitive ELISA, wherein three isolates (B. finegoldii, B. faecis, and B. caccae) showed high GABA production (4.5-7 mM range) in supernatant whereas 2.2 to 4 uM GABA concentration was detected inside microvesicles extracted using ultracentrifugation. To test the biodistribution of MEVs from the gut to other parts of the body, CACO-2, RIN-14 B, and hCMEC/D3 cells showed a capacity to internalize labeled MEVs through an endocytic mechanism. Additionally, MEVs exhibited a dose dependent paracellular transport through CACO-2 intestinal cells and hCMEC/D3 brain endothelial cells. In vivo results showed biodistribution of MEVs to liver, stomach and spleen. Overall, our results reveal the capabilities of MEVs to cross the intestinal and blood brain barriers to deliver their cargoes of neuroactive molecules to the brain as a new signaling mechanism in microbiota-gut-brain axis communications.

microbiology↗

bioRxiv2021

Cytoplasmic zinc regulates IL-1β production by monocytes/macrophages via mTORC1-induced glycolysis in rheumatoid arthritis (RA)

The essential micronutrient zinc plays regulatory roles in immune responses through its ability to affect signaling pathways. In activated monocytes/macrophages, signaling networks mediate metabolic reprogramming in order to meet the demands of participating in immune responses. Despite its known immunoregulatory roles, the effect of zinc on metabolic reprogramming in monocytes/macrophages remains unclear. Here, we demonstrate that cytoplasmic bioavailable zinc is essential for regulating IL-1{beta} production in activated human monocytes/macrophages downstream of mTORC1-induced glycolysis. The cytoplasmic zinc level was influenced by extracellular zinc concentration through a zinc-specific importer, Zip8, which was markedly increased in monocytes of patients with rheumatoid arthritis (RA), a chronic inflammatory disease, and even in LPS-stimulated monocytes/macrophages of healthy individuals. Mechanically, phosphorylation of S6 kinase, a substrate of mTORC1, was significantly enhanced by zinc-mediated inhibition of PP2A, an S6 kinase phosphatase. As a result, IL-1{beta} production was increased due to the activation of mTORC1-induced glycolysis. The expression of Zip8 and MT2A, a zinc-inducible gene, and the phosphorylation of S6 kinase by monocytes of RA patients was significantly enhanced compared with those of HCs and Zip8 levels positively correlated with RA clinical parameters, suggesting that Zip8-mediated zinc influx is related to inflammatory conditions. These results provide insight into the role of cytoplasmic bioavailable zinc in the metabolic reprogramming of human monocytes/macrophages which is an essential process for inflammatory responses. One Sentence SummaryCytoplasmic zinc regulates IL-1{beta} production in monocytes/macrophages downstream of mTORC1-S6K-induced glycolysis via zinc-mediated inhibition of PP2A.

immunology↗