In vivo quantitative analysis of Talin turnover in response to force

Cell adhesion to the extracellular matrix (ECM) allows cells to form and maintain three-dimensional tissue architecture. Cell–ECM adhesions are stabilized upon exposure to mechanical force. In this study, we used quantitative imaging and mathematical modeling to gain mechanistic insight into how integrin-based adhesions respond to increased and decreased mechanical forces. A critical means of regulating integrin-based adhesion is provided by modulating the turnover of integrin and its adhesion complex (integrin adhesion complex [IAC]). The turnover of the IAC component Talin, a known mechanosensor, was analyzed using fluorescence recovery after photobleaching. Experiments were carried out in live, intact flies in genetic backgrounds that increased or decreased the force applied on sites of adhesion. This analysis showed that when force is elevated, the rate of assembly of new adhesions increases such that cell–ECM adhesion is stabilized. Moreover, under conditions of decreased force, the overall rate of turnover, but not the proportion of adhesion complex components undergoing turnover, increases. Using point mutations, we identify the key functional domains of Talin that mediate its response to force. Finally, by fitting a mathematical model to the data, we uncover the mechanisms that mediate the stabilization of ECM-based adhesion during development.

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SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling

10.1101/2021.12.10.472112 ◽

2021 ◽

Author(s):

Scott B Biering ◽

Francielle Tramontini Gomes de Sousa ◽

Laurentia V. Tjang ◽

Felix Pahmeier ◽

Richard Ruan ◽

...

Keyword(s):

Transcriptional Response ◽

Barrier Dysfunction ◽

Vascular Leak ◽

Endothelial Barrier Dysfunction ◽

Mechanistic Insight ◽

Starting Point ◽

Signaling Axis ◽

Insight Into

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.

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Mechanistic Insight into the ZnO‐Assisted Growth of Sn 6 O 4 (OH) 4 Three‐Dimensional Dendritic Hexapods

ChemistrySelect ◽

10.1002/slct.202103186 ◽

2021 ◽

Vol 6 (43) ◽

pp. 12158-12164

Author(s):

Qi Chen ◽

Zhi Yun Chen ◽

Ji Hong Wu

Keyword(s):

Three Dimensional ◽

Mechanistic Insight ◽

Insight Into

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Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

Nature Communications ◽

10.1038/s41467-019-12551-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Brianna J. Klein ◽

Suk Min Jang ◽

Catherine Lachance ◽

Wenyi Mi ◽

Jie Lyu ◽

...

Keyword(s):

Posttranslational Modification ◽

Memory Impairment ◽

Target Genes ◽

Epigenetic Mark ◽

Mechanistic Insight ◽

Genomic Analyses ◽

Insight Into

Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

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Characterization of covalent protein modification by triclosan in vivo and in vitro via three-dimensional liquid chromatography-mass spectrometry: New insight into its adverse effects

Environment International ◽

10.1016/j.envint.2019.105423 ◽

2020 ◽

Vol 136 ◽

pp. 105423 ◽

Cited By ~ 1

Author(s):

Meixian Liu ◽

Na Li ◽

Yida Zhang ◽

Zhiyuan Zheng ◽

Yue Zhuo ◽

...

Keyword(s):

Mass Spectrometry ◽

Liquid Chromatography ◽

Adverse Effects ◽

Protein Modification ◽

Three Dimensional ◽

Liquid Chromatography Mass Spectrometry ◽

Insight Into

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On-chip hydrogel arrays individually encapsulating acoustic formed multicellular aggregates for high throughput drug testing

Lab on a Chip ◽

10.1039/d0lc00255k ◽

2020 ◽

Vol 20 (12) ◽

pp. 2228-2236 ◽

Cited By ~ 5

Author(s):

Xuejia Hu ◽

Shukun Zhao ◽

Ziyi Luo ◽

Yunfeng Zuo ◽

Fang Wang ◽

...

Keyword(s):

Drug Resistance ◽

High Throughput ◽

Solid Tumor ◽

Drug Testing ◽

Three Dimensional ◽

Multicellular Aggregates ◽

3D Environments ◽

On Chip ◽

Insight Into

Multicellular aggregates in three-dimensional (3D) environments provide novel solid tumor models that can provide insight into in vivo drug resistance.

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In vivo, label-free, three-dimensional quantitative imaging of kidney microcirculation using Doppler optical coherence tomography

Laboratory Investigation ◽

10.1038/labinvest.2011.112 ◽

2011 ◽

Vol 91 (11) ◽

pp. 1596-1604 ◽

Cited By ~ 25

Author(s):

Jeremiah Wierwille ◽

Peter M Andrews ◽

Maristela L Onozato ◽

James Jiang ◽

Alex Cable ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Quantitative Imaging ◽

Three Dimensional ◽

Optical Coherence ◽

Label Free ◽

Doppler Optical Coherence Tomography

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Tissue topography steers migrating Drosophila border cells

10.1101/2020.09.27.316117 ◽

2020 ◽

Author(s):

Wei Dai ◽

Xiaoran Guo ◽

Yuansheng Cao ◽

James A. Mondo ◽

Joseph P. Campanale ◽

...

Keyword(s):

Chemical Cues ◽

Path Selection ◽

Imaging Genetics ◽

Border Cells ◽

Tissue Architecture ◽

Physical Information ◽

Sense And Respond ◽

Physical Features ◽

Insight Into

AbstractMoving cells can sense and respond to physical features of the microenvironment, however in vivo the significance of tissue topography is mostly unknown. Here we use the Drosophila border cells, an established model for in vivo cell migration, to study how chemical and physical information influence migration path selection. Live imaging, genetics, modeling, and simulations show that, although chemical cues were thought to be sufficient, microtopography is also important. Chemoattractants promote predominantly posterior movement, whereas tissue architecture presents orthogonal information, a path of least resistance concentrated near the center of the egg chamber. E-cadherin supplies a permissive haptotactic cue. Our results provide insight into how cells integrate and prioritize topographical, adhesive, and chemoattractant cues to choose one path amongst many.

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Mycolactone toxin induces an inflammatory response by targeting the IL-1β pathway: Mechanistic insight into Buruli ulcer pathophysiology

PLoS Pathogens ◽

10.1371/journal.ppat.1009107 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1009107

Author(s):

M. Foulon ◽

M. Robbe-Saule ◽

J. Manry ◽

L. Esnault ◽

Y. Boucaud ◽

...

Keyword(s):

Inflammatory Response ◽

Buruli Ulcer ◽

Mycobacterium Ulcerans ◽

Inflammatory Factors ◽

Dependent Manner ◽

Local Inflammatory Response ◽

Mechanistic Insight ◽

Insight Into

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.

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Crystal structure of the FAS1 domain of the hyaluronic acid receptor stabilin-2

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798318007271 ◽

2018 ◽

Vol 74 (7) ◽

pp. 695-701 ◽

Cited By ~ 2

Author(s):

Aleksandra Twarda-Clapa ◽

Beata Labuzek ◽

Dobroslawa Krzemien ◽

Bogdan Musielak ◽

Przemyslaw Grudnik ◽

...

Keyword(s):

Hyaluronic Acid ◽

Cancer Metastasis ◽

Potential Role ◽

Three Dimensional ◽

Protein Fragments ◽

Acid Receptor ◽

X Ray ◽

Insight Into

Recent research has identified a potential role of the hyaluronic acid receptor stabilin-2 (Stab2) in cancer metastasis. Stab2 belongs to a group of scavenger receptors and is responsible for the clearance of more than ten ligands, including hyaluronic acid (HA). In vivo experiments on mice have shown that the absence of Stab2, or its blocking by an antibody, effectively opposes cancer metastasis, which is accompanied by an increase in the level of circulating HA. Knowledge of ligand recognition and signal transduction by Stab2 is limited and no three-dimensional structures of any protein fragments of this receptor have been solved to date. Here, a high-resolution X-ray structure of the seventh FAS1 domain of Stab2 is reported. This structure provides the first insight into the Stab2 structure.

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