The SIGnaling Network Open Resource 2.0 (SIGNOR 2.0) is a public repository that stores signaling information as binary causal relationships between biological entities. The captured information is represented graphically as a signed directed graph. Each signaling relationship is associated to an effect (up/down-regulation) and to the mechanism (e.g. binding, phosphorylation, transcriptional activation, etc.) causing the up/down-regulation of the target entity. Since its first release, SIGNOR has undergone a significant content increase and the number of annotated causal interactions have almost doubled. SIGNOR 2.0 now stores almost 23 000 manually-annotated causal relationships between proteins and other biologically relevant entities: chemicals, phenotypes, complexes, etc. We describe here significant changes in curation policy and a new confidence score, which is assigned to each interaction. We have also improved the compliance to the FAIR data principles by providing (i) SIGNOR stable identifiers, (ii) programmatic access through REST APIs, (iii) bioschemas and (iv) downloadable data in standard-compliant formats, such as PSI-MI CausalTAB and GMT. The data are freely accessible and downloadable at https://signor.uniroma2.it/.
Fibro/Adipogenic Progenitors (FAPs) are muscle-interstitial progenitors mediating pro-myogenic signals that are critical for muscle homeostasis and regeneration. In myopathies, the autocrine/paracrine constraints controlling FAP adipogenesis are released causing fat infiltrates. Here, by combining pharmacological screening, high-dimensional mass cytometry and in silico network modeling with the integration of single-cell/bulk RNA sequencing data, we highlighted the canonical WNT/ GSK/β-catenin signaling as a crucial pathway modulating FAP adipogenesis triggered by insulin signaling. Consistently, pharmacological blockade of GSK3, by the LY2090314 inhibitor, stabilizes β-catenin and represses PPARγ expression abrogating FAP adipogenesis ex vivo while limiting fatty degeneration in vivo. Furthermore, GSK3 inhibition improves the FAP pro-myogenic role by efficiently stimulating, via follistatin secretion, muscle satellite cell (MuSC) differentiation into mature myotubes. Combining, publicly available single-cell RNAseq datasets, we characterize FAPs as the main source of WNT ligands inferring their potential in mediating autocrine/paracrine responses in the muscle niche. Lastly, we identify WNT5a, whose expression is impaired in dystrophic FAPs, as a crucial WNT ligand able to restrain the detrimental adipogenic differentiation drift of these cells through the positive modulation of the β-catenin signaling.
Fibro-adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin-deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry–based proteomic analysis of FAPs from muscles of wild-type and mdx mice suggested that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.
In a physiological environment (e.g., blood and interstitial fluids) nanoparticles (NPs) will bind proteins shaping a "protein corona" layer. The long-lived protein layer tightly bound to the NP surface is referred to as the hard corona (HC) and encodes information that controls NP bioactivity (e.g. cellular association, cellular signaling pathways, biodistribution, and toxicity). Decrypting this complex code has become a priority to predict the NP biological outcomes. Here, we use a library of 16 lipid NPs of varying size (Ø≈ 100-250 nm) and surface chemistry (unmodified and PEGylated) to investigate the relationships between NP physicochemical properties (nanoparticle size, aggregation state and surface charge), protein corona fingerprints (PCFs), and NP-cell association. We found out that none of the NPs' physicochemical properties alone was exclusively able to account for association with human cervical cancer cell line (HeLa). For the entire library of NPs, a total of 436 distinct serum proteins were detected. We developed a predictive-validation modeling that provides a means of assessing the relative significance of the identified corona proteins. Interestingly, a minor fraction of the HC, which consists of only 8 PCFs were identified as main promoters of NP association with HeLa cells. Remarkably, identified PCFs have several receptors with high level of expression on the plasma membrane of HeLa cells.
Multiple chemical sensitivity (MCS) is a common clinical diagnosis in western populations and its symptoms are thought to be mainly related to chemical compounds exposure. Although MCS subjects refer to complain from many central nervous system symptoms, including dizziness, no study to now deepened vestibular detriment nor to what extent such an impairment could worsen MCS. Thus, the purpose of present study was to objectively highlight those clinical/subclinical aspects of vestibular impairment that could be related to MCS symptoms cohorts. A principal component analysis within a wide battery of otoneurological test scores was employed in 18 right-handed MCS patients and 20 sex- and age-matched healthy individuals. A deranged dimensionality in near-optimal re-weighting within otoneurological variables was found in MCS as compared with healthy subjects. These data seem to support the idea that MCS physiopathological underpinnings could lead to a peripheral and higher vestibular decay that could be addressed as a further aspect to better follow MCS patients up along natural history of disease in clinical practice.
CancerGeneNet (https://signor.uniroma2.it/CancerGeneNet/) is a resource that links genes that are frequently mutated in cancers to cancer phenotypes. The resource takes advantage of a curation effort aimed at embedding a large fraction of the gene products that are found altered in cancer cells into a network of causal protein relationships. Graph algorithms, in turn, allow to infer likely paths of causal interactions linking cancer associated genes to cancer phenotypes thus offering a rational framework for the design of strategies to revert disease phenotypes. CancerGeneNet bridges two interaction layers by connecting proteins whose activities are affected by cancer drivers to proteins that impact on the ‘hallmarks of cancer’. In addition, CancerGeneNet annotates curated pathways that are relevant to rationalize the pathological consequences of cancer driver mutations in selected common cancers and ‘MiniPathways’ illustrating regulatory circuits that are frequently altered in different cancers.
Motivation Mass spectrometry-based phosphoproteomics can routinely identify and quantify thousands of phosphorylated peptides from a single experiment. However interrogating possible upstream kinases and identifying key literature for phosphorylation sites is laborious and time-consuming. Results Here, we present Phosphomatics – a publicly available web resource for interrogating phosphoproteomics data. Phosphomatics allows researchers to upload phosphoproteomics data and interrogate possible relationships from a substrate-, kinase-, or pathway-centric viewpoint. Availability Phosphomatics is freely available via the internet at: https://phosphomatics.com Supplementary information Supplementary data are available at Bioinformatics online.
The skeletal muscle is populated by a variety of different mononuclear cell types that actively contribute to tissue homeostasis. When the tissue is stressed by exercise or by an acute or chronic insult, the different cell types are activated, exchange signals and initiate a finely-orchestrated regeneration process to prevent the loss of muscle mass. This cell variety is exacerbated by an additional intra population heterogeneity, where the cell population boundaries often lose their significance. Here, we applied a high-dimensional single-cell mass cytometry analysis to solve the cellular and molecular complexity of the muscle tissue in different physiological and pathological conditions. Taken together, our results provide a comprehensive picture both of muscle cell population homeostasis during ageing and of the changes induced by a perturbation of the system, be it chronic (dystrophy) or acute (cardiotoxin).
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