Previous work has shown that proteins that have the potential to be vaccine candidates can be predicted from features derived from their amino acid sequences. In this work, we make an empirical ...comparison across various machine learning classifiers on this sequence-based inference problem. Using systematic cross validation on a dataset of 200 known vaccine candidates and 200 negative examples, with a set of 525 features derived from the AA sequences and feature selection applied through a greedy backward elimination approach, we show that simple classification algorithms often perform as well as more complex support vector kernel machines. The work also includes a novel cross validation applied across bacterial species, i.e. the validation proteins all come from a specific species of bacterium not represented in the training set. We termed this type of validation Leave One Bacteria Out Validation (LOBOV).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aberrant activation of the Wnt signaling pathway is an important step in the initiation and progression of tumor development in diverse cancers. The central effector of canonical Wnt signaling, ...β-catenin (CTNNB1), is a multifunctional protein, and has been extensively studied with respect to its roles in cell-cell adhesion and in regulation of Wnt-driven transcription. Here, a novel mass spectrometry-based proteomics technique in colorectal cancer cells expressing stabilized β-catenin, was used to identify a protein-protein interaction between β-catenin and DNA methyltransferase I (Dnmt1) protein, the primary regulator of DNA methylation patterns in mammalian cells. Dnmt1 and β-catenin strongly colocalized in the nuclei of colorectal cancer cells, and the interaction is mediated by the central domain of the Dnmt1 protein. Dnmt1 protein abundance is dependent upon the levels of β-catenin, and is increased in cells expressing stabilized mutant β-catenin. Conversely, the Dnmt1 regulates the levels of nuclear β-catenin and β-catenin/TCF-driven transcription. In addition, lysine-specific demethylase 1 (LSD1/KDM1A), a regulator of DNMT1 stability, was identified as a component of the Dnmt1-β-catenin protein complex and perturbation of the Dnmt1-β-catenin interaction altered DNA methylation. In summary, a functional protein-protein interaction was identified between two critically important oncoproteins, in turn revealing a link between Wnt signaling and downstream nuclear functions mediated by Dnmt1.
Two critical oncoproteins, Dnmt1 and β-catenin, mutually regulate one each other's levels and activities in colorectal cancer cells.
The contribution of epithelial-mesenchymal transition (EMT) to human lung fibrogenesis is controversial. Here we provide evidence that ZEB1-mediated EMT in human alveolar epithelial type II (ATII) ...cells contributes to the development of lung fibrosis by paracrine signalling to underlying fibroblasts. Activation of EGFR-RAS-ERK signalling in ATII cells induced EMT via ZEB1. ATII cells had extremely low extracellular matrix gene expression even after induction of EMT, however conditioned media from ATII cells undergoing RAS-induced EMT augmented TGFβ-induced profibrogenic responses in lung fibroblasts. This epithelial-mesenchymal crosstalk was controlled by ZEB1 via the expression of tissue plasminogen activator (tPA). In human fibrotic lung tissue, nuclear ZEB1 expression was detected in alveolar epithelium adjacent to sites of extracellular matrix (ECM) deposition, suggesting that ZEB1-mediated paracrine signalling has the potential to contribute to early fibrotic changes in the lung interstitium. Targeting this novel ZEB1 regulatory axis may be a viable strategy for the treatment of pulmonary fibrosis.
Two interrelated problems in biology are understanding the regulatory logic and predictability of morphological evolution. Here, we studied these problems by comparing Arabidopsis thaliana, which has ...simple leaves, and its relative, Cardamine hirsuta, which has dissected leaves comprising leaflets. By transferring genes between the two species, we provide evidence for an inverse relationship between the pleiotropy of SHOOTMERISTEMLESS (STM) and BREVIPEDICELLUS (BP) homeobox genes and their ability to modify leaf form. We further show that cis-regulatory divergence of BP results in two alternative configurations of the genetic networks controlling leaf development. In C. hirsuta, ChBP is repressed by the microRNA164A (MIR164A)/ChCUP-SHAPED COTYLEDON (ChCUC) module and ChASYMMETRIC LEAVES1 (ChAS1), thus creating cross-talk between MIR164A/CUC and AS1 that does not occur in A. thaliana. These different genetic architectures lead to divergent interactions of network components and growth regulation in each species. We suggest that certain regulatory genes with low pleiotropy are predisposed to readily integrate into or disengage from conserved genetic networks influencing organ geometry, thus rapidly altering their properties and contributing to morphological divergence.
Glycogen-specific kinase (GSK3β) is an integral regulator of the Wnt signalling pathway as well as many other diverse signalling pathways and processes. Dys-regulation of GSK3β is implicated in many ...different pathologies, including neurodegenerative disorders as well as many different tumour types. In the context of tumour development, GSK3β has been shown to play both oncogenic and tumour suppressor roles, depending upon tissue, signalling environment or disease progression. Although multiple substrates of the GSK3β kinase have been identified, the wider protein networks within which GSK3β participates are not well known, and the consequences of these interactions not well understood. In this study, LC-MS/MS expression analysis was performed using knockout GSK3β colorectal cancer cells and isogenic controls in colorectal cancer cell lines carrying dominant stabilizing mutations of β-catenin. Consistent with the role of GSK3β, we found that β-catenin levels and canonical Wnt activity are unaffected by knockout of GSK3β and therefore used this knockout cell model to identify other processes in which GSK3β is implicated. Quantitative proteomic analysis revealed perturbation of proteins involved in cell-cell adhesion, and we characterized the phenotype and altered proteomic profiles associated with this. We also characterized the perturbation of metabolic pathways resulting from GSK3β knockout and identified defects in glycogen metabolism. In summary, using a precision colorectal cancer cell-line knockout model with constitutively activated β-catenin we identified several of the diverse pathways and processes associated with GSK3β function.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN ...non-amplified population is unknown.
A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis.
We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively.
We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.
Influenza is a common illness for its high rates of morbidity and transmission. The implementation of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic to manage its dissemination ...could affect the transmission of influenza. A retrospective analysis, between 2018 and 2023, was conducted to examine the incidence of influenza virus types A and B among patients in sentinel cities located in North or South China as well as in Wuhan City. For validations, data on the total count of influenza patients from 2018 to 2023 were collected at the Central Hospital of Wuhan, which is not included in the sentinel hospital network. Time series methods were utilized to examine seasonal patterns and to forecast future influenza trends. Northern and southern cities in China had earlier outbreaks during the NPIs period by about 8 weeks compared to the 2018-2019. The implementation of NPIs significantly reduced the influenza-like illness (ILI) rate and infection durations. Influenza B Victoria and H3N2 were the first circulating strains detected after the relaxation of NPIs, followed by H1N1 across mainland China. The SARIMA model predicted synchronized H1N1 outbreak cycles in North and South China, with H3N2 expected to occur in the summer in southern cities and in the winter in northern cities over the next 3 years. The ILI burden is expected to rise in both North and South China over the next 3 years, with higher ILI% levels in southern cities throughout the year, especially in winter, and in northern cities mainly during winter. In Wuhan City and the Central Hospital of Wuhan, influenza levels are projected to peak in the winter of 2024, with 2 smaller peaks expected during the summer of 2023. In this study, we report the impact of NPIs on future influenza trends in mainland China. We recommend that local governments encourage vaccination during the transition period between summer and winter to mitigate economic losses and mortality associated with influenza.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Computational tools for multiomics data integration have usually been designed for unsupervised detection of multiomics features explaining large phenotypic variations. To achieve this, some ...approaches extract latent signals in heterogeneous data sets from a joint statistical error model, while others use biological networks to propagate differential expression signals and find consensus signatures. However, few approaches directly consider molecular interaction as a data feature, the essential linker between different omics data sets. The increasing availability of genome-scale interactome data connecting different molecular levels motivates a new class of methods to extract interactive signals from multiomics data. Here we developed iOmicsPASS, a tool to search for predictive subnetworks consisting of molecular interactions within and between related omics data types in a supervised analysis setting. Based on user-provided network data and relevant omics data sets, iOmicsPASS computes a score for each molecular interaction, and applies a modified nearest shrunken centroid algorithm to the scores to select densely connected subnetworks that can accurately predict each phenotypic group. iOmicsPASS detects a sparse set of predictive molecular interactions without loss of prediction accuracy compared to alternative methods, and the selected network signature immediately provides mechanistic interpretation of the multiomics profile representing each sample group. Extensive simulation studies demonstrate clear benefit of interaction-level modeling. iOmicsPASS analysis of TCGA/CPTAC breast cancer data also highlights new transcriptional regulatory network underlying the basal-like subtype as positive protein markers, a result not seen through analysis of individual omics data.
Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly ...implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that zinc finger E-box-binding homeobox 1–mediated epithelial–mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-β–induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial–mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial–mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1–tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-β–activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor–like repeats. Together, these data identify that aberrant bidirectional epithelial–mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals.
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