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Dick, K.

Publications and source records attributed to Dick, K..

4 recordsLinked to original sources

Can a Sparse 29 x 29 Pixel Chaos Game Representation Predict Protein Binding Sites using Fine-Tuned State-of-the Art Deep Learning Semantic Segmentation Models?

No. While our experiments ultimately failed, this work was motivated by the seemingly reasonable hypothesis that encoding protein sequences as a fractal-based image in combination with a binary mask identifying those pixels representative of the protein binding interface could effectively be used to fine-tune a semantic segmentation model. We were wrong. Despite the shortcomings of this work, a number of insights were drawn, inspiring discussion about how this fractal-based space may be exploited to generate effective protein binding site predictors in the future. Furthermore, these realizations promise to orient complimentary studies leveraging fractal-based representations, whether in the field of bioinformatics, or more broadly within disparate fields leveraging sequence-type data, such as Natural Language Processing. In a non-traditional way, this work presents the experimental design undertaken and interleaves various insights and limitations. It is the hope of this work that those interested in leveraging fractal-based representations and deep learning architectures as part of their work will benefit from the insights arising from this work.

bioinformatics↗

Pathogen and human NDPK-proteins promote AML cell survival via monocyte NLRP3-inflammasome activation.

A history of infection has been linked with increased risk of acute myeloid leukaemia (AML) and related myelodysplastic syndromes (MDS). Furthermore, AML and MDS patients suffer frequent infections because of disease-related impaired immunity. However, the role of infections in the development and progression of AML and MDS remains poorly understood. We and others previously demonstrated that the human nucleoside diphosphate kinase (NDPK) NM23-H1 protein promotes AML blast cell survival by inducing secretion of IL-1{beta} from accessory cells. NDPKs are an evolutionary highly conserved protein family and pathogenic bacteria secrete NDPKs that regulate virulence and host-pathogen interactions. Here, we demonstrate the presence of IgM antibodies against a broad range of pathogen NDPKs and more selective IgG antibody activity against pathogen NDPKs in the blood of AML patients and normal donors, demonstrating that in vivo exposure to NDPKs likely occurs. We also show that pathogen derived NDPK-proteins faithfully mimic the catalytically independent pro-survival activity of NM23-H1 against primary AML cells. Flow cytometry identified that pathogen and human NDPKs selectively bind to monocytes in peripheral blood. We therefore used vitamin D3 differentiated monocytes from wild type and genetically modified THP1 cells as a model to demonstrate that NDPK-mediated IL-1{beta} secretion by monocytes is NLRP3-inflammasome and caspase 1 dependent, but independent of TLR4 signaling. Monocyte stimulation by NDPKs also resulted in activation of NF-{kappa}B and IRF pathways but did not include the formation of pyroptosomes or result in pyroptotic cell death which are pivotal features of canonical NLRP3 inflammasome activation. In the context of the growing importance of the NLRP3 inflammasome and IL-1{beta} in AML and MDS, our findings now implicate pathogen NDPKs in the pathogenesis of these diseases. Author SummaryAcute myeloid leukaemia (AML) and myelodysplastic syndromes MDS) are related blood cancers that are associated with frequent infections because the cancers suppress normal immunity. These infections are therefore generally considered as medical complications arising as a result of but separate to the cancer. However, we provide evidence here that infections may promote or drive cancer progression. We and others previously demonstrated that a human protein called NM23-H1 promotes the survival of AML cells by eliciting survival signals from other cells. NM23-H1 belongs to a highly conserved family of proteins that also occur in bacteria and fungi that cause infections in AML and MDS patients. Here we demonstrate that these bacterial and fungal proteins recapitulate the pro-survival effect of NM23-H1 on AML cells. We also determine that these effects are mediated via mechanisms already known to be important in the development and progression of AML and MDS. This study is the first to identify NM23-H1 like proteins from pathogenic microorganisms as novel activators of these pathways. These findings have important implications for how we understand infections in AML and MDS patients and suggest that in addition to being the consequence of these diseases, infections may also drive the cancer process.

microbiology↗

Computational Prediction of the Comprehensive SARS-CoV-2 vs. Human Interactome to Guide the Design of Therapeutics

AO_SCPLOWBSTRACTC_SCPLOWUnderstanding the disease pathogenesis of the novel coronavirus, denoted SARS-CoV-2, is critical to the development of anti-SARS-CoV-2 therapeutics. The global propagation of the viral disease, denoted COVID-19 ("coronavirus disease 2019"), has unified the scientific community in searching for possible inhibitory small molecules or polypeptides. Given the known interaction between the human ACE2 ("Angiotensin-converting enzyme 2") protein and the SARS-CoV virus (responsible for the coronavirus outbreak circa. 2003), considerable focus has been directed towards the putative interaction between the SARS-CoV-2 Spike protein and ACE2. However, a more holistic understanding of the SARS-CoV-2 vs. human inter-species interactome promises additional putative protein-protein interactions (PPI) that may be considered targets for the development of inhibitory therapeutics. To that end, we leverage two state-of-the-art, sequence-based PPI predictors (PIPE4 & SPRINT) capable of generating the comprehensive SARS-CoV-2 vs. human interactome, comprising approximately 285,000 pairwise predictions. Of these, we identify the high-scoring subset of human proteins predicted to interact with each of the 14 SARS-CoV-2 proteins by both methods, comprising 279 high-confidence putative interactions involving 225 human proteins. Notably, the Spike-ACE2 interaction was the highest ranked for both the PIPE4 and SPRINT predictors, corroborating existing evidence for this PPI. Furthermore, the PIPE-Sites algorithm was used to predict the putative subsequence that might mediate each interaction and thereby inform the design of inhibitory polypeptides intended to disrupt the corresponding host-pathogen interactions. We hereby publicly release the comprehensive set of PPI predictions and their corresponding PIPE-Sites landscapes in the following DataVerse repository: 10.5683/SP2/JZ77XA. All data and metadata are released under a CC-BY 4.0 licence. The information provided represents theoretical modeling only and caution should be exercised in its use. It is intended as a resource for the scientific community at large in furthering our understanding of SARS-CoV-2.

bioinformatics↗

Designing Anti-Zika Virus Peptides Derived from Predicted Human-Zika Virus Protein-Protein Interactions

The production of anti-Zika virus (ZIKV) therapeutics has become increasingly important as the propagation of the devastating virus continues largely unchecked. Notably, a causal relationship between ZIKV infection and neurodevelopmental abnormalities has been widely reported, yet a specific mechanism underlying impaired neurological development has not been identified. Here, we report on the design of several synthetic competitive inhibitory peptides against key pathogenic ZIKV proteins through the prediction of protein-protein interactions (PPIs). Often, PPIs between host and viral proteins are crucial for infection and pathogenesis, making them attractive targets for therapeutics. Using two complementary sequence-based PPI prediction tools, we first produced a comprehensive map of predicted human-ZIKV PPIs (involving 209 human protein candidates). We then designed several peptides intended to disrupt the corresponding host-pathogen interactions thereby acting as anti-ZIKV therapeutics. The data generated in this study constitute a foundational resource to aid in the multi-disciplinary effort to combat ZIKV infection, including the design of additional synthetic proteins.

synthetic biology↗