Large–scale data–driven network analysis of human–plasmodium falciparum interactome: extracting essential targets and processes for malaria drug discovery

Background: Plasmodium falciparum malaria is an infectious disease considered to have great impact on public health due to its associated high mortality rates especially in sub Saharan Africa. Falciparum drugresistant strains, notably, to chloroquine and sulfadoxine-pyrimethamine in Africa is traced mainly to Southeast Asia where artemisinin resistance rate is increasing. Although careful surveillance to monitor the emergence and spread of artemisinin-resistant parasite strains in Africa is on-going, research into new drugs, particularly, for African populations, is critical since there is no replaceable drug for artemisinin combination therapies (ACTs) yet. Objective: The overall objective of this study is to identify potential protein targets through host–pathogen protein–protein functional interaction network analysis to understand the underlying mechanisms of drug failure and identify those essential targets that can play their role in predicting potential drug candidates specific to the African populations through a protein-based approach of both host and Plasmodium falciparum genomic analysis. Methods: We leveraged malaria-specific genome wide association study summary statistics data obtained from Gambia, Kenya and Malawi populations, Plasmodium falciparum selective pressure variants and functional datasets (protein sequences, interologs, host-pathogen intra-organism and host-pathogen inter-organism protein-protein interactions (PPIs)) from various sources (STRING, Reactome, HPID, Uniprot, IntAct and literature) to construct overlapping functional network for both host and pathogen. Developed algorithms and a large-scale data-driven computational framework were used in this study to analyze the datasets and the constructed networks to identify densely connected subnetworks or hubs essential for network stability and integrity. The host-pathogen network was analyzed to elucidate the influence of parasite candidate key proteins within the network and predict possible resistant pathways due to host-pathogen candidate key protein interactions. We performed biological and pathway enrichment analysis on critical proteins identified to elucidate their functions. In order to leverage disease-target-drug relationships to identify potential repurposable already approved drug candidates that could be used to treat malaria, pharmaceutical datasets from drug bank were explored using semantic similarity approach based of target–associated biological processes Results: About 600,000 significant SNPs (p-value< 0.05) from the summary statistics data were mapped to their associated genes, and we identified 79 human-associated malaria genes. The assembled parasite network comprised of 8 clusters containing 799 functional interactions between 155 reviewed proteins of which 5 clusters contained 43 key proteins (selective variants) and 2 clusters contained 2 candidate key proteins(key proteins characterized by high centrality measure), C6KTB7 and C6KTD2. The human network comprised of 32 clusters containing 4,133,136 interactions between 20,329 unique reviewed proteins of which 7 clusters contained 760 key proteins and 2 clusters contained 6 significant human malaria-associated candidate key proteins or genes P22301 (IL10), P05362 (ICAM1), P01375 (TNF), P30480 (HLA-B), P16284 (PECAM1), O00206 (TLR4). The generated host-pathogen network comprised of 31,512 functional interactions between 8,023 host and pathogen proteins. We also explored the association of pfk13 gene within the host-pathogen. We observed that pfk13 cluster with host kelch–like proteins and other regulatory genes but no direct association with our identified host candidate key malaria targets. We implemented semantic similarity based approach complemented by Kappa and Jaccard statistical measure to identify 115 malaria–similar diseases and 26 potential repurposable drug hits that can be 3 appropriated experimentally for malaria treatment. Conclusion: In this study, we reviewed existing antimalarial drugs and resistance–associated variants contributing to the diminished sensitivity of antimalarials, especially chloroquine, sulfadoxine-pyrimethamine and artemisinin combination therapy within the African population. We also described various computational techniques implemented in predicting drug targets and leads in drug research. In our data analysis, we showed that possible mechanisms of resistance to artemisinin in Africa may arise from the combinatorial effects of many resistant genes to chloroquine and sulfadoxine–pyrimethamine. We investigated the role of pfk13 within the host–pathogen network. We predicted key targets that have been proposed to be essential for malaria drug and vaccine development through structural and functional analysis of host and pathogen function networks. Based on our analysis, we propose these targets as essential co-targets for combinatorial malaria drug discovery

The Computational Diet: A Review of Computational Methods Across Diet, Microbiome, and Health.

Food and human health are inextricably linked. As such, revolutionary impacts on health have been derived from advances in the production and distribution of food relating to food safety and fortification with micronutrients. During the past two decades, it has become apparent that the human microbiome has the potential to modulate health, including in ways that may be related to diet and the composition of specific foods. Despite the excitement and potential surrounding this area, the complexity of the gut microbiome, the chemical composition of food, and their interplay in situ remains a daunting task to fully understand. However, recent advances in high-throughput sequencing, metabolomics profiling, compositional analysis of food, and the emergence of electronic health records provide new sources of data that can contribute to addressing this challenge. Computational science will play an essential role in this effort as it will provide the foundation to integrate these data layers and derive insights capable of revealing and understanding the complex interactions between diet, gut microbiome, and health. Here, we review the current knowledge on diet-health-gut microbiota, relevant data sources, bioinformatics tools, machine learning capabilities, as well as the intellectual property and legislative regulatory landscape. We provide guidance on employing machine learning and data analytics, identify gaps in current methods, and describe new scenarios to be unlocked in the next few years in the context of current knowledge

Applications of Machine Learning in Human Microbiome Studies: A Review on Feature Selection, Biomarker Identification, Disease Prediction and Treatment

The number of microbiome-related studies has notably increased the availability of data on human microbiome composition and function. These studies provide the essential material to deeply explore host-microbiome associations and their relation to the development and progression of various complex diseases. Improved data-analytical tools are needed to exploit all information from these biological datasets, taking into account the peculiarities of microbiome data, i.e., compositional, heterogeneous and sparse nature of these datasets. The possibility of predicting host-phenotypes based on taxonomy-informed feature selection to establish an association between microbiome and predict disease states is beneficial for personalized medicine. In this regard, machine learning (ML) provides new insights into the development of models that can be used to predict outputs, such as classification and prediction in microbiology, infer host phenotypes to predict diseases and use microbial communities to stratify patients by their characterization of state-specific microbial signatures. Here we review the state-of-the-art ML methods and respective software applied in human microbiome studies, performed as part of the COST Action ML4Microbiome activities. This scoping review focuses on the application of ML in microbiome studies related to association and clinical use for diagnostics, prognostics, and therapeutics. Although the data presented here is more related to the bacterial community, many algorithms could be applied in general, regardless of the feature type. This literature and software review covering this broad topic is aligned with the scoping review methodology. The manual identification of data sources has been complemented with: (1) automated publication search through digital libraries of the three major publishers using natural language processing (NLP) Toolkit, and (2) an automated identification of relevant software repositories on GitHub and ranking of the related research papers relying on learning to rank approach.This study was supported by COST Action CA18131 “Statistical and machine learning techniques in human microbiome studies”. Estonian Research Council grant PRG548 (JT). Spanish State Research Agency Juan de la Cierva Grant IJC2019-042188-I (LM-Z). EO was founded and OA was supported by Estonian Research Council grant PUT 1371 and EMBO Installation grant 3573. AG was supported by Statutory Research project of the Department of Computer Networks and Systems

Applications of Machine Learning in Human Microbiome Studies: A Review on Feature Selection, Biomarker Identification, Disease Prediction and Treatment

COST Action CA18131 Cierva Grant IJC2019-042188-I (LM-Z) Estonian Research Council grant PUT 1371The number of microbiome-related studies has notably increased the availability of data on human microbiome composition and function. These studies provide the essential material to deeply explore host-microbiome associations and their relation to the development and progression of various complex diseases. Improved data-analytical tools are needed to exploit all information from these biological datasets, taking into account the peculiarities of microbiome data, i.e., compositional, heterogeneous and sparse nature of these datasets. The possibility of predicting host-phenotypes based on taxonomy-informed feature selection to establish an association between microbiome and predict disease states is beneficial for personalized medicine. In this regard, machine learning (ML) provides new insights into the development of models that can be used to predict outputs, such as classification and prediction in microbiology, infer host phenotypes to predict diseases and use microbial communities to stratify patients by their characterization of state-specific microbial signatures. Here we review the state-of-the-art ML methods and respective software applied in human microbiome studies, performed as part of the COST Action ML4Microbiome activities. This scoping review focuses on the application of ML in microbiome studies related to association and clinical use for diagnostics, prognostics, and therapeutics. Although the data presented here is more related to the bacterial community, many algorithms could be applied in general, regardless of the feature type. This literature and software review covering this broad topic is aligned with the scoping review methodology. The manual identification of data sources has been complemented with: (1) automated publication search through digital libraries of the three major publishers using natural language processing (NLP) Toolkit, and (2) an automated identification of relevant software repositories on GitHub and ranking of the related research papers relying on learning to rank approach.publishersversionpublishe

Applications of Machine Learning in Human Microbiome Studies: A Review on Feature Selection, Biomarker Identification, Disease Prediction and Treatment

The number of microbiome-related studies has notably increased the availability of data on human microbiome composition and function. These studies provide the essential material to deeply explore host-microbiome associations and their relation to the development and progression of various complex diseases. Improved data-analytical tools are needed to exploit all information from these biological datasets, taking into account the peculiarities of microbiome data, i.e., compositional, heterogeneous and sparse nature of these datasets. The possibility of predicting host-phenotypes based on taxonomy-informed feature selection to establish an association between microbiome and predict disease states is beneficial for personalized medicine. In this regard, machine learning (ML) provides new insights into the development of models that can be used to predict outputs, such as classification and prediction in microbiology, infer host phenotypes to predict diseases and use microbial communities to stratify patients by their characterization of state-specific microbial signatures. Here we review the state-of-the-art ML methods and respective software applied in human microbiome studies, performed as part of the COST Action ML4Microbiome activities. This scoping review focuses on the application of ML in microbiome studies related to association and clinical use for diagnostics, prognostics, and therapeutics. Although the data presented here is more related to the bacterial community, many algorithms could be applied in general, regardless of the feature type. This literature and software review covering this broad topic is aligned with the scoping review methodology. The manual identification of data sources has been complemented with: (1) automated publication search through digital libraries of the three major publishers using natural language processing (NLP) Toolkit, and (2) an automated identification of relevant software repositories on GitHub and ranking of the related research papers relying on learning to rank approach

White Paper 5: Brain, Mind & Behaviour

© CSICThe study of the brain will tell us what makes us humans and how our social behavior generates. Increasing our understanding of how the brain functions and interacts with the ecosystem to interpret the world will not only help to find effective means to treat and/or cure neurological and psychiatric disorders but will also change our vision on questions pertaining to philosophy and humanities and transform other fields such as economy and law. Neurosciences research at the CSIC is already valuable and should be intensified mainly focused on the eight major challenges described in this volume

Challenge 2: From genes & circuits to behavior

Understanding the brain from genes and circuits to behavior is a major scientific challenge. The large repertoire of cell activities supporting behavior stems from an equally diverse range of specialized cell types, from neuron to glia. To untangle mechanisms underlying brain function, elementary processes should be dissected, from the complex machinery of signaling pathways at the level of single cells and synapses, to the intricate phenomena leading to orchestrated ensemble activity and the establishment of engrams driving memory-guided behaviors. In this chapter we identify the main key tasks required to address some of the open questions in the field, and discuss on the main issues and strategies

Applications of Machine Learning in Human Microbiome Studies: A Review on Feature Selection, Biomarker Identification, Disease Prediction and Treatment

The number of microbiome-related studies has notably increased the availability of data on human microbiome composition and function. These studies provide the essential material to deeply explore host-microbiome associations and their relation to the development and progression of various complex diseases. Improved data-analytical tools are needed to exploit all information from these biological datasets, taking into account the peculiarities of microbiome data, i.e., compositional, heterogeneous and sparse nature of these datasets. The possibility of predicting host-phenotypes based on taxonomy-informed feature selection to establish an association between microbiome and predict disease states is beneficial for personalized medicine. In this regard, machine learning (ML) provides new insights into the development of models that can be used to predict outputs, such as classification and prediction in microbiology, infer host phenotypes to predict diseases and use microbial communities to stratify patients by their characterization of state-specific microbial signatures. Here we review the state-of-the-art ML methods and respective software applied in human microbiome studies, performed as part of the COST Action ML4Microbiome activities. This scoping review focuses on the application of ML in microbiome studies related to association and clinical use for diagnostics, prognostics, and therapeutics. Although the data presented here is more related to the bacterial community, many algorithms could be applied in general, regardless of the feature type. This literature and software review covering this broad topic is aligned with the scoping review methodology. The manual identification of data sources has been complemented with: (1) automated publication search through digital libraries of the three major publishers using natural language processing (NLP) Toolkit, and (2) an automated identification of relevant software repositories on GitHub and ranking of the related research papers relying on learning to rank approach