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Abstract Background The emergence and spread of malaria drug resistance have resulted in the need to understand disease mechanisms and importantly identify essential targets and potential drug candidates. Malaria infection involves the complex interaction between the host and pathogen, thus, functional interactions between human and Plasmodium falciparum is essential to obtain a holistic view of the genetic architecture of malaria. Several functional interaction studies have extended the understanding of malaria disease and integrating such datasets would provide further insights towards understanding drug resistance and/or genetic resistance/susceptibility, disease pathogenesis, and drug discovery. Methods This study curated and analysed data including pathogen and host selective genes, host and pathogen protein sequence data, protein–protein interaction datasets, and drug data from literature and databases to perform human-host and P. falciparum network-based analysis. An integrative computational framework is presented that was developed and found to be reasonably accurate based on various evaluations, applications, and experimental evidence of outputs produced, from data-driven analysis. Results This approach revealed 8 hub protein targets essential for parasite and human host-directed malaria drug therapy. In a semantic similarity approach, 26 potential repurposable drugs involved in regulating host immune response to inflammatory-driven disorders and/or inhibiting residual malaria infection that can be appropriated for malaria treatment. Further analysis of host–pathogen network shortest paths enabled the prediction of immune-related biological processes and pathways subverted by P. falciparum to increase its within-host survival. Conclusions Host–pathogen network analysis reveals potential drug targets and biological processes and pathways subverted by P. falciparum to enhance its within malaria host survival. The results presented have implications for drug discovery and will inform experimental studies.

Advances in omics technologies allow for holistic studies into biological systems. These studies rely on integrative data analysis techniques to obtain a comprehensive view of the dynamics of cellular processes, and molecular mechanisms. Network-based integrative approaches have revolutionized multi-omics analysis by providing the framework to represent interactions between multiple different omics-layers in a graph, which may faithfully reflect the molecular wiring in a cell. Here we review network-based multi-omics/multi-modal integrative analytical approaches. We classify these approaches according to the type of omics data supported, the methods and/or algorithms implemented, their node and/or edge weighting components, and their ability to identify key nodes and subnetworks. We show how these approaches can be used to identify biomarkers, disease subtypes, crosstalk, causality, and molecular drivers of physiological and pathological mechanisms. We provide insight into the most appropriate methods and tools for research questions as showcased around the aetiology and treatment of COVID-19 that can be informed by multi-omics data integration. We conclude with an overview of challenges associated with multi-omics network-based analysis, such as reproducibility, heterogeneity, (biological) interpretability of the results, and we highlight some future directions for network-based integration.

BackgroundRenal dysfunctions are associated with increased morbidity and mortality in sickle cell disease (SCD). Early detection and subsequent management of SCD patients at risk for renal failure and dysfunctions are essential, however, predictors that can identify patients at risk of developing renal dysfunction are not fully understood.MethodsIn this study, we have investigated the association of 31 known kidney dysfunctions-related variants detected in African Americans from multi-ethnic genome wide studies (GWAS) meta-analysis, to kidney-dysfunctions in a group of 413 Cameroonian patients with SCD. Systems level bioinformatics analyses were performed, employing protein-protein interaction networks to further interrogate the putative associations.ResultsUp to 61% of these patients had micro-albuminuria, 2.4% proteinuria, 71% glomerular hyperfiltration, and 5.9% had renal failure. Six variants are significantly associated with the two quantifiable phenotypes of kidney dysfunction (eGFR and crude-albuminuria): A1CF-rs10994860 (P = 0.02020), SYPL2-rs12136063 (P = 0.04208), and APOL1 (G1)-rs73885319 (P = 0.04610) are associated with eGFR; and WNT7A-rs6795744 (P = 0.03730), TMEM60-rs6465825 (P = 0.02340), and APOL1 (G2)-rs71785313 (P = 0.03803) observed to be protective against micro-albuminuria. We identified a protein-protein interaction sub-network containing three of these gene variants: APOL1, SYPL2, and WNT7A, connected to the Nuclear factor NF-kappa-B p105 subunit (NFKB1), revealed to be essential and might indirectly influence extreme phenotypes. Interestingly, clinical variables, including body mass index (BMI), systolic blood pressure, vaso-occlusive crisis (VOC), and haemoglobin (Hb), explain better the kidney phenotypic variations in this SCD population.ConclusionThis study highlights a strong contribution of haematological indices (Hb level), anthropometric variables (BMI, blood pressure), and clinical events (i.e., vaso-occlusive crisis) to kidney dysfunctions in SCD, rather than known genetic factors. Only 6/31 characterised gene-variants are associated with kidney dysfunction phenotypes in SCD samples from Cameroon. The data reveal and emphasise the urgent need to extend GWAS studies in populations of African ancestries living in Africa, and particularly for kidney dysfunctions in SCD.

High-throughput technologies have resulted in an exponential growth of publicly available and accessible datasets for biomedical research. Efficient computational models, algorithms and tools are required to exploit the datasets for knowledge discovery to aid medical decisions. Here, we introduce a new tool, MSclassifier, based on median-supplement approaches to machine learning to enable an automated and effective binary classification for optimal decision making. The MSclassifier package estimates medians of features (attributes) to deduce supplementary data, which is subsequently introduced into the training set for balancing and building superior models for classification. To test our approach, it is used to determine HER2 receptor expression status phenotypes in breast cancer and also predict protein subcellular localization (plasma membrane and nucleus). Using independent sample and cross-validation tests, the performance of MSclassifier is evaluated and compared with well established tools that could perform such tasks. In the HER2 receptor expression status phenotype identification tasks, MSclassifier achieved statistically significant higher classification rates than the best performing existing tool (90.30% versus 89.83%, p=8.62e-3). In the subcellular localization prediction tasks, MSclassifier and one other existing tool achieved equally high performances (93.42% versus 93.19%, p=0.06) although they both outperformed tools based on Naive Bayes classifiers. Overall, the application and evaluation of MSclassifier reveal its potential to be applied to varieties of binary classification problems. The MSclassifier package provides an R-portable and user-friendly application to a broad audience, enabling experienced end-users as well as non-programmers to perform an effective classification in biomedical and other fields of study.

The ongoing Ebola virus disease (EVD) outbreak in the eastern Democratic Republic of Congo is raising unprecedented health concerns, with potential to wipe out large proportions of the population in this part of the world. Established control strategies to contain the outbreak are failing due to several reasons, including lack of a data/information repository and ongoing violence and armed conflict. In this paper, we propose a potential roadmap from a computational perspective, which may provide solutions to contain the current outbreak, predict future outbreaks and facilitate development of novel solutions and therapeutics. This roadmap includes the implementation of an integrated information system through a centralized data coordinating center unifying existing and future EVD data and information to enhance innovative EVD translational research. This work will leverage off tools, guidelines and protocols developed by established data coordinating centers based in Africa or centers that address infectious disease outbreaks. The proposed EVD computational strategy is expected to inform optimal strategies at the national or global level towards strengthened responses to future EVD outbreaks and potential emergency of therapy resistant. Keywords: Ebola virus disease, rVSV-ZEBOV, Monoclonal antibody, Translational research, FAIR data

Abstract Background Advances in forward and reverse genetic techniques have enabled the discovery and identification of several plant defence genes based on quantifiable disease phenotypes in mutant populations. Existing models for testing the effect of gene inactivation or genes causing these phenotypes do not take into account eventual uncertainty of these datasets and potential noise inherent in the biological experiment used, which may mask downstream analysis and limit the use of these datasets. Moreover, elucidating biological mechanisms driving the induced disease resistance and influencing these observable disease phenotypes has never been systematically tackled, eliciting the need for an efficient model to characterize completely the gene target under consideration. Results We developed a post-gene silencing bioinformatics (post-GSB) protocol which accounts for potential biases related to the disease phenotype datasets in assessing the contribution of the gene target to the plant defence response. The post-GSB protocol uses Gene Ontology semantic similarity and pathway dataset to generate enriched process regulatory network based on the functional degeneracy of the plant proteome to help understand the induced plant defence response. We applied this protocol to investigate the effect of the NPR1 gene silencing to changes in Arabidopsis thaliana plants following Pseudomonas syringae pathovar tomato strain DC3000 infection. Results indicated that the presence of a functionally active NPR1 reduced the plant’s susceptibility to the infection, with about 99% of variability in Pseudomonas spore growth between npr1 mutant and wild-type samples. Moreover, the post-GSB protocol has revealed the coordinate action of target-associated genes and pathways through an enriched process regulatory network, summarizing the potential target-based induced disease resistance mechanism. Conclusions This protocol can improve the characterization of the gene target and, potentially, elucidate induced defence response by more effectively utilizing available phenotype information and plant proteome functional knowledge.

Genomic medicine is set to drastically improve clinical care globally due to high throughput technologies which enable speedy in silico detection and analysis of clinically relevant mutations. However, the variability in the in silico prediction methods and categorization of functionally relevant genetic variants can pose specific challenges in some populations. In silico mutation prediction tools could lead to high rates of false positive/negative results, particularly in African genomes that harbor the highest genetic diversity and that are disproportionately underrepresented in public databases and reference panels. These issues are particularly relevant with the recent increase in initiatives, such as the Human Heredity and Health (H3Africa), that are generating huge amounts of genomic sequence data in the absence of policies to guide genomic researchers to return results of variants in so-called actionable genes to research participants. This report (i) provides an inventory of publicly available Whole Exome/Genome data from Africa which could help improve reference panels and explore the frequency of pathogenic variants in actionable genes and related challenges, (ii) reviews available in silico prediction mutation tools and the criteria for categorization of pathogenicity of novel variants, and (iii) proposes recommendations for analyzing pathogenic variants in African genomes for their use in research and clinical practice. In conclusion, this work proposes criteria to define mutation pathogenicity and actionability in human genetic research and clinical practice in Africa and recommends setting up an African expert panel to oversee the proposed criteria.

Hydroxyurea (HU) is clinically beneficial in sickle cell disease (SCD) through fetal hemoglobin (HbF) induction; however, the mechanism of HU is not yet fully elucidated. Selected miRNAs have been associated with HU-induced HbF production. We have investigated differential HU-induced global miRNA expression in peripheral blood of adult SCD patients in patients from Congo, living in South Africa. We found 22 of 798 miRNAs evaluated that were differentially expressed under HU treatment, with the majority (13/22) being functionally associated with HbF-regulatory genes, including BCL11A (miR-148b-3p, miR-32-5p, miR-340-5p, and miR-29c-3p), MYB (miR-105-5p), and KLF-3 (miR-106b-5), and SP1 (miR-29b-3p, miR-625-5p, miR-324-5p, miR-125a-5p, miR-99b-5p, miR-374b-5p, and miR-145-5p). The preliminary study provides potential additional miRNA candidates for therapeutic exploration.