Topological analysis of protein co-abundance networks identifies novel host targets important for HCV infection and pathogenesis

<p>Abstract</p> <p>Background</p> <p>High-throughput methods for obtaining global measurements of transcript and protein levels in biological samples has provided a large amount of data for identification of 'target' genes and proteins of interest. These targets may be mediators of functional processes involved in disease and therefore represent key points of control for viruses and bacterial pathogens. Genes and proteins that are the most highly differentially regulated are generally considered to be the most important. We present topological analysis of co-abundance networks as an alternative to differential regulation for confident identification of target proteins from two related global proteomics studies of hepatitis C virus (HCV) infection.</p> <p>Results</p> <p>We analyzed global proteomics data sets from a cell culture study of HCV infection and from a clinical study of liver biopsies from HCV-positive patients. Using lists of proteins known to be interaction partners with pathogen proteins we show that the most differentially regulated proteins in both data sets are indeed enriched in pathogen interactors. We then use these data sets to generate co-abundance networks that link proteins based on similar abundance patterns in time or across patients. Analysis of these co-abundance networks using a variety of network topology measures revealed that both degree and betweenness could be used to identify pathogen interactors with better accuracy than differential regulation alone, though betweenness provides the best discrimination. We found that though overall differential regulation was not correlated between the cell culture and liver biopsy data, network topology was conserved to an extent. Finally, we identified a set of proteins that has high betweenness topology in both networks including a protein that we have recently shown to be essential for HCV replication in cell culture.</p> <p>Conclusions</p> <p>The results presented show that the network topology of protein co-abundance networks can be used to identify proteins important for viral replication. These proteins represent targets for further experimental investigation that will provide biological insight and potentially could be exploited for novel therapeutic approaches to combat HCV infection.</p

Maternal synapsin autoantibodies are associated with neurodevelopmental delay

Maternal autoantibodies can be transmitted diaplacentally, with potentially deleterious effects on neurodevelopment. Synapsin 1 (SYN1) is a neuronal protein that is important for synaptic communication and neuronal plasticity. While monoallelic loss of function (LoF) variants in the SYN1 gene result in X-linked intellectual disability (ID), learning disabilities, epilepsy, behavioral problems, and macrocephaly, the effect of SYN1 autoantibodies on neurodevelopment remains unclear. We recruited a clinical cohort of 208 mothers and their children with neurologic abnormalities and analyzed the role of maternal SYN1 autoantibodies. We identified seropositivity in 9.6% of mothers, and seropositivity was associated with an increased risk for ID and behavioral problems. Furthermore, children more frequently had epilepsy, macrocephaly, and developmental delay, in line with the SYN1 LoF phenotype. Whether SYN1 autoantibodies have a direct pathogenic effect on neurodevelopment or serve as biomarkers requires functional experiments

δ18O-inferred salinity from Littorina littorea (L.) gastropods in a Danish shell midden at the Mesolithic–Neolithic transition

Norsminde Fjord has received extensive geoarchaeological investigation, hosting one of the classic Stone Age shell midden sites in Denmark, and one of the best examples of the widespread oyster decline at the Mesolithic–Neolithic transition. Here, intra-shell δ18O (and δ13C) analyses from the common periwinkle Littorina littorea (L.) are used to infer inter-annual environmental changes at the Mesolithic–Neolithic transition (four from each period). This study utilises a modern δ18O L. littorea-salinity training set previously developed for the Limfjord, Denmark to quantify winter salinity. δ18O values range between +1.6% and +4.0% in the late Mesolithic and ‒6.3% to +2.0% in the early Neolithic. Using maximum δ18O values, winter salinity at the known temperature of growth cessation in L. littorea (i.e. +3.7 ± 1°C) for the first annual cycle of each shell ranges between 25.5 and 26.8 psu (standard deviation (SD): 0.56) for the late Mesolithic, with an average salinity of 26.1 psu. Early-Neolithic shells range between 19.4 and 28.2 psu (SD: 4.59) with an average salinity of 23.7 psu. No statistically significant change in salinity occurs between the late Mesolithic and early Neolithic. This result supports recent diatom/mollusc-based inferences that salinity was not the sole cause of the oyster decline, although some evidence is presented here for more variable seasonal salinity conditions in the early Neolithic, which (along sedimentary change and temperature deterioration) might have increased stress on oyster populations in some years. It is recommended here that for robust palaeoenvironmental inferences, where possible, multiple specimens should be used from the same time period in conjunction with multiproxy data

Infection with Mers-Cov Causes Lethal Pneumonia in the Common Marmoset

The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies

Maternal Thyroid Disease, Thyroid Medication Use, and Selected Birth Defects in the National Birth Defects Prevention Study

BACKGROUND: Although thyroid disorders are present in approximately 3% of pregnant women, little is known about the association between maternal thyroid disease and birth defects. METHODS: We assessed the association between maternal thyroid disease, thyroid medication use, and 38 types of birth defects among 14,067 cases and 5875 controls in the National Birth Defects Prevention Study, a multisite, population-based, case-control study. Infants in this study were born between October 1997 and December 2004. Information on exposures including maternal diseases and use of medications was collected by telephone interview. RESULTS: We found statistically significant associations between maternal thyroid disease and left ventricular outflow tract obstruction heart defects (1.5; 95% CI, 1.0-2.3), hydrocephaly (2.9; 95% CI, 1.6-5.2), hypospadias (1.6; 95% CI, 1.0-2.5), and isolated anorectal atresia (2.4; 95% CI, 1.2-4.6). Estimates for the association between periconceptional use of thyroxine and specific types of birth defects were similar to estimates for any thyroid disease. Given that antithyroid medication use was rare, we could not adequately assess risks for their use for most case groups. CONCLUSIONS: Our results are consistent with the positive associations between maternal thyroid disease or thyroid medication use and both hydrocephaly and hypospadias observed in some previous studies. New associations with left ventricular outflow tract obstruction heart defects and anorectal atresia may be chance findings. Birth Defects Research (Part A) 85:621-628, 2009.

Towards a coordinated strategy for intercepting human disease emergence in Africa

Non peer reviewe

The future of zoonotic risk prediction

In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges? This article is part of the theme issue 'Infectious disease macroecology: parasite diversity and dynamics across the globe'.Peer reviewe