Biology subjects

Swaminathan, S.

Publications and source records attributed to Swaminathan, S..

4 recordsLinked to original sources

bioRxiv2018

Genetic evidence that the latency III stage of Epstein-Barr Virus infection is a therapeutic target for Multiple Sclerosis

Genome wide association studies have identified >200 susceptibility loci accounting for much of the heritability of Multiple Sclerosis (MS). Epstein Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS, with evidence for disease causation. The molecular and immunological basis for this has not been established. LCL proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. We show that the CD40 ligand, CD40L, potentially through competitive signalling with LMP1, reduces LCL proliferation (p<0.001). The MS risk variants of the LMP1 signalling inhibitor, TRAF3, had altered expression in B cells and LCLs. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2. We have investigated transcriptomes of B cells and EBV infected B cells at Latency III (LCLs) and identified 47 MS risk genes with altered expression, associated with the risk genotype. Overall these MS risk SNPs were overrepresented in target loci of the EBV transcription factor EBNA2 (p<10-16), in genes dysregulated between B and LCLs (p<10-5), and as targets for EBV miRNAs (p<10-4). The risk gene ZC3HAV1 is the putative target for multiple EBV miRNAs. It amplifies the interferon response, and was shown to have reduced expression in LCLs for the risk allele. These data indicate targeting EBV EBNA2, miRNAs, and MS risk genes on the LMP1/LMP2 pathways, and the pathways themselves, may be of therapeutic benefit in MS.

genomics↗

bioRxiv2018

TNF-α induces reactivation of human cytomegalovirus independently of myeloid cell differentiation following post-transcriptional establishment of latency

We used the Kasumi-3 model to study HCMV latency and reactivation in myeloid progenitor cells. Kasumi-3 cells were infected with HCMV strain TB40/Ewt-GFP, flow sorted for GFP+ cells, and cultured for various times to monitor establishment of latency, as judged by repression of viral gene expression (RNA/DNA ratio) and loss of virus production. We found that, in the vast majority of cells, latency was established post-transcriptionally in the GFP+ infected cells: transcription was initially turned on, and then turned off. We also found that some of the GFP-cells were infected, suggesting that latency might be established in these cells at the outset of infection. We were not able to test this hypothesis because some GFP-cells expressed lytic genes, and thus, it was not possible to separate them from GFP-quiescent cells. In addition, we found that the pattern of expression of lytic genes that have been associated with latency, including UL138, US28, and RNA2.7, was the same as that of other lytic genes, indicating that there was no preferential expression of these genes once latency is established. We confirmed previous studies showing that TNF- induced reactivation of infectious virus, and by analyzing expression of the progenitor cell marker CD34 as well as myeloid cell differentiation markers in IE+ cells after treatment with TNF-, we showed that TNF- induced transcriptional reactivation of IE gene expression independently of differentiation. TNF--mediated reactivation in Kasumi-3 cells was correlated with activation of NF-{kappa}B, KAP-1 and ATM.\n\nIMPORTANCEHCMV is an important human pathogen that establishes lifelong latent infection in myeloid progenitor cells, and reactivates frequently to cause significant disease in immunocompromised people. Our observation that viral gene expression is first turned on, and then turned off to establish latency suggests that there is a host defense, which may be myeloid-specific, responsible for transcriptional silencing of viral gene expression. Our observation that TNF- induces reactivation independently of differentiation provides insight into molecular mechanisms that control reactivation.

microbiology↗

bioRxiv2017

Transparency in Authors’ Contributions and Responsibilities to Promote Integrity in Scientific Publication

In keeping with the growing movement in scientific publishing toward transparency in data and methods, we argue that the names of authors accompanying journal articles should provide insight into who is responsible for which contributions, a process should exist to confirm that the list is complete, clearly articulated standards should establish whether and when the contributions of an individual justify authorship credit, and those involved in the generation of scientific knowledge should follow these best practices.\n\nTo accomplish these goals, we recommend that journals adopt common and transparent standards for authorship, outline responsibilities for corresponding authors, adopt the CRediT (Contributor Roles Taxonomy)1 methodology for attributing contributions, include this information in article metadata, and encourage authors to use the digital persistent identifier ORCID.2 Furthermore, we suggest that research institutions have regular open conversations on authorship criteria and ethics and that funding agencies adopt ORCID and accept CRediT. Scientific societies should further authorship transparency by promoting these recommendations through their meetings and publications programs.

scientific communication and education↗

bioRxiv2017

Standardising and harmonising research data policy in scholarly publishing

Practice paper Practice paper References Research data policies influence researchers willingness to share research data to varying extents (Meadows, 2014; Schmidt, Gemeinholzer, & Treloar, 2016). A growing number of research funders and institutions are introducing policies on research data sharing. These include the National Institutes of Health (NIH), Gates Foundation, the EU Horizon 2020 programme, Wellcome Trust and the seven UK research councils (Hahnel, 2015). Policy requirements vary, with some requiring researchers to prepare data management plans and others, such as the Engineering and Physical Sciences Research Council (EPSRC), requiring evidence of public data archiving to be included in published research papers. To support publication of more reproducible research scholarly journals, societies and conferences ...

scientific communication and education↗