Digital entrepreneurship from cellular data: How omics afford the emergence of a new wave of digital ventures in health

Data has become an indispensable input, throughput, and output for the healthcare industry. In recent years, omics technologies such as genomics and proteomics have generated vast amounts of new data at the cellular level including molecular, structural, and functional levels. Cellular data holds the potential to innovate therapeutics, vaccines, diagnostics, consumer products, or even ancestry services. However, data at the cellular level is generated with rapidly evolving omics technologies. These technologies use scientific knowledge from resource-rich environments. This raises the question of how new ventures can use cellular-level data from omics technologies to create new products and scale their business. We report on a series of interviews and a focus group discussion with entrepreneurs, investors, and data providers. By conceptualizing omics technologies as external enablers, we show how characteristics of cellular-level data negatively affect the combination mechanisms that drive venture creation and growth. We illustrate how data characteristics set boundary conditions for innovation and entrepreneurship and highlight how ventures seek to mitigate their impact

Poxviruses and paramyxoviruses use a conserved mechanism of STAT1 antagonism to inhibit interferon signaling.

The induction of interferon (IFN)-stimulated genes by STATs is a critical host defense mechanism against virus infection. Here, we report that a highly expressed poxvirus protein, 018, inhibits IFN-induced signaling by binding to the SH2 domain of STAT1, thereby preventing the association of STAT1 with an activated IFN receptor. Despite encoding other inhibitors of IFN-induced signaling, a poxvirus mutant lacking 018 was attenuated in mice. The 2.0 Å crystal structure of the 018:STAT1 complex reveals a phosphotyrosine-independent mode of 018 binding to the SH2 domain of STAT1. Moreover, the STAT1-binding motif of 018 shows similarity to the STAT1-binding proteins from Nipah virus, which, similar to 018, block the association of STAT1 with an IFN receptor. Overall, these results uncover a conserved mechanism of STAT1 antagonism that is employed independently by distinct virus families

A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses

Vaccinia virus (VACV) is a member of the poxviridae, a family of viruses with large double-stranded, linear DNA genomes that replicate in the cytoplasm of cells. The genome of vaccinia encodes over 200 proteins, many of which have been shown to function as inhibitors of the innate immune response. This includes at least four proteins that directly target interferon (IFN)-induced signalling. Here we report the first function of the uncharacterised, 60 aa 018 protein from VACV strain western reserve. The 018 protein was expressed early during infection and found to potently inhibit type I and type II IFN-induced signalling. Cellular protein STAT1, a crucial protein required for IFN-induced signal transduction, was identified as a direct binding partner of 018. Mapping experiment identified the SH2 domain of STAT1, a region important for STAT1 recruitment to IFN-receptors, as the site of 018 binding. In cells expressing 018, STAT1 failed to be phosphorylated, thereby preventing STAT1 activation. Taking the type II IFN pathway as a model, we demonstrated mechanistically, 018 was able to outcompete the binding of STAT1 to the activated IFN receptor. To gain further mechanistic insight, the co-crystal structure of the 018:STAT1 complexed was determined. This showed 018 forms a -hairpin fold whereby the two strands of the peptide augment the central -sheet of the SH2 domain. Unlike canonical SH2 ligand interactions, 018 did not bind into the pTyr pocket and thus presents a novel pTyr pocket binding independent mode of binding at an SH2 domain. To further study the role of 018 during infection, recombinant viruses lacking 018 were constructed and tested in an in vivo mouse model. Deletion 018 viruses were found to be attenuated despite the presence of addition viral IFN-induced signalling inhibitors, confirming the biological importance of 018 during infection. Comparison of the IFN antagonist V protein from Nipah virus, a member of the paramyxovirus family showed sequence similarity to the STAT1-binding region of 018. We showed, like 018, Nipah V protein blocks STAT1 association with the active IFN receptor. Furthermore, we provide mechanistic detail of the Nipah V:STAT1 interaction by solving the crystal structure of this protein complex.BBSRC DT

Digital entrepreneurship from cellular data: How omics afford the emergence of a new wave of digital ventures in health.

UNLABELLED: Data has become an indispensable input, throughput, and output for the healthcare industry. In recent years, omics technologies such as genomics and proteomics have generated vast amounts of new data at the cellular level including molecular, structural, and functional levels. Cellular data holds the potential to innovate therapeutics, vaccines, diagnostics, consumer products, or even ancestry services. However, data at the cellular level is generated with rapidly evolving omics technologies. These technologies use scientific knowledge from resource-rich environments. This raises the question of how new ventures can use cellular-level data from omics technologies to create new products and scale their business. We report on a series of interviews and a focus group discussion with entrepreneurs, investors, and data providers. By conceptualizing omics technologies as external enablers, we show how characteristics of cellular-level data negatively affect the combination mechanisms that drive venture creation and growth. We illustrate how data characteristics set boundary conditions for innovation and entrepreneurship and highlight how ventures seek to mitigate their impact. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12525-023-00669-w

Digital entrepreneurship from cellular data: How omics afford the emergence of a new wave of digital ventures in health.

Acknowledgements: We are grateful for the continuous support of this research by ELIXIR Europe and thank the European Commission for the funding that we have received as part of the Horizon 2020 program (No. 871075, ELIXIR-CONVERGE). In addition, we thank the Biotechnology and Biological Sciences Research Council for providing a doctoral training partnership. Finally, we extend our gratitude to the constructive reviewer comments and fantastic editorial guidance.Funder: Universität Duisburg-Essen (3149)UNLABELLED: Data has become an indispensable input, throughput, and output for the healthcare industry. In recent years, omics technologies such as genomics and proteomics have generated vast amounts of new data at the cellular level including molecular, structural, and functional levels. Cellular data holds the potential to innovate therapeutics, vaccines, diagnostics, consumer products, or even ancestry services. However, data at the cellular level is generated with rapidly evolving omics technologies. These technologies use scientific knowledge from resource-rich environments. This raises the question of how new ventures can use cellular-level data from omics technologies to create new products and scale their business. We report on a series of interviews and a focus group discussion with entrepreneurs, investors, and data providers. By conceptualizing omics technologies as external enablers, we show how characteristics of cellular-level data negatively affect the combination mechanisms that drive venture creation and growth. We illustrate how data characteristics set boundary conditions for innovation and entrepreneurship and highlight how ventures seek to mitigate their impact. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12525-023-00669-w

Digital entrepreneurship from cellular data: How omics afford the emergence of a new wave of digital ventures in health

Acknowledgements: We are grateful for the continuous support of this research by ELIXIR Europe and thank the European Commission for the funding that we have received as part of the Horizon 2020 program (No. 871075, ELIXIR-CONVERGE). In addition, we thank the Biotechnology and Biological Sciences Research Council for providing a doctoral training partnership. Finally, we extend our gratitude to the constructive reviewer comments and fantastic editorial guidance.Funder: Universität Duisburg-Essen (3149)AbstractData has become an indispensable input, throughput, and output for the healthcare industry. In recent years, omics technologies such as genomics and proteomics have generated vast amounts of new data at the cellular level including molecular, structural, and functional levels. Cellular data holds the potential to innovate therapeutics, vaccines, diagnostics, consumer products, or even ancestry services. However, data at the cellular level is generated with rapidly evolving omics technologies. These technologies use scientific knowledge from resource-rich environments. This raises the question of how new ventures can use cellular-level data from omics technologies to create new products and scale their business. We report on a series of interviews and a focus group discussion with entrepreneurs, investors, and data providers. By conceptualizing omics technologies as external enablers, we show how characteristics of cellular-level data negatively affect the combination mechanisms that drive venture creation and growth. We illustrate how data characteristics set boundary conditions for innovation and entrepreneurship and highlight how ventures seek to mitigate their impact.</jats:p

Digital entrepreneurship from cellular data: How omics afford the emergence of a new wave of digital ventures in health

Acknowledgements: We are grateful for the continuous support of this research by ELIXIR Europe and thank the European Commission for the funding that we have received as part of the Horizon 2020 program (No. 871075, ELIXIR-CONVERGE). In addition, we thank the Biotechnology and Biological Sciences Research Council for providing a doctoral training partnership. Finally, we extend our gratitude to the constructive reviewer comments and fantastic editorial guidance.Funder: Universität Duisburg-Essen (3149)Data has become an indispensable input, throughput, and output for the healthcare industry. In recent years, omics technologies such as genomics and proteomics have generated vast amounts of new data at the cellular level including molecular, structural, and functional levels. Cellular data holds the potential to innovate therapeutics, vaccines, diagnostics, consumer products, or even ancestry services. However, data at the cellular level is generated with rapidly evolving omics technologies. These technologies use scientific knowledge from resource-rich environments. This raises the question of how new ventures can use cellular-level data from omics technologies to create new products and scale their business. We report on a series of interviews and a focus group discussion with entrepreneurs, investors, and data providers. By conceptualizing omics technologies as external enablers, we show how characteristics of cellular-level data negatively affect the combination mechanisms that drive venture creation and growth. We illustrate how data characteristics set boundary conditions for innovation and entrepreneurship and highlight how ventures seek to mitigate their impact

Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6.

Interferons (IFNs) represent an important host defense against viruses. Type I IFNs induce JAK-STAT signaling and expression of IFN-stimulated genes (ISGs), which mediate antiviral activity. Histone deacetylases (HDACs) perform multiple functions in regulating gene expression and some class I HDACs and the class IV HDAC, HDAC11, influence type I IFN signaling. Here, HDAC4, a class II HDAC, is shown to promote type I IFN signaling and coprecipitate with STAT2. Pharmacological inhibition of class II HDAC activity, or knockout of HDAC4 from HEK-293T and HeLa cells, caused a defective response to IFN-α. This defect in HDAC4-/- cells was rescued by reintroduction of HDAC4 or catalytically inactive HDAC4, but not HDAC1 or HDAC5. ChIP analysis showed HDAC4 was recruited to ISG promoters following IFN stimulation and was needed for binding of STAT2 to these promoters. The biological importance of HDAC4 as a virus restriction factor was illustrated by the observations that (i) the replication and spread of vaccinia virus (VACV) and herpes simplex virus type 1 (HSV-1) were enhanced in HDAC4-/- cells and inhibited by overexpression of HDAC4; and (ii) HDAC4 is targeted for proteasomal degradation during VACV infection by VACV protein C6, a multifunctional IFN antagonist that coprecipitates with HDAC4 and is necessary and sufficient for HDAC4 degradation.This work was supported by the Wellcome Trust. GLS is a Wellcome Trust Principal Research Fellow. Yongxu Lu, Andrei I. Smid, Jennifer H. Stuart and Liane Dupont were supported by the Wellcome Trust, Joseph S. Snowden was supported by the Lister Institute and Callum Talbot-Cooper was supported by the BBSRC