77 research outputs found
The Role of Response Elements Organization in Transcription Factor Selectivity: The IFN-Ξ² Enhanceosome Example
What is the mechanism through which transcription factors (TFs) assemble specifically along the enhancer DNA? The IFN-Ξ² enhanceosome provides a good model system: it is small; its components' crystal structures are available; and there are biochemical and cellular data. In the IFN-Ξ² enhanceosome, there are few protein-protein interactions even though consecutive DNA response elements (REs) overlap. Our molecular dynamics (MD) simulations on different motif combinations from the enhanceosome illustrate that cooperativity is achieved via unique organization of the REs: specific binding of one TF can enhance the binding of another TF to a neighboring RE and restrict others, through overlap of REs; the order of the REs can determine which complexes will form; and the alternation of consensus and non-consensus REs can regulate binding specificity by optimizing the interactions among partners. Our observations offer an explanation of how specificity and cooperativity can be attained despite the limited interactions between neighboring TFs on the enhancer DNA. To date, when addressing selective TF binding, attention has largely focused on RE sequences. Yet, the order of the REs on the DNA and the length of the spacers between them can be a key factor in specific combinatorial assembly of the TFs on the enhancer and thus in function. Our results emphasize cooperativity via RE binding sites organization
Π‘ΠΎΡΡΡΠ΄Π½ΠΈΡΠ΅ΡΡΠ²ΠΎ Π² ΠΎΠ±Π»Π°ΡΡΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡΠ²Π° ΡΡΠ°Π½Π΄Π°ΡΡΠ½ΡΡ ΠΎΠ±ΡΠ°Π·ΡΠΎΠ², ΡΠΈΠ½Π°Π½ΡΠΈΡΡΠ΅ΠΌΠΎΠ³ΠΎ Π³ΠΎΡΡΠ΄Π°ΡΡΡΠ²ΠΎΠΌ
Emteborg H. et al. Cooperation in publicly funded reference material production. Accred Qual Assur. 2018;23(6):371-377. DOI.org/10.1007/s00769-018-1349-1.Β ΠΠ΅ΡΠ²ΠΎΠΈΡΡΠΎΡΠ½ΠΈΠΊ ΡΡΠ°ΡΡΠΈ: Accred Qual Assur (2018) 23:371. https://doi.org/10.1007/s00769-018-1349-
Murine Gamma Herpesvirus 68 Hijacks MAVS and IKKΞ² to Abrogate NFΞΊB Activation and Antiviral Cytokine Production
Upon viral infection, mitochondrial antiviral signaling (MAVS) protein serves as a key adaptor to promote cytokine production. We report here that murine gamma herpesvirus 68 (Ξ³HV68), a model virus for oncogenic human gamma herpesviruses, subverts cytokine production via the MAVS adaptor. During early infection, Ξ³HV68 hijacks MAVS and IKKΞ² to induce the site-specific phosphorylation of RelA, a crucial subunit of the transcriptionally active NFΞΊB dimer, which primes RelA for the proteasome-mediated degradation. As such, Ξ³HV68 efficiently abrogated NFΞΊB activation and cytokine gene expression. Conversely, uncoupling RelA degradation from Ξ³HV68 infection promoted NFΞΊB activation and elevated cytokine production. Loss of MAVS increased cytokine production and immune cell infiltration in the lungs of Ξ³HV68-infected mice. Moreover, exogenous expression of the phosphorylation- and degradation-resistant RelA variant restored Ξ³HV68-induced cytokine production. Our findings uncover an intricate strategy whereby signaling via the upstream MAVS adaptor is intercepted by a pathogen to nullify the immediate downstream effector, RelA, of the innate immune pathway
The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response
TANK-binding kinase 1 (TBK1) is of central importance for the induction of type-I interferon (IFN) in response to pathogens. We identified the DEAD-box helicase DDX3X as an interaction partner of TBK1. TBK1 and DDX3X acted synergistically in their ability to stimulate the IFN promoter, whereas RNAi-mediated reduction of DDX3X expression led to an impairment of IFN production. Chromatin immunoprecipitation indicated that DDX3X is recruited to the IFN promoter upon infection with Listeria monocytogenes, suggesting a transcriptional mechanism of action. DDX3X was found to be a TBK1 substrate in vitro and in vivo. Phosphorylation-deficient mutants of DDX3X failed to synergize with TBK1 in their ability to stimulate the IFN promoter. Overall, our data imply that DDX3X is a critical effector of TBK1 that is necessary for type I IFN induction
Looking inside the spiky bits : a critical review and conceptualisation of entrepreneurial ecosystems
The authors wish to thank the Organisational for Economic Cooperation and Development (OECD) for funding their original research on entrepreneurial ecosystems.The concept of entrepreneurial ecosystems has quickly established itself as one of the latest βfadsβ in entrepreneurship research. At face value, this kind of systemic approach to entrepreneurship offers a new and distinctive path for scholars and policy makers to help understand and foster growth-oriented entrepreneurship. However, its lack of specification and conceptual limitations has undoubtedly hindered our understanding of these complex organisms. Indeed, the rapid adoption of the concept has tended to overlook the heterogeneous nature of ecosystems. This paper provides a critical review and conceptualisation of the ecosystems concept: it unpacks the dynamics of the concept; outlines its theoretical limitations; measurement approaches and use in policy-making. It sets out a preliminary taxonomy of different archetypal ecosystems. The paper concludes that entrepreneurial ecosystems are a highly variegated, multi-actor and multi-scalar phenomenon, requiring bespoke policy interventions.Publisher PDFPeer reviewe
Intronic Cis-Regulatory Modules Mediate Tissue-Specific and Microbial Control of angptl4/fiaf Transcription
The intestinal microbiota enhances dietary energy harvest leading to increased fat storage in adipose tissues. This effect is caused in part by the microbial suppression of intestinal epithelial expression of a circulating inhibitor of lipoprotein lipase called Angiopoietin-like 4 (Angptl4/Fiaf). To define the cis-regulatory mechanisms underlying intestine-specific and microbial control of Angptl4 transcription, we utilized the zebrafish system in which host regulatory DNA can be rapidly analyzed in a live, transparent, and gnotobiotic vertebrate. We found that zebrafish angptl4 is transcribed in multiple tissues including the liver, pancreatic islet, and intestinal epithelium, which is similar to its mammalian homologs. Zebrafish angptl4 is also specifically suppressed in the intestinal epithelium upon colonization with a microbiota. In vivo transgenic reporter assays identified discrete tissue-specific regulatory modules within angptl4 intron 3 sufficient to drive expression in the liver, pancreatic islet Ξ²-cells, or intestinal enterocytes. Comparative sequence analyses and heterologous functional assays of angptl4 intron 3 sequences from 12 teleost fish species revealed differential evolution of the islet and intestinal regulatory modules. High-resolution functional mapping and site-directed mutagenesis defined the minimal set of regulatory sequences required for intestinal activity. Strikingly, the microbiota suppressed the transcriptional activity of the intestine-specific regulatory module similar to the endogenous angptl4 gene. These results suggest that the microbiota might regulate host intestinal Angptl4 protein expression and peripheral fat storage by suppressing the activity of an intestine-specific transcriptional enhancer. This study provides a useful paradigm for understanding how microbial signals interact with tissue-specific regulatory networks to control the activity and evolution of host gene transcription
Looking inside the spiky bits: a critical review and conceptualisation of entrepreneurial ecosystems
In situ SyXRD Analysis of Cement Hydration on the ms Scale
The backbone of our infrastructure and modern architecture are cementitious materials. Despite their substantial role for the society and their common involvement in the built environment, basic aspects of the hydration processes of cement are still not understood. During the first seconds of a building s life, highly dynamic reaction processes prevail. The reactions have a direct influence on the properties of the final building. Typically, these reactions are actively influenced by organic additives. These additives affect the initial formation of hydrate phases which is often interpreted based on the changes in fluid behavior and zeta potential. [1,2] Up to now, their influence has not been characterized by analyzing the crystallization processes directly. High resolution synchrotron X ray diffraction on the ms scale was utilized to characterize the initial hydration processes of this complex phase system on a structural level Figure 1 . The experiments were carried out under levitated conditions using small droplets as sample specimen. This kind of sample positioning avoids any contact with surfaces, which might influence nucleation, crystallization, and adsorption processes. The hydration of cement was influenced by polycarboxylate ethers, which belong to the most common superplasticizers. For the first time, it was possible to describe the effect of this organic additive to the early stages of the cement hydration. The combination of high resolution X ray diffraction and data processing represents a perfect analytical tool for analyzing the influence of any other organic additive to different cementitious material
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