Outgroup, alignment and modelling improvements indicate that two TNFSF13-like genes existed in the vertebrate ancestor

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Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network.

BACKGROUND: Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored. METHODS: We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies. RESULTS: Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits. CONCLUSIONS: This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases.The Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Library of Medicine of the US National Institutes of Health (Intramural Research Program) , Wellcome Trust (080327/Z/06/Z, 087007/Z/08/Z, 094227/Z/10/Z, Clinical PhD Programme, 079895, 076113 and 085475) , Medical Research Council (G0400929) , National Institute for Health Research , National Institutes of Health (Oxford-Cambridge Scholars Program) , Istanbul University Research Fund and UK Behcet’s Syndrome Society.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13073-016-0329-

Comparative biochemical and functional analysis of viral and human secreted tumor necrosis factor (TNF) decoy receptors

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs.Ministry of Economy and Competitiveness Grants SAF2009-07857 and SAF2012-38957Peer Reviewe

TLR3 Deficiency Leads to a Dysregulation in the Global Gene-Expression Profile in Murine Oviduct Epithelial Cells Infected with Chlamydia muridarum

OBJECTIVE Describe the implementation and effects of Mobile Acute Care for Elders (MACE) consultation at a Veterans Affairs Medical Center (VAMC). DESIGN Retrospective cohort analysis. INTERVENTION Veterans aged 65 or older who were admitted to the medicine service between October 1, 2012, and September 30, 2014, were screened for geriatric syndromes via review of medical records within 48 hours of admission. If the screen was positive, the MACE team offered the admitting team a same-day consultation involving comprehensive geriatric assessment and ongoing collaboration with the admitting team and supportive services to implement patient-centric recommendations for geriatric syndromes. RESULTS Veterans seen by MACE (n = 421) were compared with those with positive screens but without consultation (n = 372). The two groups did not significantly differ in age, comorbidity, sex, or race. All outcomes (30-day readmission, 30-day mortality, readmission costs) were in the expected direction for patients receiving MACE but did not reach statistical significance. Patients receiving MACE had lower odds of 30-day readmission (11.9% vs 14.8%; odds ratio [OR] = 0.82; 95% confidence interval [CI] = 0.54-1.25; p = .360) and 30-day mortality (5.5% vs 8.6%; OR = 0.64; CI = 0.36-1.12; p = .115), and they had lower 30-day readmission costs (MACE $15,502; CI =$12,242-$19,631; comparison =$18,335; CI = $14,641-$22,962; p = .316) than those who did not receive MACE after adjusting for age and Charlson Comorbidity Index. CONCLUSION Our MACE consultation model for older veterans with geriatric syndromes leverages the limited supply of clinicians with expertise in geriatrics. Although not statistically significant in this study of 793 subjects, MACE patients had lower odds of 30-day readmission and mortality, and lower readmission costs. J Am Geriatr Soc 67:818–824, 2019

CD40 is a major regulator of dendrite growth from developing excitatory and inhibitory neurons

Dendrite size and morphology are key determinants of the functional properties of neurons and neural circuits. Here we show that CD40, a member of the TNF receptor superfamily, is a major regulator of dendrite growth and elaboration in the developing brain. The dendrites of hippocampal excitatory neurons were markedly stunted in Cd40-/- mice, whereas those of striatal inhibitory neurons were much more exuberant. These striking and opposite phenotypic changes were also observed in excitatory and inhibitory neurons cultured from Cd40-/- mice and were rescued by soluble CD40. The changes in excitatory and inhibitory neurons cultured from Cd40-/- mice were mimicked in neurons of Cd40+/+ mice by treatment with soluble CD40L and were dependent on PKC-β and PKC-γ, respectively. These results suggest that CD40-activated CD40L reverse signalling has striking and opposite effects on the growth and elaboration of dendrites among major classes of brain neurons by PKC-dependent mechanisms

Poxvirus-encoded TNF decoy receptors inhibit the biological activity of transmembrane TNF

© 2015 The Authors. Poxviruses encode up to four different soluble TNF receptors, named cytokine response modifier B (CrmB), CrmC, CrmD and CrmE. These proteins mimic the extracellular domain of the cellular TNF receptors to bind and inhibit the activity of TNF and, in some cases, other TNF superfamily ligands. Most of these ligands are released after the enzymic cleavage of a membrane precursor. However, transmembrane TNF (tmTNF) is not only a precursor of soluble TNF but also exerts specific pro-inflammatory and immunological activities. Here, we report that viral TNF receptors bound and inhibited tmTNF and describe some interesting differences in their activity against the soluble cytokine. Thus, CrmE, which does not inhibit mouse soluble TNF, could block murine tmTNF-induced cytotoxicity. We propose that this anti-tmTNF effect should be taken into consideration when assessing the role of viral TNF decoy receptors in the pathogenesis of poxvirus.Ministry of Economy and Competitiveness Grants SAF2009-07857 and SAF2012-38957.S. M. P. was recipient of a JAE PhD Studentship from Consejo Superior de Investigaciones Científicas and a studentship from Fundación Severo OchoaPeer Reviewe

A decoy receptor 3 analogue reduces localised defects in phagocyte function in pneumococcal pneumonia

Background. Therapeutic strategies to modulate the host response to bacterial pneumonia are needed to improve outcomes during community-acquired pneumonia. This study used mice with impaired Fas signalling to examine susceptibility to pneumococcal pneumonia and decoy receptor 3 analogue (DcR3-a) to correct factors associated with increased susceptibility. Methods. Wild-type mice and those with varying degrees of impairment of Fas (lpr) or Fas ligand signalling (gld) were challenged with Streptococcus pneumoniae and microbiological and immunological outcomes measured in the presence or absence of DcR3-a. Results. During established pneumonia, neutrophils became the predominant cell in the airway and gld mice were less able to clear bacteria from the lungs, demonstrating localised impairment of pulmonary neutrophil function in comparison to lpr or wild-type mice. T-cells from gld mice had enhanced activation and reduced apoptosis in comparison to wild-type and lpr mice during established pneumonia. Treatment with DcR3-a reduced T-cell activation and corrected the defect in pulmonary bacterial clearance in gld mice. Conclusions. The results suggest that imbalance in tumour necrosis factor superfamily signalling and excessive T-cell activation can impair bacterial clearance in the lung but that DcR3-a treatment can reduce T-cell activation, restore optimal pulmonary neutrophil function and enhance bacterial clearance during S pneumoniae infection

Tumor necrosis factor superfamily members CD137 and OX40 ligand in vascular inflammation

Atherosclerosis, an inflammatory disease, is the major cause of cardiovascular disease - the main cause of death worldwide. T cells are central orchestrators of inflammation in atherosclerosis and critically depend on costimulation for adequate function. Hence, costimulation is pivotal for maintaining immunological homeostasis of inflammatory responses, and a dysregulated immune response may aggravate inflammation in atherosclerosis. Costimulators are therefore of central interest in the pathogenesis of cardiovascular disease. CD137 and OX40 ligand are important costimulatory molecules of the tumor necrosis factor superfamily, but their role in vascular inflammation has been unclear. We used human biobanks and clinical cohorts in combination with experimental models of atherosclerosis and atherothrombosis to investigate the involvement of CD137 and OX40 ligand in the pathogenesis of cardiovascular disease. We observed that CD137 was expressed in human and murine atherosclerosis, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. By studying gene expression in cell lines, we found an association between the single nucleotide polymorphism (SNP) rs2453021 and CD137 mRNA expression in human lymphoid cells. The minor allele of this SNP was associated with an increased intima media thickness in human carotid arteries in individuals with risk factors of cardiovascular disease. To study the influence of CD137 activation on atherothrombosis, we turned to an experimental plaque rupture model. We observed that CD137 mRNA expression was higher in ruptured compared to non-ruptured murine carotid lesions. Stimulation of CD137 promoted vascular and systemic inflammation, but did not increase plaque rupture frequency. Others have reported an association between the SNP rs3850641 in OX40 ligand and cardiovascular risk. We did observe expression of OX40 ligand on endothelial cells within human carotid atherosclerotic lesions, and the OX40 ligand expression was induced by tumor necrosis factor (TNF) in cultured vascular endothelial cells. However, we found no association with the risk for stroke in two independent populations. In conclusion, the studies in this thesis demonstrate expression of CD137 and OX40 ligand in human atherosclerotic lesions, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. These new insights on the pathophysiology of atherosclerosis warrant further studies of the therapeutic potential of interventions in costimulation for treatment of cardiovascular disease

Canonical coordinates for partial differential equations

Necessary and sufficient conditions are found under which operators of the form Sigma(m, j=1) X(2)sub j + X sub 0 can be made constant coefficient. In addition, necessary and sufficient conditions are derived which classify those linear partial differential operators that can be moved to the Kolmogorov type

Exploring tradeoffs in pleiotropy and redundancy using evolutionary computing

Evolutionary computation algorithms are increasingly being used to solve optimization problems as they have many advantages over traditional optimization algorithms. In this paper we use evolutionary computation to study the trade-off between pleiotropy and redundancy in a client-server based network. Pleiotropy is a term used to describe components that perform multiple tasks, while redundancy refers to multiple components performing one same task. Pleiotropy reduces cost but lacks robustness, while redundancy increases network reliability but is more costly, as together, pleiotropy and redundancy build flexibility and robustness into systems. Therefore it is desirable to have a network that contains a balance between pleiotropy and redundancy. We explore how factors such as link failure probability, repair rates, and the size of the network influence the design choices that we explore using genetic algorithms.Comment: 10 pages, 6 figure