Tiede tuottaa kansallisuutta : nationalismi kulttuurien tutkimuksessa-seminaari 23.3.2007 Helsingin yliopistossa

Ajankohtaista

Interleukin-1- and type I interferon-dependent enhanced immunogenicity of an NYVAC-HIV-1 Env-Gag-Pol-Nef vaccine vector with dual deletions of type I and type II interferon-binding proteins.

UNLABELLED: NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (ΔB19R) or type II (ΔB8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C-ΔB19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C-ΔB8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C-ΔB19R and NYVAC-C-ΔB8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C-ΔB8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C-ΔB19R as well as a strong inflammasome response (caspase-1 and IL-1β) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C-ΔB8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4(+) T cell response than monocytes infected with NYVAC-C or NYVAC-C-ΔB19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1β and make it an attractive candidate HIV vaccine vector. IMPORTANCE: NYVAC is a replication-deficient poxvirus developed as a vaccine vector against HIV. NYVAC expresses several genes known to impair the host immune defenses by interfering with innate immune receptors, cytokines, or interferons. Given the crucial role played by interferons against viruses, we postulated that targeting the type I and type II decoy receptors used by poxvirus to subvert the host innate immune response would be an attractive approach to improve the immunogenicity of NYVAC vectors. Using systems biology approaches, we report that deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus resulted in the robust expression of type I IFNs and interferon-stimulated genes (ISGs), a strong activation of the inflammasome, and upregulated expression of IL-1β and proinflammatory cytokines. Dual deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus improves its immunogenic profile and makes it an attractive candidate HIV vaccine vector.

Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes.

BACKGROUND: Increasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS. METHODS: IL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood. Identification of the IL-22 receptor subunit, IL-22R1, was performed by immunohistochemistry and immunofluorescence in human brain tissues and human primary astrocytes. The role of IL-22 on human primary astrocytes was evaluated using 7-AAD and annexin V, markers of cell viability and apoptosis, respectively. RESULTS: In a cohort of 141 MS patients and healthy control (HC) subjects, we found that serum levels of IL-22 were significantly higher in relapsing MS patients than in HC but also remitting and progressive MS patients. Monocytes and monocyte-derived dendritic cells contained an enhanced expression of mRNA coding for IL-22BP as compared to HC. Using immunohistochemistry and confocal microscopy, we found that IL-22 and its receptor were detected on astrocytes of brain tissues from both control subjects and MS patients, although in the latter, the expression was higher around blood vessels and in MS plaques. Cytometry-based functional assays revealed that addition of IL-22 improved the survival of human primary astrocytes. Furthermore, tumor necrosis factor α-treated astrocytes had a better long-term survival capacity upon IL-22 co-treatment. This protective effect of IL-22 seemed to be conferred, at least partially, by a decreased apoptosis. CONCLUSIONS: We show that (1) there is a dysregulation in the expression of IL-22 and its antagonist, IL-22BP, in MS patients, (2) IL-22 targets specifically astrocytes in the human brain, and (3) this cytokine confers an increased survival of the latter cells.

Polymorphisms cyclooxygenase-2 -765G>C and interleukin-6 -174G>C are associated with serum inflammation markers in a high cardiovascular risk population and do not modify the response to a Mediterranean diet supplemented with virgin olive oil or nuts

Inflammation is involved in cardiovascular diseases. Some studies have found that the Mediterranean diet (MD) can reduce serum concentrations of inflammation markers. However, none of these studies have analyzed the influence of genetic variability in such a response. Our objective was to study the effect of the -765G.C polymorphism in the cyclooxygenase-2 (COX-2) gene and the -174G.C polymorphism in the interleukin-6 (IL-6) gene on serum concentrations of IL-6, C-reactive protein, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 as well as their influence on the response toa nutritional interventionwithMD.An intervention study ina high cardiovascular riskMediterranean population (314 men and 407 women) was undertaken. Participants were randomly assigned to consume a low-fat control diet or a MD supplementedwith virgin olive oil ornuts.Measureswereobtained at baseline and after a 3-mointervention period.At baseline, the COX-2 -765G.C polymorphismwas associated with lower serum IL-6 (5.85 6 4.82 in GG vs. 4.74 6 4.14 ng/L in C-allele carriers; P ¼ 0.002) and ICAM-1 (265.8 6 114.8 in GG vs. 243.0 6 107.1 mg/L in C-carriers; P ¼ 0.018) concentrations. These differences remained significant aftermultivariate adjustment. The IL-6 -174G.C polymorphism was associatedwith higher (CC vs. G-carriers) serumICAM-1concentrations in bothmenandwomenandwithhigherserumIL-6 concentrations inmen.Following the dietary intervention, no significant gene x diet interactions were found. In conclusion, although COX-2 -765G.C and IL-6 -174G.C polymorphismswere associatedwith inflammation, consuming aMD(either supplemented with virgin olive oil or nuts) reduced the concentration of inflammation markers regardless of these polymorphisms.

Angiotensin receptor blockers are not associated with reduced inflammatory markers in the general population.

OBJECTIVE: Angiotensin receptor blockers (ARBs) have been suggested to reduce inflammation in randomized controlled trials. We assessed the association between ARBs and inflammatory markers in a general population setting. METHODS: This is a population-based prospective study conducted in Lausanne, Switzerland. Baseline data from 933 participants on antihypertensive drugs (424 on ARBs) was collected in 2003-2006. Follow-up data from 1120 participants (572 on ARBs) was collected in 2009-2012. C-reactive protein (CRP), interleukins 1β and 6 and tumor necrosis factor alpha (TNF-α) were assessed and categorized in quartiles. RESULTS: At baseline, no differences were found between participants taking or not taking ARBs for all inflammatory markers studied, and this association persisted after multivariate adjustment: odds ratios (ORs) and (95% confidence interval) for being in the highest quartile of interleukin-1β, interleukin-6, TNF-α and CRP for participants on ARB compared to participants not on ARB were 1.23 (0.89-1.70), 1.26 (0.93-1.70), 1.14 (0.85-1.53) and 1.27 (0.96-1.69) respectively (P > 0.05). These findings were further replicated in the follow-up study: OR and (95% CI) of 1.10 (0.78-1.55), 0.87 (0.64-1.19), 0.83 (0.61-1.14) and 0.91 (0.68-1.22) for interleukin-1β, interleukin-6, TNF-α and CRP respectively (P > 0.05). Finally, no effect of ARBs was found when comparing participants who received ARBs throughout the 5.4-year follow-up with participants on other antihypertensive drugs: OR and (95% CI) of 0.93 (0.61-1.42), 0.80 (0.54-1.17), 0.86 (0.59-1.25) and 0.95 (0.67-1.35) for interleukin-1β, interleukin-6, TNF-α and CRP respectively (P > 0.05). CONCLUSION: ARBs are not associated with reduced levels of inflammatory markers in the general population.

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The aim of this chapter is to provide an understanding of retirement adjustment by specifically focusing on meaning in life for retirees and meaningful work for older workers who are close to retirement. After a first outline of global issues of aging and work, we approach transition to retirement from the standpoint of sustainable careers within its main dimensions of continuity and importance of personal agency. Next, we review and synthesize literature on meaningful work and meaning in life, distinguishing three levels that constitute meaningful work and five dimensions of meaning in life. To illustrate our points, we present quotations from semi-structured interviews realized with Swiss older workers who were going to retire within a few months. Then, we describe ways to promote meaningful work for older workers and how to create a new meaning or to pursue a previous meaning as a retiree. Finally, we suggest ways individuals, organizations, and career counselors can facilitate a meaningful transition to retirement.

Interleukin-6 and chondrocyte mineralisation act in tandem to promote experimental osteoarthritis.

OBJECTIVES: Basic calcium phosphate (BCP) crystal and interleukin 6 (IL-6) have been implicated in osteoarthritis (OA). We hypothesise that these two factors may be linked in a reciprocal amplification loop which leads to OA. METHODS: Primary murine chondrocytes and human cartilage explants were incubated with hydroxyapatite (HA) crystals, a form of BCP, and the modulation of cytokines and matrix-degrading enzymes assayed. The ability of IL-6 to stimulate chondrocyte calcification was assessed in vitro. The mechanisms underlying the effects of HA on chondrocytes were investigated using chemical inhibitors, and the pathways mediating IL-6-induced calcification characterised by quantifying the expression of genes involved in chondrocyte mineralisation. The role of calcification in vivo was studied in the meniscectomy model of murine OA (MNX), and the link between IL-6 and cartilage degradation investigated by histology. RESULTS: In chondrocytes, BCP crystals stimulated IL-6 secretion, further amplified in an autocrine loop, through signalling pathways involving Syk and PI3 kinases, Jak2 and Stat3 molecules. Exogenous IL-6 promoted calcium-containing crystal formation and upregulation of genes involved in calcification: the pyrophosphate channel Ank, the calcium channel Annexin5 and the sodium/phosphate cotransporter Pit-1. Treatment of chondrocytes with IL-6 inhibitors significantly inhibited IL-6-induced crystal formation. In meniscectomised mice, increasing deposits of BCP crystals were observed around the joint and correlated with cartilage degradation and IL-6 expression. Finally, BCP crystals induced proteoglycan loss and IL-6 expression in human cartilage explants, which were reduced by an IL-6 inhibitor. CONCLUSIONS: BCP crystals and IL-6 form a positive feedback loop leading to OA. Targeting calcium-containing crystal formation and/or IL-6 are promising therapeutic strategies in OA.

Nitric oxide sustains IL-1β expression in human dendritic cells enhancing their capacity to induce IL-17-producing T-cells.

The role played by lung dendritic cells (DCs) which are influenced by external antigens and by their redox state in controlling inflammation is unclear. We studied the role played by nitric oxide (NO) in DC maturation and function. Human DCs were stimulated with a long-acting NO donor, DPTA NONOate, prior to exposure to lipopolysaccharide (LPS). Dose-and time-dependent experiments were performed with DCs with the aim of measuring the release and gene expression of inflammatory cytokines capable of modifying T-cell differentiation, towardsTh1, Th2 and Th17 cells. NO changed the pattern of cytokine release by LPS-matured DCs, dependent on the concentration of NO, as well as on the timing of its addition to the cells during maturation. Addition of NO before LPS-induced maturation strongly inhibited the release of IL-12, while increasing the expression and release of IL-23, IL-1β and IL-6, which are all involved in Th17 polarization. Indeed, DCs treated with NO efficiently induced the release of IL-17 by T-cells through IL-1β. Our work highlights the important role that NO may play in sustaining inflammation during an infection through the preferential differentiation of the Th17 lineage.

Elaborated Literary Violence: Genre and Ideology of the Two Stories I Sam 22,6-23 and II Sam 21,1-14

The present article focuses on two stories dealing with acts of big blood shed. I Sam 22,6-23 relates the massacre of the priests of Nob; II Sam 21,1-14 is about the execution of seven descendents of Saul, as atonement for Saul's attempt to exterminate the Gibeonites. Most researchers consider both stories or at least certain parts of them old.1 For both stories few verses are regarded as secondary. In this paper I try to reassess the analysis of these stories and will point to indices favoring a late date of origin for both of them. They concern the language in use, intertextual connections and particular motifs. A further indication consists in the fact that the reported events of the stories lack significant resonance in the corpus of the Hebrew Bible. There are only two texts, I Sam 2,33 and Ps 52,2, which allude or refer to I Sam 22,6-23.With regard to the importance of the related events and acts this silence in the Biblical context is astonishing. Interestingly, also in the Book of Chronicles one does not find any allusions to these stories. This raises the question whether the latter were composed after the formation of the book of Chronicles.

Changes in cannabis and tobacco use trajectories from age 17 to age 23

Much like the first volume published in 2011, the second volume of this anthology series gathers a selection of analyses which are empirically based on the data of the Swiss panel study TREE (Transitions from Education to Employment). The contributions of this volume carry on the investigation of the critical transitions during youth and young adulthood, drawing on sociological, economic, psychological and pedagogical research questions and thus highlighting the analytic and pluri-disciplinary research potential of the TREE data. One of the topical foci is the long-term influence of social origin on education and labour market pathways, particularly with regard to access to higher education.

Fibroblast growth factor-23 (FGF-23) levels differ across populations by degree of industrialization.

CONTEXT: Compensatory increases in FGF23 with increasing phosphate intake may adversely impact health. However, population and clinical studies examining the link between phosphate intake and FGF23 levels have focused mainly on populations living in highly industrialized societies in which phosphate exposure may be homogenous. OBJECTIVE: Contrast dietary phosphate intake, urinary measures of phosphate excretion and FGF23 levels across populations that differ by level of industrialization. DESIGN: Cross-sectional analysis of three populations Setting: Maywood, IL, U.S., Mah|fe Island, Seychelles, and Kumasi, Ghana Participants: Adults with African ancestry aged 25-45 years Main Outcome: Fibroblast growth factor 23 (FGF23) levels Results: The mean age was 35.1 (6.3) years and 47.9% were male. Mean phosphate intake and fractional excretion of phosphate were significantly higher in the U.S. vs. Ghana while no significant difference in phosphate intake or fractional excretion of phosphate was noted between U.S. and Seychelles for men or women. Overall, median FGF23 values were 57.41 RU/ml (IQR 43.42, 75.09) in U.S., 42.49 RU/ml (IQR 33.06, 55.39) in Seychelles and 33.32 RU/ml (IQR 24.83, 47.36) in Ghana. In the pooled sample, FGF23 levels were significantly and positively correlated with dietary phosphate intake (r=0.11; P < 0.001), and the fractional excretion of phosphate (r=0.13; P < 0.001) but not with plasma phosphate levels (-0.001; P = 0.8). Dietary phosphate intake was significantly and positively associated with the fractional excretion of phosphate (r=0.23; P < 0.001). CONCLUSION: The distribution of FGF23 levels in a given population may be influenced by the level of industrialization, likely due to differences in access to foods preserved with phosphate additives.

Ballade No. 1 in G minor, Op. 23

Soitinnus: Piano.