| 1. |
- Wegmann, F., et al.
(författare)
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Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens
- 2012
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 30:9
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Tidskriftsartikel (refereegranskat)abstract
- Protection against mucosally transmitted infections probably requires immunity at the site of pathogen entry(1), yet there are no mucosal adjuvant formulations licensed for human use. Polyethyleneimine (PEI) represents a family of organic polycations used as nucleic acid transfection reagents in vitro and DNA vaccine delivery vehicles in vivo(2,3). Here we show that diverse PEI forms have potent mucosal adjuvant activity for viral subunit glycoprotein antigens. A single intranasal administration of influenza hemagglutinin or herpes simplex virus type-2 (HSV-2) glycoprotein D with PEI elicited robust antibody-mediated protection from an otherwise lethal infection, and was superior to existing experimental mucosal adjuvants. PEI formed nanoscale complexes with antigen, which were taken up by antigen-presenting cells in vitro and in vivo, promoted dendritic cell trafficking to draining lymph nodes and induced non-proinflammatory cytokine responses. PEI adjuvanticity required release of host double-stranded DNA that triggered Irf3-dependent signaling. PEI therefore merits further investigation as a mucosal adjuvant for human use.
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| 2. |
- Arora, Tulika, et al.
(författare)
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Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice
- 2016
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 5:8, s. 725-730
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The enteroendocrine hormone glucagon-like peptide 1 (GLP-1) is an attractive anti-diabetic therapy. Here, we generated a recombinant Lactococcus lactis strain genetically modified to produce GLP-1 and investigated its ability to improve glucose tolerance in mice on chow or high-fat diet (HFD). Methods: We transformed L. lactis FI5876 with either empty vector (pUK200) or murine GLP-1 expression vector to generate LL-UK200 and LL-GLP1, respectively, and determined their potential to induce insulin secretion by incubating primary islets from wild-type (WT) and GLP-1 receptor knockout (GLP1R-KO) mice with culture supernatant of these strains. In addition, we administered these strains to mice on chow or HFD. At the end of the study period, we measured plasma GLP-1 levels, performed intraperitoneal glucose tolerance and insulin tolerance tests, and determined hepatic expression of the gluconeogenic genes G6pc and Pepck. Results: Insulin release from primary islets of WT but not GLP1R-KO mice was higher following incubation with culture supernatant from LL-GLP1 compared with LL-UK200. In mice on chow, supplementation with LL-GLP1 versus LL-UK200 promoted increased vena porta levels of GLP1 in both WT and GLP1R-KO mice; however, LL-GLP1 promoted improved glucose tolerance in WT but not in GLP1R-KO mice, indicating a requirement for the GLP-1 receptor. In mice on HFD and thus with impaired glucose tolerance, supplementation with LL-GLP1 versus LL-UK200 promoted a pronounced improvement in glucose tolerance together with increased insulin levels. Supplementation with LL-GLP1 versus LL-UK200 did not affect insulin tolerance but resulted in reduced expression of G6pc in both chow and HFD-fed mice. Conclusions: The L. lactis strain genetically modified to produce GLP-1 is capable of stimulating insulin secretion from islets and improving glucose tolerance in mice. (C) 2016 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 3. |
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| 4. |
- Sheppard, Neil C, et al.
(författare)
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Polyethyleneimine is a potent systemic adjuvant for glycoprotein antigens.
- 2014
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377 .- 0953-8178. ; 26:10, s. 531-538
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Tidskriftsartikel (refereegranskat)abstract
- Polyethyleneimine (PEI) is an organic polycation used extensively as a gene- and DNA vaccine delivery reagent. Although the DNA targeting activity of PEI is well documented, its immune activating activity is not. We recently reported that PEI has robust mucosal adjuvanticity when administered intranasally with glycoprotein antigens. Here we show that PEI has strong immune activating activity after systemic delivery. PEI administered subcutaneously with viral glycoprotein (HIV-1 gp140) enhanced antigen-specific serum IgG production in the context of mixed Th1/Th2-type immunity. PEI elicited higher titers of both antigen binding and neutralizing antibodies than alum in mice and rabbits, and induced an increased proportion of antibodies reactive with native antigen. In an intraperitoneal model, PEI recruited neutrophils followed by monocytes to the site of administration, and enhanced antigen uptake by antigen presenting cells. The Th bias was modulated by PEI activation of the Nlrp3 inflammasome, however its global adjuvanticity was unchanged in Nlrp3-deficient mice. When co-formulated with CpG oligodeoxynucleotides, PEI adjuvant potency was synergistically increased and biased towards a Th1-type immune profile. Taken together these data support the use of PEI as a versatile systemic adjuvant platform with particular utility for induction of secondary structure-reactive antibodies against glycoprotein antigens.
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| 5. |
- Wegmann, A., et al.
(författare)
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Augmenting the Zachman enterprise architecture Framework with a systemic conceptualization
- 2008
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Ingår i: Proc. - IEEE Int. Enterp. Distrib. Object Comput. Conf., EDOC. - 9780769533735 ; , s. 3-13
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Konferensbidrag (refereegranskat)abstract
- The Zachman Framework offers a classification of the models created in an enterprise architecture project. These models form a holistic representation of the organization. Despite the prominent position of the Framework, there is little information publicly available to help designers create exact models that fit each other. In this paper, we propose a conceptualization based on General Systems Thinking. Our conceptualization provides concrete guidelines for creating the models required by the Framework. The proposed conceptualization establishes a better understanding of the models and of their relationships. This facilitates the creation and interpretation of the models. It also improves the traceability between them. We illustrate our approach with the results of a case study.
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| 7. |
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| 8. |
- Blanckenhorn, Wolf U, et al.
(författare)
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Sexual size dimorphism is associated with reproductive life history trait differentiation in coexisting sepsid flies
- 2020
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Ingår i: Oikos. - : Wiley. - 0030-1299 .- 1600-0706. ; 129:8
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Tidskriftsartikel (refereegranskat)abstract
- Organismal life histories evolve as syndromes, resulting in correlated evolutionary differentiation of key traits that ultimately aid in discerning species. Reproductive success depends both on the absolute body size of an individual and its size relative to the opposite sex: sexual size dimorphism. In an attempt to further elucidate their coexistence and ecological diversification, we compared standard life history (first reproduction, clutch size, egg size) and associated reproductive trait differentiation of 15 widespread European sepsid fly species (Diptera: Sepsidae) under laboratory common garden conditions. Despite relatively uniform body sizes, sexual dimorphism ranged from female‐ to male‐biased, and development time varied twofold across species. We expected, and found, the abundant and relatively large species (Sepsis cynipsea, punctum, thoracica) with often male‐biased SSD to lay larger but fewer eggs and show fast‐developing, fast‐reproducing life histories with aggressive (coercive) mating behavior characterized by short mating latencies and male conflict. In contrast, the smaller and more dispersed species with female‐biased SSD (S. flavimana, orthocnemis, violacea) laid smaller but more eggs, showing a generally slower life history with long and delayed copulation and oviposition, high mating reluctance fostering extensive inter‐sexual conflict, and more elaborate male (pre‐)copulatory courtship. Two Saltella species were exceptional, being large, developing slowly, nevertheless copulating soon after adult emergence, profusely and briefly. The documented life history differentiation seems partly driven by sexual selection leading to male‐biased dimorphism, rather than undetermined ecological selection, but regardless appears insufficient to explain the coexistence and diversification of these sepsid species in European pastoral landscapes.
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| 9. |
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| 10. |
- Pelet, J. -É, et al.
(författare)
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Don’t believe the hype : a grounded exploratory six country wine purchasing study
- 2017
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Ingår i: Journal of Wine Research. - : Routledge. - 0957-1264 .- 1469-9672. ; 28:2, s. 91-104
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this exploratory study was to understand the extent that consumers report purchasing wine on mobile devices and to empirically examine potential drivers of m-wine purchasing across six countries to guide theoretical research enquiry moving forward. Purposive sampling was employed. An online survey involving 2853 respondents from France, Germany, Greece, Canada, US and South Africa forms the basis for the current study. The results of the study indicate that though mobile phone usage, wine consumption and purchasing rates are high, mobile-wine purchasing prevalence is low within all six countries. While technology hype has us believe an online presence is essential for business revenue growth and performance; the current study indicates wineries should carefully consider consumer readiness towards mobile-wine purchasing. Limitations and recommendations for future research are identified.
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| 11. |
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| 12. |
- Thalmann, Olaf, et al.
(författare)
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Historical sampling reveals dramatic demographic changes in western gorilla populations
- 2011
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Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Today many large mammals live in small, fragmented populations, but it is often unclear whether this subdivision is the result of long-term or recent events. Demographic modeling using genetic data can estimate changes in long-term population sizes while temporal sampling provides a way to compare genetic variation present today with that sampled in the past. In order to better understand the dynamics associated with the divergences of great ape populations, these analytical approaches were applied to western gorillas (Gorilla gorilla) and in particular to the isolated and Critically Endangered Cross River gorilla subspecies (G. g. diehli). Results: We used microsatellite genotypes from museum specimens and contemporary samples of Cross River gorillas to infer both the long-term and recent population history. We find that Cross River gorillas diverged from the ancestral western gorilla population similar to 17,800 years ago (95% HDI: 760, 63,245 years). However, gene flow ceased only similar to 420 years ago (95% HDI: 200, 16,256 years), followed by a bottleneck beginning similar to 320 years ago (95% HDI: 200, 2,825 years) that caused a 60 fold decrease in the effective population size of Cross River gorillas. Direct comparison of heterozygosity estimates from museum and contemporary samples suggests a loss of genetic variation over the last 100 years. Conclusions: The composite history of western gorillas could plausibly be explained by climatic oscillations inducing environmental changes in western equatorial Africa that would have allowed gorilla populations to expand over time but ultimately isolate the Cross River gorillas, which thereafter exhibited a dramatic population size reduction. The recent decrease in the Cross River population is accordingly most likely attributable to increasing anthropogenic pressure over the last several hundred years. Isolation of diverging populations with prolonged concomitant gene flow, but not secondary admixture, appears to be a typical characteristic of the population histories of African great apes, including gorillas, chimpanzees and bonobos.
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| 13. |
- Wegmann, Mathilde Gersel, et al.
(författare)
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Increases in bioactive IGF do not parallel increases in total IGF-I during growth hormone treatment of children born SGA
- 2020
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 105:4, s. 1291-1298
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Tidskriftsartikel (refereegranskat)abstract
- Background: Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. Aim: To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). Material and method: In NESGAS, short SGA children (n = 101, 61 males) received GH at 67 µg/ kg/day for 1 year. IGF-I concentrations were measured by Immulite immunoassay and bioactive IGF by in-house KIRA assay. Results: Bioactive IGF increased with age in healthy pre-pubertal children (n = 94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, P < 0.01. Following high-dose GH, 68% (n = 65) of SGA children had a total IGF-I concentration >2SD (mean IGF-I 2.8 SDS), whereas only 15% (n = 15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r = 0.29, P = 0.005), in contrast to IGF-I (SDS) (r = 0.17, P = 0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r = -0.22, P = 0.02). Conclusion: In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment.
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| 14. |
- Wegmann, Mathilde Gersel, et al.
(författare)
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The exon3-deleted growth hormone receptor gene polymorphism (d3-GHR) is associated with insulin and spontaneous growth in short SGA children (NESGAS)
- 2017
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Ingår i: Growth Hormone and IGF Research. - : Elsevier BV. - 1096-6374. ; 35, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- Objective The effect of a common polymorphism in the Growth Hormone (GH) receptor (d3-GHR) gene on growth, metabolism and body composition was examined in short children born small for gestational age (SGA) on GH treatment. Design In 96 prepubertal, short SGA children treated with high-dose GH (67 μg/kg/day) in the NESGAS study, insulin sensitivity (IS), insulin secretion and disposition index (DI) were determined during the first year of treatment. Body composition was analysed by DXA. The d3-GHR locus was determined by simple multiplex PCR. Results At baseline, children in the d3-GHR group (d3/fl (n = 37), d3/d3 (n = 7)) had significantly lower IS (median (25–75 percentile)) (223.3% (154.4–304.8)) vs. (269.7% (185.1–356.7)) (p = 0.03) and higher concentrations of glucose (mean (SD)) (4.4 mmol/L (0.6) vs. 4.2 mmol/L (0.7)) (p = 0.03), C-peptide (232.1 pmol/L (168.8–304.1) vs. 185.1 pmol/L (137.7–253.9)) (p = 0.04) and insulin (19.2 pmol/L (11.8–32.2)) vs. (13.7 pmol/L (9.3–20.8)) (p = 0.04) compared to children homozygous for the full length allele (fl/fl-GHR (n = 52)). There were no differences in DI or insulin secretion. Postnatal, spontaneous growth was significantly greater in the d3-GHR group compared to the fl/fl-GHR group (p = 0.02). There were no significant differences in growth response, body composition or metabolism after one year of GH therapy. Conclusion Short SGA children carrying the d3-GHR polymorphism had increased spontaneous growth, lower IS and a compensatory increase in glucose, C-peptide and insulin before GH therapy compared to children homozygous for the full-length allele.
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