Publications by authors named "Johan Mattsson"

36 Publications

Influence of Liquid Crystallinity and Mechanical Deformation on the Molecular Relaxations of an Auxetic Liquid Crystal Elastomer.

Molecules 2021 Dec 2;26(23). Epub 2021 Dec 2.

School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, UK.

Liquid Crystal Elastomers (LCEs) combine the anisotropic ordering of liquid crystals with the elastic properties of elastomers, providing unique physical properties, such as stimuli responsiveness and a recently discovered molecular auxetic response. Here, we determine how the molecular relaxation dynamics in an acrylate LCE are affected by its phase using broadband dielectric relaxation spectroscopy, calorimetry and rheology. Our LCE is an excellent model system since it exhibits a molecular auxetic response in its nematic state, and chemically identical nematic or isotropic samples can be prepared by cross-linking. We find that the glass transition temperatures (Tg) and dynamic fragilities are similar in both phases, and the T-dependence of the α relaxation shows a crossover at the same T* for both phases. However, for T>T*, the behavior becomes Arrhenius for the nematic LCE, but only more Arrhenius-like for the isotropic sample. We provide evidence that the latter behavior is related to the existence of pre-transitional nematic fluctuations in the isotropic LCE, which are locked in by polymerization. The role of applied strain on the relaxation dynamics and mechanical response of the LCE is investigated; this is particularly important since the molecular auxetic response is linked to a mechanical Fréedericksz transition that is not fully understood. We demonstrate that the complex Young's modulus and the α relaxation time remain relatively unchanged for small deformations, whereas for strains for which the auxetic response is achieved, significant increases are observed. We suggest that the observed molecular auxetic response is coupled to the strain-induced out-of-plane rotation of the mesogen units, in turn driven by the increasing constraints on polymer configurations, as reflected in increasing elastic moduli and α relaxation times; this is consistent with our recent results showing that the auxetic response coincides with the emergence of biaxial order.
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http://dx.doi.org/10.3390/molecules26237313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659252PMC
December 2021

Spatiotemporal variation of the indoor mycobiome in daycare centers.

Microbiome 2021 Nov 9;9(1):220. Epub 2021 Nov 9.

Section for Genetics and Evolutionary Biology (Evogene), Department of Biosciences, University of Oslo, P.O. Box 1066, Blindern, 0316, Oslo, Norway.

Background: Children spend considerable time in daycare centers in parts of the world and are exposed to the indoor micro- and mycobiomes of these facilities. The level of exposure to microorganisms varies within and between buildings, depending on occupancy, climate, and season. In order to evaluate indoor air quality, and the effect of usage and seasonality, we investigated the spatiotemporal variation in the indoor mycobiomes of two daycare centers. We collected dust samples from different rooms throughout a year and analyzed their mycobiomes using DNA metabarcoding.

Results: The fungal community composition in rooms with limited occupancy (auxiliary rooms) was similar to the outdoor samples, and clearly different from the rooms with higher occupancy (main rooms). The main rooms had higher abundance of Ascomycota, while the auxiliary rooms contained comparably more Basidiomycota. We observed a strong seasonal pattern in the mycobiome composition, mainly structured by the outdoor climate. Most markedly, basidiomycetes of the orders Agaricales and Polyporales, mainly reflecting typical outdoor fungi, were more abundant during summer and fall. In contrast, ascomycetes of the orders Saccharomycetales and Capnodiales were dominant during winter and spring.

Conclusions: Our findings provide clear evidences that the indoor mycobiomes in daycare centers are structured by occupancy as well as outdoor seasonality. We conclude that the temporal variability should be accounted for in indoor mycobiome studies and in the evaluation of indoor air quality of buildings. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01167-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576891PMC
November 2021

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Commun Biol 2021 03 23;4(1):392. Epub 2021 Mar 23.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10, odds ratio = 2.87, 95% confidence interval: 2.03-4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.
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http://dx.doi.org/10.1038/s42003-021-01910-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988141PMC
March 2021

Antibodies to SARS-CoV-2 and risk of past or future sick leave.

Sci Rep 2021 03 4;11(1):5160. Epub 2021 Mar 4.

Karolinska University Hospital, 141 86, Stockholm, Sweden.

The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. We invited all employees (n = 15,300) at work at the Karolinska University Hospital, Stockholm, Sweden to participate in a study examining SARS-Cov-2 antibodies in relation to registered sick leave. For consenting 12,928 healthy hospital employees antibodies to SARS-CoV-2 could be determined and compared to participant sick leave records. Subjects with viral serum antibodies were not at excess risk for future sick leave (adjusted odds ratio (OR) controlling for age and sex: 0.85 [95% confidence interval (CI) (0.85 (0.43-1.68)]. By contrast, subjects with antibodies had an excess risk for sick leave in the weeks prior to testing [adjusted OR in multivariate analysis: 3.34 (2.98-3.74)]. Thus, presence of viral antibodies marks past disease and protection against excess risk of future disease. Knowledge of whether exposed subjects have had disease in the past or are at risk for future disease is essential for planning of control measures.Trial registration: First registered on 02/06/20, ClinicalTrials.gov NCT04411576.
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http://dx.doi.org/10.1038/s41598-021-84356-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933367PMC
March 2021

High Amounts of SARS-CoV-2 Precede Sickness Among Asymptomatic Health Care Workers.

J Infect Dis 2021 07;224(1):14-20

Karolinska University Hospital, Stockholm, Sweden.

Background: Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity among asymptomatic subjects reflects past or future disease may be difficult to ascertain.

Methods: We tested 9449 employees at Karolinska University Hospital, Stockholm, Sweden for SARS-CoV-2 RNA and antibodies, linked the results to sick leave records, and determined associations with past or future sick leave using multinomial logistic regression.

Results: Subjects with high amounts of SARS-CoV-2 virus, indicated by polymerase chain reaction (PCR) cycle threshold (Ct) value, had the highest risk for sick leave in the 2 weeks after testing (odds ratio [OR], 11.97; 95% confidence interval [CI], 6.29-22.80) whereas subjects with low amounts of virus had the highest risk for sick leave in the 3 weeks before testing (OR, 6.31; 95% CI, 4.38-9.08). Only 2.5% of employees were SARS-CoV-2 positive while 10.5% were positive by serology and 1.2% were positive in both tests. Serology-positive subjects were not at excess risk for future sick leave (OR, 1.06; 95% CI, .71-1.57).

Conclusions: High amounts of SARS-CoV-2 virus, as determined using PCR Ct values, was associated with development of sickness in the next few weeks. Results support the concept that PCR Ct may be informative when testing for SARS-CoV-2. Clinical Trials Registration. NCT04411576.
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http://dx.doi.org/10.1093/infdis/jiab099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928785PMC
July 2021

A MALT1 inhibitor suppresses human myeloid DC, effector T-cell and B-cell responses and retains Th1/regulatory T-cell homeostasis.

PLoS One 2020 1;15(9):e0222548. Epub 2020 Sep 1.

Research & Early Development, Respiratory, Inflammation & Autoimmune, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden.

The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) regulates nuclear-factor-kappa-B (NF-κB) activation downstream of surface receptors with immunoreceptor tyrosine-based activation motifs (ITAMs), such as the B-cell or T-cell receptor and has thus emerged as a therapeutic target for autoimmune diseases. However, recent reports demonstrate the development of lethal autoimmune inflammation due to the excessive production of interferon gamma (IFN-ɣ) and defective differentiation of regulatory T-cells in genetically modified mice deficient in MALT1 paracaspase activity. To address this issue, we explored the effects of pharmacological MALT1 inhibition on the balance between T-effector and regulatory T-cells. Here we demonstrate that allosteric inhibition of MALT1 suppressed Th1, Th17 and Th1/Th17 effector responses, and inhibited T-cell dependent B-cell proliferation and antibody production. Allosteric MALT1 inhibition did not interfere with the suppressive function of human T-regulatory cells, although it impaired de novo differentiation of regulatory T-cells from naïve T-cells. Treatment with an allosteric MALT1 inhibitor alleviated the cytokine storm, including IFN-ɣ, in a mouse model of acute T-cell activation, and long-term treatment did not lead to an increase in IFN-ɣ producing CD4 cells or tissue inflammation. Together, our data demonstrate that the effects of allosteric inhibition of MALT1 differ from those seen in mice with proteolytically inactive MALT1, and thus we believe that MALT1 is a viable target for B and T-cell driven autoimmune diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222548PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462277PMC
October 2020

The regulatory role of PGC1α-related coactivator in response to drug-induced liver injury.

FASEB Bioadv 2020 Aug 11;2(8):453-463. Epub 2020 Jul 11.

Clinical Pharmacology and Safety Sciences AstraZeneca R&D Mölndal Sweden.

PGC1α-Related Coactivator (PRC) is a transcriptional coactivator promoting cytokine expression in vitro in response to mitochondrial injury and oxidative stress, however, its physiological role has remained elusive. Herein we investigate aspects of the immune response function of PRC, first in an in vivo thioacetamide (TAA)-induced mouse model of drug-induced liver injury (DILI), and subsequently in vitro in human monocytes, HepG2, and dendritic (DC) cells. TAA treatment resulted in the dose-dependent induction of PRC mRNA and protein, both of which were shown to correlate with liver injury markers. Conversely, an adenovirus-mediated knockdown of PRC attenuated this response, thereby reducing hepatic cytokine mRNA expression and monocyte infiltration. Subsequent in vitro studies with conditioned media from HepG2 cells overexpressing PRC, activated human monocytes and monocyte-derived DC, demonstrated up to 20% elevated expression of CD86, CD40, and HLA-DR. Similarly, siRNA-mediated knockdown of PRC abolished this response in oligomycin stressed HepG2 cells. A putative mechanism was suggested by the co-immunoprecipitation of Signal Transducer and Activator of Transcription 1 (STAT1) with PRC, and induction of a STAT-dependent reporter. Furthermore, PRC co-activated an NF-κB-dependent reporter, indicating interaction with known major inflammatory factors. In summary, our study indicates PRC as a novel factor modulating inflammation in DILI.
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http://dx.doi.org/10.1096/fba.2020-00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429352PMC
August 2020

Human Lung Conventional Dendritic Cells Orchestrate Lymphoid Neogenesis during Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2020 08;202(4):535-548

Laboratory of Immunoregulation, VIB-UGhent Center for Inflammation Research, Ghent, Belgium.

Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined. To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD. Myeloid cell heterogeneity and phenotype were studied in an unbiased manner via single-cell RNA sequencing on HLA-DR cells sorted from human lungs. We measured the capability of control and COPD lung DC subsets, sorted using a fluorescence-activated cell sorter, to polarize IL-21CXCL13 (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs. Single-cell RNA-sequencing analysis revealed a high degree of heterogeneity among human lung myeloid cells. Among these, conventional dendritic type 2 cells (cDC2s) showed increased induction of IL-21CXCL13 Tfh-like cells. Importantly, the capacity to induce IL-21 Tfh-like cells was higher in cDC2s from patients with COPD than in those from control patients. Increased Tfh-cell induction by COPD cDC2s correlated with increased presence of Tfh-like cells in COPD lungs as compared with those in control lungs, and cDC2s colocalized with Tfh-like cells in TLOs of COPD lungs. Mechanistically, cDC2s exhibited a unique migratory signature and (transcriptional) expression of several pathways and genes related to DC-induced Tfh-cell priming. Importantly, blocking the costimulatory OX40L (OX40 ligand)-OX40 axis reduced Tfh-cell induction by control lung cDC2s. In COPD lungs, we found lung EBI2 (Epstein-Barr virus-induced gene 2-positive) OX-40L-expressing cDC2s that induced IL-21 Tfh-like cells, suggesting an involvement of these cells in TLO formation.
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http://dx.doi.org/10.1164/rccm.201906-1123OCDOI Listing
August 2020

The CTA1-DD adjuvant strongly potentiates follicular dendritic cell function and germinal center formation, which results in improved neonatal immunization.

Mucosal Immunol 2020 05 20;13(3):545-557. Epub 2020 Jan 20.

Mucosal Immunobiology and Vaccine Center (MIVAC), Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

Vaccination of neonates and young infants is hampered by the relative immaturity of their immune systems and the lack of safe and efficacious vaccine adjuvants. Immaturity of the follicular dendritic cells (FDCs), in particular, appears to play a critical role for the inability to stimulate immune responses. Using the CD21mT/mG mouse model we found that at 7 days of life, FDCs exhibited a mature phenotype only in the Peyer´s patches (PP), but our unique adjuvant, CTA1-DD, effectively matured FDCs also in peripheral lymph nodes following systemic, as well as mucosal immunizations. This was a direct effect of complement receptor 2-binding to the FDC and a CTA1-enzyme-dependent enhancing effect on gene transcription, among which CR2, IL-6, ICAM-1, IL-1β, and CXCL13 encoding genes were upregulated. This way we achieved FDC maturation, increased germinal center B-cell- and Tfh responses, and enhanced specific antibody levels close to adult magnitudes. Oral priming immunization of neonates against influenza infection with CTA1-3M2e-DD effectively promoted anti-M2e-immunity and significantly reduced morbidity against a live virus challenge infection. To the best of our knowledge, this is the first study to demonstrate direct effects of an adjuvant on FDC gene transcriptional functions and the subsequent enhancement of neonatal immune responses.
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http://dx.doi.org/10.1038/s41385-020-0253-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223721PMC
May 2020

Bleomycin hydrolase regulates the release of chemokines important for inflammation and wound healing by keratinocytes.

Sci Rep 2019 12 31;9(1):20407. Epub 2019 Dec 31.

Bioscience COPD/IPF, Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Bleomycin hydrolase (BLMH) is a well-conserved cysteine protease widely expressed in several mammalian tissues. In skin, which contains high levels of BLMH, this protease is involved in the degradation of citrullinated filaggrin monomers into free amino acids important for skin hydration. Interestingly, the expression and activity of BLMH is reduced in patients with atopic dermatitis (AD) and psoriasis, and BLMH knockout mice acquire tail dermatitis. Apart from its already known function, we have discovered a novel role of BLMH in the regulation of inflammatory chemokines and wound healing. We show that lowered BLMH levels in keratinocytes result in increased release of the pro-inflammatory chemokines CXCL8 and GROα, which are upregulated in skin from AD patients compared to healthy individuals. Conditioned media from keratinocytes expressing low levels of BLMH increased chemotaxis by neutrophils and caused a delayed wound healing in the presence of low-level TNFα. This defective wound healing was improved by blocking the shared receptor of CXCL8 and GROα, namely CXCR2, using a specific receptor antagonist. Collectively, our results present a novel function of BLMH in regulating the secretion of chemokines involved in inflammation and wound healing in human keratinocytes.
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http://dx.doi.org/10.1038/s41598-019-56667-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938525PMC
December 2019

Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus.

Ann Rheum Dis 2019 10 12;78(10):1363-1370. Epub 2019 Jul 12.

Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden

Objectives: Genetic variations in (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.

Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and KI cells. Functional studies were performed in A20 U937 cells and in immune cells from A20 mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 mice and SLE-patients with rs2230926.

Results: Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with mutation or rs2230926 polymorphism presented an upregulated expression of , an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.

Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of with resultant protein citrullination and extracellular trap formation.
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http://dx.doi.org/10.1136/annrheumdis-2019-215434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788882PMC
October 2019

Nanoscale mechanics of microgel particles.

Nanoscale 2018 Aug;10(34):16050-16061

AMOLF, 1098 XG Amsterdam, The Netherlands.

Microgel particles are highly tuneable materials that are useful for a wide range of industrial applications, such as drug delivery, sensing, nanoactuation, emulsion stabilisation and use as cell substrates. Microgels have also been used as model systems investigating physical phenomena such as crystallization, glass-formation, jamming, ageing and complex flow behaviour. The responsiveness of microgel systems such as poly(N-isopropylacrylamide) (PNIPAm) to external stimuli has been established in fundamental investigations and in applications and recent work has begun to quantify the mechanics of individual particles. However little focus has been placed on determining their internal mechanical properties, which is likely to relate to their nonuniform internal structure. In this work we combine atomic force microscopy, force spectroscopy and dynamic light scattering to mechanically profile the internal structure of microgel particles in the size range of ∼100 nm, which is commonly used both in practical applications and in fundamental studies. Nanoindentation using thermally stable cantilevers allows us to determine the particle moduli and the deformation profiles during particle compression with increasing force, while peak force nanomechanical mapping (PF-QNM) AFM is used to capture high resolution images of the particles' mechanical response. Combining these approaches with dynamic light scattering allows a quantitative profile of the particles' internal elastic response to be determined. Our results provide clear evidence for a radial distribution in particle mechanical response with a softer outer "corona" and a stiffer particle core. We determine the particle moduli in the core and corona, using different force microscopy approaches, and find them to vary systematically both in the core (∼17-50 kPa) and at the outer periphery of the particles (∼3-40 kPa). Importantly, we find that highly crosslinked particles have equivalent moduli across their radial profile, reflecting their significantly lower radial heterogeneity. This ability to accurately and precisely probe microgel radial profiles has clear implications both for fundamental science and for industrial applications.
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http://dx.doi.org/10.1039/c8nr02911cDOI Listing
August 2018

Determination of the Endocannabinoids Anandamide and 2-Arachidonoyl Glycerol with Gas Chromatography-Mass Spectrometry: Analytical and Preanalytical Challenges and Pitfalls.

Med Cannabis Cannabinoids 2018 Jun 12;1(1):9-18. Epub 2018 Jun 12.

Department of Clinical Research, University of Bern, Bern, Switzerland.

Background: The endocannabinoids anandamide (-arachidonoyl ethanolamide [AEA]) and 2-arachidonoyl glycerol (2-AG) are involved in the regulation of neuronal, immune, metabolic, vascular, and reproductory functions.

Methods: The development and validation of an analytical method for the determination of AEA and 2-AG in human plasma based on liquid-liquid extraction and gas chromatography-mass spectrometry after silylation is described and (pre)-analytical pitfalls are identified.

Results: In contrast to 2-AG, AEA was unstable in whole blood and increased by a factor of 2.3 within 3 h on ice. AEA was stable in plasma on ice for 4 h while 2-AG tended to decrease. Excellent stability at room/ambient temperature was found for both derivatized compounds over 45 h. Furthermore, 3 freeze-thaw cycles revealed a complex pattern: endogenous AEA was stable in plasma but slightly increased in spiked samples (+12.8%), while endogenous 2-AG concentrations increased by 51% and declined by 24% in spiked samples. A long-term study over 4 weeks at -80°C showed that low endogenous AEA and spiked 2-AG concentrations were stable. However, spiked AEA tended to increase (+19%) and endogenous 2-AG significantly increased by 50% after 2 weeks. Food intake 2 h before blood collection showed no effect on AEA concentrations, whereas 2-AG increased significantly by a factor of 3.

Conclusions: Overall, limited in vitro and/or in vivo/ex vivo chemical stability of endocannabinoids has to be taken into account.
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http://dx.doi.org/10.1159/000489032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489342PMC
June 2018

Diffusing-wave spectroscopy in a standard dynamic light scattering setup.

Phys Rev E 2017 Dec 18;96(6-1):062611. Epub 2017 Dec 18.

Department of Mechanical Engineering, Eindhoven University of Technology, 5600MB Eindhoven, The Netherlands.

Diffusing-wave spectroscopy (DWS) extends dynamic light scattering measurements to samples with strong multiple scattering. DWS treats the transport of photons through turbid samples as a diffusion process, thereby making it possible to extract the dynamics of scatterers from measured correlation functions. The analysis of DWS data requires knowledge of the path length distribution of photons traveling through the sample. While for flat sample cells this path length distribution can be readily calculated and expressed in analytical form; no such expression is available for cylindrical sample cells. DWS measurements have therefore typically relied on dedicated setups that use flat sample cells. Here we show how DWS measurements, in particular DWS-based microrheology measurements, can be performed in standard dynamic light scattering setups that use cylindrical sample cells. To do so we perform simple random-walk simulations that yield numerical predictions of the path length distribution as a function of both the transport mean free path and the detection angle. This information is used in experiments to extract the mean-square displacement of tracer particles in the material, as well as the corresponding frequency-dependent viscoelastic response. An important advantage of our approach is that by performing measurements at different detection angles, the average path length through the sample can be varied. For measurements performed on a single sample cell, this gives access to a wider range of length and time scales than obtained in a conventional DWS setup. Such angle-dependent measurements also offer an important consistency check, as for all detection angles the DWS analysis should yield the same tracer dynamics, even though the respective path length distributions are very different. We validate our approach by performing measurements both on aqueous suspensions of tracer particles and on solidlike gelatin samples, for which we find our DWS-based microrheology data to be in good agreement with rheological measurements performed on the same samples.
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http://dx.doi.org/10.1103/PhysRevE.96.062611DOI Listing
December 2017

Migratory CD11b conventional dendritic cells induce T follicular helper cell-dependent antibody responses.

Sci Immunol 2017 12;2(18)

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

T follicular helper (Tfh) cells are a subset of CD4 T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding which cDC instructs Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist because of the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different antigen formulations, we determined that CD11b migratory type 2 cDCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b cDC2, but not CD103 cDC1, migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific or knockout mice, respectively, led to reduced Tfh cell priming, whereas loss of CD103 cDC1s in mice did not. Loss of cDC2-dependent Tfh cell priming impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the subanatomic regions of the lymph node where Tfh cell priming occurs-the T-B border. This work identifies the DC subset responsible for Tfh cell-dependent antibody responses, particularly when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.
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http://dx.doi.org/10.1126/sciimmunol.aam9169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847246PMC
December 2017

Limited clonal relatedness between gut IgA plasma cells and memory B cells after oral immunization.

Nat Commun 2016 09 6;7:12698. Epub 2016 Sep 6.

Mucosal Immunobiology and Vaccine Research Center and the Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, S-405-30 Gothenburg, Sweden.

Understanding how memory B cells are induced and relate to long-lived plasma cells is important for vaccine development. Immunity to oral vaccines has been considered short-lived because of a poor ability to develop IgA B-cell memory. Here we demonstrate that long-lived mucosal IgA memory is readily achieved by oral but not systemic immunization in mouse models with NP hapten conjugated with cholera toxin and transfer of B1-8(high)/GFP(+) NP-specific B cells. Unexpectedly, memory B cells are poorly related to long-lived plasma cells and less affinity-matured. They are α4β7-integrin(+)CD73(+)PD-L2(+)CD80(+) and at systemic sites mostly IgM(+), while 80% are IgA(+) in Peyer's patches. On reactivation, most memory B cells in Peyer's patches are GL7(-), but expand in germinal centres and acquire higher affinity and more mutations, demonstrating strong clonal selection. CCR9 expression is found only in Peyer's patches and appears critical for gut homing. Thus, gut mucosal memory possesses unique features not seen after systemic immunization.
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http://dx.doi.org/10.1038/ncomms12698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025876PMC
September 2016

Sucrose diffusion in aqueous solution.

Phys Chem Chem Phys 2016 Jul 1;18(28):19207-16. Epub 2016 Jul 1.

School of Earth and Environment, University of Leeds, Leeds, UK.

The diffusion of sugar in aqueous solution is important both in nature and in technological applications, yet measurements of diffusion coefficients at low water content are scarce. We report directly measured sucrose diffusion coefficients in aqueous solution. Our technique utilises a Raman isotope tracer method to monitor the diffusion of non-deuterated and deuterated sucrose across a boundary between the two aqueous solutions. At a water activity of 0.4 (equivalent to 90 wt% sucrose) at room temperature, the diffusion coefficient of sucrose was determined to be approximately four orders of magnitude smaller than that of water in the same material. Using literature viscosity data, we show that, although inappropriate for the prediction of water diffusion, the Stokes-Einstein equation works well for predicting sucrose diffusion under the conditions studied. As well as providing information of importance to the fundamental understanding of diffusion in binary solutions, these data have technological, pharmaceutical and medical implications, for example in cryopreservation. Moreover, in the atmosphere, slow organic diffusion may have important implications for aerosol growth, chemistry and evaporation, where processes may be limited by the inability of a molecule to diffuse between the bulk and the surface of a particle.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5044753PMC
http://dx.doi.org/10.1039/c6cp03238aDOI Listing
July 2016

Medicinal Cannabis: In Vitro Validation of Vaporizers for the Smoke-Free Inhalation of Cannabis.

PLoS One 2016 19;11(1):e0147286. Epub 2016 Jan 19.

Department of Clinical Research, Laboratory of Phytopharmacology, Bioanalytics and Pharmacokinetics, University of Bern, Bern, Switzerland.

Inhalation by vaporization is a promising application mode for cannabis in medicine. An in vitro validation of 5 commercial vaporizers was performed with THC-type and CBD-type cannabis. Gas chromatography/mass spectrometry was used to determine recoveries of total THC (THCtot) and total CBD (CBDtot) in the vapor. High-performance liquid chromatography with photodiode array detection was used for the quantitation of acidic cannabinoids in the residue and to calculate decarboxylation efficiencies. Recoveries of THCtot and CBDtot in the vapor of 4 electrically-driven vaporizers were 58.4 and 51.4%, 66.8 and 56.1%, 82.7 and 70.0% and 54.6 and 56.7% for Volcano Medic®, Plenty Vaporizer®, Arizer Solo® and DaVinci Vaporizer®, respectively. Decarboxylation efficiency was excellent for THC (≥ 97.3%) and CBD (≥ 94.6%). The gas-powered Vape-or-Smoke™ showed recoveries of THCtot and CBDtot in the vapor of 55.9 and 45.9%, respectively, and a decarboxylation efficiency of ≥ 87.7 for both cannabinoids. However, combustion of cannabis was observed with this device. Temperature-controlled, electrically-driven vaporizers efficiently decarboxylate inactive acidic cannabinoids and reliably release their corresponding neutral, active cannabinoids. Thus, they offer a promising application mode for the safe and efficient administration of medicinal cannabis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147286PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718604PMC
July 2016

Water diffusion in atmospherically relevant α-pinene secondary organic material.

Chem Sci 2015 Aug 4;6(8):4876-4883. Epub 2015 Jun 4.

School of Earth and Environment , University of Leeds , Leeds , LS2 9JT , UK . Email: ; Email: ; Tel: +44-(0)113-343-9085 ; Tel: +44(0)-0113-343-2887.

Secondary organic material (SOM) constitutes a large mass fraction of atmospheric aerosol particles. Understanding its impact on climate and air quality relies on accurate models of interactions with water vapour. Recent research shows that SOM can be highly viscous and can even behave mechanically like a solid, leading to suggestions that particles exist out of equilibrium with water vapour in the atmosphere. In order to quantify any kinetic limitation we need to know water diffusion coefficients for SOM, but this quantity has, until now, only been estimated and has not yet been measured. We have directly measured water diffusion coefficients in the water soluble fraction of α-pinene SOM between 240 and 280 K. Here we show that, although this material can behave mechanically like a solid, at 280 K water diffusion is not kinetically limited on timescales of 1 s for atmospheric-sized particles. However, diffusion slows as temperature decreases. We use our measured data to constrain a Vignes-type parameterisation, which we extend to lower temperatures to show that SOM can take hours to equilibrate with water vapour under very cold conditions. Our modelling for 100 nm particles predicts that under mid- to upper-tropospheric conditions radial inhomogeneities in water content produce a low viscosity surface region and more solid interior, with implications for heterogeneous chemistry and ice nucleation.
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http://dx.doi.org/10.1039/c5sc00685fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502394PMC
August 2015

Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation.

Int J Mol Sci 2015 Mar 27;16(4):7057-76. Epub 2015 Mar 27.

Department of Clinical Research, University of Bern, Bern 3010, Switzerland.

The endocannabinoid (EC) system is implicated in many chronic liver diseases, including hepatitis C viral (HCV) infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC), however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH) and monoaclyglycerol lipase (MAGL) activity was assessed by [3H]AEA and [3H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC), ECs inhibited IFN-γ, TNF-α, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC) co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects.
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http://dx.doi.org/10.3390/ijms16047057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425004PMC
March 2015

Similar cellular migration patterns from niches in intervertebral disc and in knee-joint regions detected by in situ labeling: an experimental study in the New Zealand white rabbit.

Stem Cell Res Ther 2013 ;4(5):104

Introduction: Potential stem cell niches (SNs) were recently reported in intervertebral discs (IVDs) and knee joints (KJs) in different mammals (located adjacent to the epiphyseal plate; EP). The aim here was to examine further possible cellular migration and migration directions of cells originating from niches possibly involved in regeneration of cartilaginous tissues in the IVD and in the KJ regions in adult mammals.

Methods: In total, 33 rabbits were used in studies A through C. A. IVD cells were sorted; fluorescence-activated cell sorting (FACS) by size (forward scatter; ≤ 10 μm or >10 μm or GDF5+ cells (anti-GDF5 antibody). Sorted cells, labeled with cell tracer (carboxyfluorescein-diacetate-succinimidyl ester; CDFA-SE) were applied on IVD explants in vitro. Migrating cells/distance was evaluated by fluorescence- and confocal-microscopy (FC). B. DNA labeling was performed with BrdU (oral administration). Animals were killed (14 to 56 days), KJs collected, and BrdU+ cells visualized with immunohistochemistry (IHC)/anti-BrdU antibody in SN and articular cartilage (AC). C. Cell tracer: (Fe-nanoparticles: Endorem) were injected into SNs of IVDs (LI-LV) and KJs (tibia). Animals were killed after 2 to 6 weeks. Fe-labeled cells were traced by ferric-iron staining (Prussian blue reaction; Mallory method).

Results: A. GDF5+ cells and ≤ 10-μm cells displayed the best migration capability in IVD explants. GDF5+ cells were detected at a tissue depth of 1,300 μm (16 days). B. BrdU+ cells were observed in early time points in niches of KJs, and at later time points in AC, indicating a gradual migration of cells. C. Fe+ cells were detected in IVDs; in annulus fibrosus (AF) in 11 of 12 animals and in nucleus pulposus (NP) in two of 12 animals. In AC (tibia), Fe+ cells were detected in six of 12 animals. In the potential migration route (PMR), from niches toward the IVD, Fe+ cells (three of 12 animals) and in PMR toward AC (KJs) (six of 12 animals) were detected.

Conclusions: Results indicate similar cellular migration patterns in cartilage regions (IVD and KJs) with migration from stem cell niche areas into the mature cartilaginous tissues of both the KJs and the IVD. These findings of a cellular migration pattern in mature cartilage are of interest from tissue-repair and engineering perspectives.
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http://dx.doi.org/10.1186/scrt315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854713PMC
September 2014

The temperature dependent structure of liquid 1-propanol as studied by neutron diffraction and EPSR simulations.

J Chem Phys 2013 Jun;138(21):214501

Applied Physics, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.

The structure of liquid 1-propanol is investigated as a function of temperature using neutron diffraction together with Empirical Potential Structure Refinement modelling. The combined diffraction and computer modelling analysis demonstrates that propanol molecules form hydrogen bonded clusters with a relatively wide size distribution, which broadens at lower temperatures. We find that the cluster size distribution is well described by a recently proposed statistical model for branched H-bonded networks [P. Sillrén, J. Bielecki, J. Mattsson, L. Börjesson, and A. Matic, J. Chem. Phys. 136, 094514 (2012)]. The average cluster size increases from ~3 to 7 molecules, whilst the standard deviation of the size distribution increases from 3.3 to 8.5 as the temperature is decreased from 293 to 155 K. The clusters are slightly branched, with a higher degree of branching towards lower temperatures. An analysis of the cluster gyration tensor (R(mn)) reveals an average elongated ellipsoidal shape with axes having proportions 1:1.4:1.9. We find that the average radius of gyration has a cluster size dependence consistent with that of fractal clusters, R(g) ∝ n(1/D), with a fractal dimension D ≈ 2.20, which is close to D = 2.00 expected for an ideal random walk or D = 2.11 expected for reaction limited aggregation. The characteristic angles between the H-bonded OH-groups that constitute the clusters show only a weak temperature dependence with O-H···O angles becoming more narrowly distributed around 180° at lower temperatures.
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http://dx.doi.org/10.1063/1.4807863DOI Listing
June 2013

A statistical model of hydrogen bond networks in liquid alcohols.

J Chem Phys 2012 Mar;136(9):094514

Applied Physics, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.

We here present a statistical model of hydrogen bond induced network structures in liquid alcohols. The model generalises the Andersson-Schulz-Flory chain model to allow also for branched structures. Two bonding probabilities are assigned to each hydroxyl group oxygen, where the first is the probability of a lone pair accepting an H-bond and the second is the probability that given this bond also the second lone pair is bonded. The average hydroxyl group cluster size, cluster size distribution, and the number of branches and leaves in the tree-like network clusters are directly determined from these probabilities. The applicability of the model is tested by comparison to cluster size distributions and bonding probabilities obtained from Monte Carlo simulations of the monoalcohols methanol, propanol, butanol, and propylene glycol monomethyl ether, the di-alcohol propylene glycol, and the tri-alcohol glycerol. We find that the tree model can reproduce the cluster size distributions and the bonding probabilities for both mono- and poly-alcohols, showing the branched nature of the OH-clusters in these liquids. Thus, this statistical model is a useful tool to better understand the structure of network forming hydrogen bonded liquids. The model can be applied to experimental data, allowing the topology of the clusters to be determined from such studies.
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http://dx.doi.org/10.1063/1.3690137DOI Listing
March 2012

Complement activation and complement receptors on follicular dendritic cells are critical for the function of a targeted adjuvant.

J Immunol 2011 Oct 31;187(7):3641-52. Epub 2011 Aug 31.

Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Center, Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden.

A detailed understanding of how activation of innate immunity can be exploited to generate more effective vaccines is critically required. However, little is known about how to target adjuvants to generate safer and better vaccines. In this study, we describe an adjuvant that, through complement activation and binding to follicular dendritic cells (FDC), dramatically enhances germinal center (GC) formation, which results in greatly augmented Ab responses. The nontoxic CTA1-DD adjuvant hosts the ADP-ribosylating CTA1 subunit from cholera toxin and a dimer of the D fragment from Staphylococcus aureus protein A. We found that T cell-dependent, but not -independent, responses were augmented by CTA1-DD. GC reactions and serum Ab titers were both enhanced in a dose-dependent manner. This effect required complement activation, a property of the DD moiety. Deposition of CTA1-DD to the FDC network appeared to occur via the conduit system and was dependent on complement receptors on the FDC. Hence, Cr2(-/-) mice failed to augment GC reactions and exhibited dramatically reduced Ab responses, whereas Ribi adjuvant demonstrated unperturbed adjuvant function in these mice. Noteworthy, the adjuvant effect on priming of specific CD4 T cells was found to be intact in Cr2(-/-) mice, demonstrating that the CTA1-DD host both complement-dependent and -independent adjuvant properties. This is the first demonstration, to our knowledge, of an adjuvant that directly activates complement, enabling binding of the adjuvant to the FDC, which subsequently strongly promoted the GC reaction, leading to augmented serum Ab titers and long-term memory development.
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http://dx.doi.org/10.4049/jimmunol.1101107DOI Listing
October 2011

Hydrogen bond induced nonmonotonic composition behavior of the glass transition in aqueous binary mixtures.

J Phys Chem B 2011 Aug 2;115(33):10013-7. Epub 2011 Aug 2.

Department of Applied Physics, Chalmers University of Technology, SE-412 96, Göteborg, Sweden.

The glass transition temperature, T(g), of a binary mixture commonly varies monotonically between the T(g)s of its two components. However, mixtures of strongly associating liquids can instead exhibit a nonmonotonic T(g) variation. The origins of such nonideal mixing behavior have often been correlated with composition dependent structural variations. For binary mixtures between a hydrogen- (H-) bonded liquid and water, however, such behavior is generally not well understood. The ubiquity and importance of aqueous mixtures both in nature and in man-made applications stresses the needed for a better understanding. We here demonstrate nonmonotonic T(g) variations in binary mixtures of n-propylene glycol monomethyl ethers (nPGMEs) and water, where the composition dependent T(g) show maxima within an intermediate composition range. We show that these T(g) maxima correspond to crossovers in the composition dependence of the step amplitude in the isobaric heat capacity at T(g). We further demonstrate that the observed effects are caused by H-bond interactions involving the nPGME hydroxyl group. We can account for our obervations using a simple model based on two effects due to the added water: (i) an H-bond induced formation of effective relaxing entities and (ii) a plasticizing effect at high water contents.
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http://dx.doi.org/10.1021/jp2024186DOI Listing
August 2011

Effects of water contamination on the supercooled dynamics of a hydrogen-bonded model glass former.

J Phys Chem B 2011 Mar 7;115(8):1842-7. Epub 2011 Feb 7.

Department of Applied Physics, Chalmers University of Technology, SE-41296 Göteborg, Sweden.

Broad-band dielectric spectroscopy is a commonly used tool in the study of glass-forming liquids. The high sensitivity of the technique together with the wide range of probed time scales makes it a powerful method for investigating the relaxation spectra of liquids. One particularly important class of glass-forming liquids that is often studied using this technique consists of liquids dominated by hydrogen (H) bond interactions. When investigating such liquids, particular caution has to be taken during sample preparation due to their often highly hygroscopic nature. Water can easily be absorbed from the atmosphere, and dielectric spectroscopy is a very sensitive probe of such contamination due to the large dipole moment of water. Our knowledge concerning the effects of small quantities of water on the dielectric properties of these commonly investigated liquids is limited. We here demonstrate the effects due to the presence of small amounts of water on the dielectric response of a typical H-bonded model glass former, tripropylene glycol. We show how the relaxation processes present in the pure liquid are affected by addition of water, and we find that a characteristic water induced relaxation response is observed for water contents as low as 0.15 wt%. We stress the importance of careful purification of hygroscopic liquids before experiments and quantify what the effects are if such procedures are not undertaken.
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http://dx.doi.org/10.1021/jp108070cDOI Listing
March 2011

A unique role of the cholera toxin A1-DD adjuvant for long-term plasma and memory B cell development.

J Immunol 2011 Feb 3;186(3):1399-410. Epub 2011 Jan 3.

Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD-adjuvanted responses were maintained for >16 mo with a half-life of anti-NP IgG ∼36 wk, but <15 wk after Ribi or Alum. A CTA1-DD dose-dependent increase in germinal center (GC) size and numbers was found, with >60% of splenic B cell follicles hosting GC at an optimal CTA1-DD dose. Roughly 7% of these GC were NP specific. This GC-promoting effect correlated well with the persistence of long-term plasma cells in the bone marrow and memory B cells in the spleen. CTA1-DD also facilitated increased somatic hypermutation and affinity maturation of NP-specific IgG Abs in a dose-dependent fashion, hence arguing that large GC not only promotes higher Ab titers but also high-quality Ab production. Adoptive transfer of splenic CD80(+), but not CD80(-), B cells, at 1 y after immunization demonstrated functional long-term anti-NP IgG and IgM memory cells. To our knowledge, this is the first report to specifically compare and document that adjuvants can differ considerably in their support of long-term immune responses. Differential effects on the GC reaction appear to be the basis for these differences.
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http://dx.doi.org/10.4049/jimmunol.1002881DOI Listing
February 2011

Drug delivery of lipophilic pyrenyl derivatives by encapsulation in a water soluble metalla-cage.

Dalton Trans 2010 Sep 5;39(35):8248-55. Epub 2010 Aug 5.

Institute of Chemistry, University of Neuchatel, 51 Ave de Bellevaux, CH-2000, Neuchatel, Switzerland.

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (p-Pr(i)C(6)H(4)Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) bridges, in the presence of a functionalised pyrenyl derivative (pyrene-R), affords the triangular prismatic host-guest compounds [(pyrene-R) [symbol: see text] Ru(6)(p-Pr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3)](6+) ([(pyrene-R) [symbol: see text] 1](6+)). The inclusion of eight mono-substituted pyrenyl derivatives including biologically relevant structures (a = 1-pyrenebutyric acid, b = 1-pyrenebutanol, c = 1-pyrenemethylamine, d = 1-pyrenemethylbutanoate, e = 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene, f = N-hexadecylpyrene-1-sulfonamide, g = pyrenyl ethacrynic amide and h = 2-(pyren-1-ylmethylcarbamoyl) phenyl acetate), and a di-substituted pyrenyl derivative (i = 1,8-bis(3-methyl-butyn-1-yl-3-ol)pyrene), has been accomplished. The carceplex nature of these systems with the pyrenyl moiety being firmly encapsulated in the hydrophobic cavity of the cage with the functional groups pointing outwards was confirmed by NMR ((1)H, 2D, DOSY) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 cancer cells. All the host-guest systems are more cytotoxic than the empty cage itself [1][CF(3)SO(3)](6) (IC(50) = 23 microM), the most active carceplex [f [symbol: see text] 1][CF(3)SO(3)](6) is an order of magnitude more cytotoxic.
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http://dx.doi.org/10.1039/c0dt00436gDOI Listing
September 2010

Mast cells contribute to the mucosal adjuvant effect of CTA1-DD after IgG-complex formation.

J Immunol 2010 Sep 30;185(5):2935-41. Epub 2010 Jul 30.

Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

Mast cell activation is one of the most dramatic immune-mediated responses the body can encounter. In the worst scenario (i.e., anaphylaxis), this response is fatal. However, the importance of mast cells as initiators and effectors of both innate and adaptive immunity in healthy individuals has recently been appreciated. It was reported that mast cell activation can be used as an adjuvant to promote Ag-specific humoral immune responses upon vaccination. In this study, we have used a clinically relevant mucosal adjuvant, cholera toxin A1 subunit (CTA1)-DD, which is a fusion protein composed of CTA1, the ADP-ribosylating part of cholera toxin, and DD, two Ig-binding domains derived from Staphylococcus aureus protein A. CTA1-DD in combination with polyclonal IgG induced degranulation and production of TNF-alpha from mouse mast cells. Furthermore, CTA1-DD and polyclonal IgG complex induced mast cell degranulation in mouse skin tissue and nasal mucosa. We also found that intranasal immunization with hapten (4-hydroxy-3-nitrophenyl) acetyl (NP) coupled to chicken gammaglobulin admixed with CTA1-DD complexed with polyclonal IgG greatly enhanced serum IgG anti-NP Ab responses and stimulated higher numbers of NP-specific plasma cells in the bone marrow as compared with that observed in mice immunized with NP-chicken gammaglobulin with CTA1-DD alone. This CTA1-DD/IgG complex-mediated enhancement was mast cell dependent because it was absent in mast cell-deficient Kit(W-sh/W-sh) mice. In conclusion, our data suggest that a clinically relevant adjuvant, CTA1-DD, exerts additional augmenting effects through activation of mucosal mast cells, clearly demonstrating that mast cells could be further exploited for improving the efficacy of mucosal vaccines.
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http://dx.doi.org/10.4049/jimmunol.1000589DOI Listing
September 2010

Dielectric secondary relaxation of water in aqueous binary glass-formers.

Phys Chem Chem Phys 2010 Sep 3;12(35):10452-6. Epub 2010 Jul 3.

Department of Applied Physics, Chalmers University of Technology, SE-41296 Göteborg, Sweden.

Glassy aqueous binary mixtures generally exhibit a water induced dielectric relaxation. The characteristic time-scale of this relaxation follows an Arrhenius temperature dependence with a nearly universal activation energy. We here demonstrate for a series of model aqueous mixtures that the relaxation time also follows a remarkably general exponential dependence on the weight fraction of water. By comparison to literature data we show that this behaviour is shared by a wide range of molecular systems. Neither the detailed nature of the water molecules' glassy environment nor the details of the route of formation of the glassy state has a significant effect on the observed behaviour.
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http://dx.doi.org/10.1039/c001275kDOI Listing
September 2010
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