Differential induction of inflammatory cytokines by dendritic cells treated with novel TLR-agonist and cytokine based cocktails: targeting dendritic cells in autoimmunity

<p>Abstract</p> <p>Background</p> <p>Dendritic cells (DC) are main gate-keepers of the immune system, bridging the innate and adaptive immune system. DCs are able to mature into inflammatory DCs at sites of inflammation in both autoimmune and allergic disease, thereby sustaining a continuous activation of the adaptive immune system at sites of inflammation. This function of DCs makes them attractive target cells for therapeutic intervention in inflammatory diseases. We have designed a DC-based screening model by which drug candidates can be evaluated for their ability to suppress DC maturation into an inflammatory and disease promoting phenotype.</p> <p>Methods</p> <p>Human monocyte derived DCs were differentiated using IL-4 and GM-CSF to immature DCs (imDCs). The imDCs were treated with various combinations of TLR-agonists and pro-inflammatory cytokines to identify cocktails with ability to mature imDCs into inflammatory DCs. The effect of the cocktails on DC maturation was evaluated using ELISA and cytokine arrays to measure secreted cytokines and chemokines. FACS analysis was used to assess expression of maturation markers, and functional studies were carried out using naïve allogeneic T-cells to assay for a Th1-promoting DC phenotype.</p> <p>Results</p> <p>Nine cocktails were designed with potent ability to induce secretion of the Th1-promoting cytokines IL-12p70 and TNFα from imDCs, and three were able to induce the Th17-promoting cytokine IL-23. The cocktails were further characterized using cytokine arrays, showing induction of inflammation related cytokines and chemokines like CXCL10, CCL2, CCL4, CCL8, CCL15, CCL20 and IL-8, of which some are present in a range of autoimmune pathologies. Prostaglandin E2 secretion was identified from DCs treated with TLR agonists poly I:C and peptidoglycan, but not LPS. The cocktails were able to induce DC maturation markers like HLA-DR, CD40, CD80, CD83 and CD86, except the TLR7/8 agonist R848. Functional end-points made by co-culture of allogeneic CD4⁺T cells with the cocktail treated DCs, showed that five cocktails in particular could induce a classical Th1-phenotype with ability to secrete high amounts of the hall-mark cytokine IFNγ. The model was validated using dexamethasone and two COX-inhibitors, which were able to suppress the cocktail driven pro-inflammatory DC maturation.</p> <p>Conclusions</p> <p>The identification of novel Th1-promoting cocktails allows screening of anti-inflammatory drug candidates by assessing the ability to suppress the activation and differentiation of imDCs into inflammatory DCs with a specific Th1-promoting phenotype. The model thus provides a screening tool, which can identify potential anti-inflammatory effects on the natural regulator of the immune response, the dendritic cell.</p

Tosio Kato (1917–1999)

Tosio Kato was born August 25, 1917, in Kanuma City, Tochigi-ken, Japan. His early training was in physics. He obtained a B.S. in 1941 and the degree of Doctor of Science in 1951, both at the University of Tokyo. Between these events he published papers on a variety of subjects, including pair creation by gamma rays, motion of an object in a fluid, and results on spectral theory of operators arising in quantum mechanics. His dissertation was entitled “On the convergence of the perturbation method”. Kato was appointed assistant professor of physics at the University of Tokyo in 1951 and was promoted to professor of physics in 1958. During this time he visited the University of California at Berkeley in 1954–55, New York University in 1955, the National Bureau of Standards in 1955–56, and Berkeley and the California Institute of Technology in 1957–58. He was appointed professor of mathematics at Berkeley in 1962 and taught there until his retirement in 1988. He supervised twenty-one Ph.D. students at Berkeley and three at the University of Tokyo. Kato published over 160 papers and 6 monographs, including his famous book Perturbation Theory for Linear Operators [K66b]. Recognition for his important work included the Norbert Wiener Prize in Applied Mathematics, awarded in 1980 by the AMS and the Society for Industrial and Applied Mathematics. He was particularly well known for his work on Schrödinger equations of nonrelativistic quantum mechanics and his work on the Navier-Stokes and Euler equations of classical fluid mechanics. His activity in the latter area remained at a high level well past retirement and continued until his death on October 2, 1999

Weakly bound states of polar molecules in bilayers

We investigate a system of two polarized molecules in a layered trap. The molecules reside in adjacent layers and interact purely via the dipole-dipole interaction. We determine the properties of the ground state of the system as a function of the dipole moment and polarization angle. A bound state is always present in the system and in the weak binding limit the bound state extends to a very large distance and shows universal behavior.Comment: Presented at the 21st European Conference on Few-Body Problems in Physics, Salamanca, Spain, 30 August - 3 September 201

The resection angle in apical surgery: a CBCT assessment.

OBJECTIVES The primary objective of the present radiographic study was to analyse the resection angle in apical surgery and its correlation with treatment outcome, type of treated tooth, surgical depth and level of root-end filling. MATERIALS AND METHODS In the context of a prospective clinical study, cone beam computed tomography (CBCT) scans were taken before and 1 year after apical surgery to measure the angle of the resection plane relative to the longitudinal axis of the root. Further, the surgical depth (distance from the buccal cortex to the most lingual/palatal point of the resection plane) as well as the level of the root-end filling relative to the most coronal point of the cut root face was determined. Treated teeth were categorized into four groups (maxillary and mandibular anterior and posterior teeth). The final material comprised 62 treated roots in 55 teeth. RESULTS The mean calculated resection angle of all roots was 17.7° ± 11.4° (range -9.6° to 43.4°). Anterior maxillary roots presented the highest mean angle (25.8° ± 10.3°) that was significantly different from the mean angle in posterior maxillary roots (10.7° ± 9.4°; p 20°), however without reaching statistical significance (p = 0.0905). Angles did not correlate either with the surgical depth or with the retrofilling length. CONCLUSIONS Statistically significant differences were observed comparing resection angles of different tooth groups. However, the angle had no significant effect on treatment outcome. CLINICAL RELEVANCE Contrary to common belief, the resection angle in maxillary anterior teeth was greater than in the other teeth. The surgeon is advised to pay attention to the resection angle when bevelling maxillary anterior teeth in apical surgery

Some improvements in the method of the weakly conjugate operator

We present some improvements in the method of the weakly conjugate operator, one variant of the Mourre theory. When applied to certain two-body Schroedinger operators, this leads to a limiting absorption principle that is uniform on the positive real axis.Comment: 11 page

Lattice dynamics reveals a local symmetry breaking in the emergent dipole phase of PbTe

Local symmetry breaking in complex materials is emerging as an important contributor to materials properties but is inherently difficult to study. Here we follow up an earlier structural observation of such a local symmetry broken phase in the technologically important compound PbTe with a study of the lattice dynamics using inelastic neutron scattering (INS). We show that the lattice dynamics are responsive to the local symmetry broken phase, giving key insights in the behavior of PbTe, but also revealing INS as a powerful tool for studying local structure. The new result is the observation of the unexpected appearance on warming of a new zone center phonon branch in PbTe. In a harmonic solid the number of phonon branches is strictly determined by the contents and symmetry of the unit cell. The appearance of the new mode indicates a crossover to a dynamic lower symmetry structure with increasing temperature. No structural transition is seen crystallographically but the appearance of the new mode in inelastic neutron scattering coincides with the observation of local Pb off-centering dipoles observed in the local structure. The observation resembles relaxor ferroelectricity but since there are no inhomogeneous dopants in pure PbTe this anomalous behavior is an intrinsic response of the system. We call such an appearance of dipoles out of a non-dipolar ground-state "emphanisis" meaning the appearance out of nothing. It cannot be explained within the framework of conventional phase transition theories such as soft-mode theory and challenges our basic understanding of the physics of materials

Mycoplasma genitalium: whole genome sequence analysis, recombination and population structure.

BACKGROUND: Although Mycoplasma genitalium is a common sexually transmitted pathogen causing clinically distinct diseases both in male and females, few genomes have been sequenced up to now, due mainly to its fastidious nature and slow growth. Hence, we lack a robust phylogenetic framework to provide insights into the population structure of the species. Currently our understanding of the nature and diversity of M. genitalium relies on molecular tests targeting specific genes or regions of the genome and knowledge is limited by a general under-testing internationally. This is set against a background of drug resistance whereby M. genitalium has developed resistance to mainly all therapeutic antimicrobials. RESULTS: We sequenced 28 genomes of Mycoplasma genitalium from temporally (1980-2010) and geographically (Europe, Japan, Australia) diverse sources. All the strain showed essentially the same genomic content without any accessory regions found. However, we identified extensive recombination across their genomes with a total of 25 regions showing heightened levels of SNP density. These regions include the MgPar loci, associated with host interactions, as well as other genes that could also be involved in this role. Using these data, we generated a robust phylogeny which shows that there are two main clades with differing degrees of genomic variability. SNPs found in region V of 23S rRNA and parC were consistent with azithromycin/erythromycin and fluoroquinolone resistances, respectively, and with their phenotypic MIC data. CONCLUSIONS: The sequence data here generated is essential for designing rational approaches to type and track Mycoplasma genitalium as antibiotic resistance increases. It represents a first approach to its population genetics to better appreciate the role of this organism as a sexually transmitted pathogen