Dendritic cell metabolism

The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism

Finite-temperature ordering in a two-dimensional highly frustrated spin model

We investigate the classical counterpart of an effective Hamiltonian for a strongly trimerized kagome lattice. Although the Hamiltonian only has a discrete symmetry, the classical groundstate manifold has a continuous global rotational symmetry. Two cases should be distinguished for the sign of the exchange constant. In one case, the groundstate has a 120^\circ spin structure. To determine the transition temperature, we perform Monte-Carlo simulations and measure specific heat, the order parameter as well as the associated Binder cumulant. In the other case, the classical groundstates are macroscopically degenerate. A thermal order-by-disorder mechanism is predicted to select another 120^\circ spin-structure. A finite but very small transition temperature is detected by Monte-Carlo simulations using the exchange method.Comment: 11 pages including 9 figures, uses IOP style files; to appear in J. Phys.: Condensed Matter (proceedings of HFM2006

The Heisenberg antiferromagnet on a triangular lattice: topological excitations

We study the topological defects in the classical Heisenberg antiferromagnet in two dimensions on a triangular lattice (HAFT). While the topological analysis of the order parameter space indicates that the defects are of $Z_2$ type, consideration of the energy leads us to a description of the low--energy stationary points of the action in terms of $\pm$ vortices, as in the planar XY model. Starting with the continuum description of the HAFT, we show analytically that its partition function can be reduced to that of a 2--dimensional Coulomb gas with logarithmic interaction. Thus, at low temperatures, the correlation length is determined by the spinwaves, while at higher temperatures we expect a crossover to a Kosterlitz--Thouless type behaviour. The results of recent Monte Carlo calculations of the correlation length are consistent with such a crossover.Comment: 9 pages, revtex, preprint: ITP-UH 03/9

Colloid-oil-water-interface interactions in the presence of multiple salts: charge regulation and dynamics

We theoretically and experimentally investigate colloid-oil-water-interface interactions of charged, sterically stabilized, poly(methyl-methacrylate) colloidal particles dispersed in a low-polar oil (dielectric constant $\epsilon=5-10$) that is in contact with an adjacent water phase. In this model system, the colloidal particles cannot penetrate the oil-water interface due to repulsive van der Waals forces with the interface whereas the multiple salts that are dissolved in the oil are free to partition into the water phase. The sign and magnitude of the Donnan potential and/or the particle charge is affected by these salt concentrations such that the effective interaction potential can be highly tuned. Both the equilibrium effective colloid-interface interactions and the ion dynamics are explored within a Poisson-Nernst-Planck theory, and compared to experimental observations.Comment: 13+2 pages, 5+3 figures; V2: small clarifications in the tex

Functional annotation of novel lineage-specific genes using co-expression and promoter analysis

<p>Abstract</p> <p>Background</p> <p>The diversity of placental architectures within and among mammalian orders is believed to be the result of adaptive evolution. Although, the genetic basis for these differences is unknown, some may arise from rapidly diverging and lineage-specific genes. Previously, we identified 91 novel lineage-specific transcripts (LSTs) from a cow term-placenta cDNA library, which are excellent candidates for adaptive placental functions acquired by the ruminant lineage. The aim of the present study was to infer functions of previously uncharacterized lineage-specific genes (LSGs) using co-expression, promoter, pathway and network analysis.</p> <p>Results</p> <p>Clusters of co-expressed genes preferentially expressed in liver, placenta and thymus were found using 49 previously uncharacterized LSTs as seeds. Over-represented composite transcription factor binding sites (TFBS) in promoters of clustered LSGs and known genes were then identified computationally. Functions were inferred for nine previously uncharacterized LSGs using co-expression analysis and pathway analysis tools. Our results predict that these LSGs may function in cell signaling, glycerophospholipid/fatty acid metabolism, protein trafficking, regulatory processes in the nucleus, and processes that initiate parturition and immune system development.</p> <p>Conclusions</p> <p>The placenta is a rich source of lineage-specific genes that function in the adaptive evolution of placental architecture and functions. We have shown that co-expression, promoter, and gene network analyses are useful methods to infer functions of LSGs with heretofore unknown functions. Our results indicate that many LSGs are involved in cellular recognition and developmental processes. Furthermore, they provide guidance for experimental approaches to validate the functions of LSGs and to study their evolution.</p

Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte–derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte–derived DCs

Mitochondrial respiratory capacity is a critical regulator of CD8⁺ T cell memory development

CD8+ T cells undergo major metabolic changes upon activation, but how metabolism influences the establishment of long-lived memory T cells after infection remains a key question. We have shown here that CD8+ memory T cells, but not CD8+ T effector (Teff) cells, possessed substantial mitochondrial spare respiratory capacity (SRC). SRC is the extra capacity available in cells to produce energy in response to increased stress or work and as such is associated with cellular survival. We found that interleukin-15 (IL-15), a cytokine critical for CD8+ memory T cells, regulated SRC and oxidative metabolism by promoting mitochondrial biogenesis and expression of carnitine palmitoyl transferase (CPT1a), a metabolic enzyme that controls the rate-limiting step to mitochondrial fatty acid oxidation (FAO). These results show how cytokines control the bioenergetic stability of memory T cells after infection by regulating mitochondrial metabolism

Neural correlates of working memory and its association with metabolic parameters in early-treated adults with phenylketonuria.

BACKGROUND Phenylketonuria (PKU) is an inborn error of metabolism affecting the conversion of phenylalanine (Phe) into tyrosine. Previous research has found cognitive and functional brain alterations in individuals with PKU even if treated early. However, little is known about working memory processing and its association with task performance and metabolic parameters. The aim of the present study was to examine neural correlates of working memory and its association with metabolic parameters in early-treated adults with PKU. METHODS This cross-sectional study included 20 early-treated adults with PKU (mean age: 31.4 years ± 9.0) and 40 healthy controls with comparable age, sex, and education (mean age: 29.8 years ± 8.2). All participants underwent functional magnetic resonance imaging (fMRI) of working memory to evaluate the fronto-parietal working memory network. Fasting blood samples were collected from the individuals with PKU to acquire a concurrent plasma amino acid profile, and retrospective Phe concentrations were obtained to estimate an index of dietary control. RESULTS On a cognitive level, early-treated adults with PKU displayed significantly lower accuracy but comparable reaction time in the working memory task compared to the control group. Whole-brain analyses did not reveal differences in working memory-related neural activation between the groups. Exploratory region-of-interest (ROI) analyses indicated reduced neural activation in the left and right middle frontal gyri and the right superior frontal gyrus in the PKU group compared to the control group. However, none of the ROI analyses survived correction for multiple comparisons. Neural activation was related to concurrent Phe, tyrosine, and tryptophan concentrations but not to retrospective Phe concentrations. CONCLUSION In early-treated adults with PKU, cognitive performance and neural activation are slightly altered, a result that is partly related to metabolic parameters. This study offers a rare insight into the complex interplay between metabolic parameters, neural activation, and cognitive performance in a sample of individuals with PKU