Biochemical Underpinnings of Immune Cell Metabolic Phenotypes

The metabolism of immune cells affects their function and influences host immunity. This review explores how immune cell metabolic phenotypes reflect biochemical dependencies and highlights evidence that both the metabolic state of immune cells and nutrient availability can alter immune responses. The central importance of oxygen, energetics, and redox homeostasis in immune cell metabolism, and how these factors are reflected in different metabolic phenotypes, is also discussed. Linking immune cell metabolic phenotype to effector functions is important to understand how altering metabolism can impact the way in which immune cells meet their metabolic demands and affect the immune response in various disease contexts.National Institutes of Health (U.S.) (Grant R01CA168653)National Institutes of Health (U.S.) (Grant R01CA201276

Emerging concepts: linking hypoxic signaling and cancer metabolism

The Joint Keystone Symposia on Cancer and Metabolism and Advances in Hypoxic Signaling: From Bench to Bedside were held in Banff, Alberta, Canada from 12 to 17 February 2012. Drs. Reuben Shaw and David Sabatini organized the Cancer and Metabolism section, and Drs. Volker Haase, Cormac Taylor, Johanna Myllyharju and Paul Schumacker organized the Advances in Hypoxic Signaling section. Accumulating data illustrate that both hypoxia and rewired metabolism influence cancer biology. Indeed, these phenomena are tightly coupled, and a joint meeting was held to foster interdisciplinary interactions and enhance our understanding of these two processes in neoplastic disease. In this report, we highlight the major themes of the conference paying particular attention to areas of intersection between hypoxia and metabolism in cancer. One opening keynote address was delivered by Craig Thompson (Memorial Sloan-Kettering, USA), in which he provided a comprehensive perspective on the current thinking around how altered metabolism supports cancer cell growth and survival, and discussed areas likely to be important for future discovery. In particular, Thompson highlighted the essential roles of glucose and glutamine in cell growth, how glucose- and glutamine-consuming processes are rewired in cancer and how this rewiring facilitates anabolic metabolism. These topics were at the core of many of the metabolism presentations that described in detail how some metabolic alterations contribute to the properties of transformed cells. The other keynote address was delivered by Peter Ratcliffe (University of Oxford, UK), in which he provided a historical perspective on the progress of how signaling events sense oxygen. Mammals have evolved multiple acute and long-term adaptive responses to low oxygen levels (hypoxia). This response prevents a disparity in ATP utilization and produc- tion that would otherwise result in a bioenergetic collapse when oxygen level is low. Multiple effectors have been proposed to mediate the response to hypoxia including prolyl hydroxylases, AMPK, NADPH oxidases and the mitochondrial complex III. Currently, however, the precise mechanism by which oxygen is sensed in various physiological contexts remains unknown. Indeed, this was an active point of debate, with Peter Ratcliffe favoring the prolyl hydroxylase PHD2 as the primary cellular oxygen sensor.Burrough’s Wellcome FundDamon Runyon Cancer Research FoundationLustgarten FoundationSmith family and the Stern famil

Vortex microavalanches in superconducting Pb thin films

Local magnetization measurements on 100 nm type-II superconducting Pb thin films show that flux penetration changes qualitatively with temperature. Small flux jumps at the lowest temperatures gradually increase in size, then disappear near T = 0.7Tc. Comparison with other experiments suggests that the avalanches correspond to dendritic flux protrusions. Reproducibility of the first flux jumps in a decreasing magnetic field indicates a role for defect structure in determining avalanches. We also find a temperature-independent final magnetization after flux jumps, analogous to the angle of repose of a sandpile.Comment: 6 pages, 5 figure

Winner-take-all selection in a neural system with delayed feedback

We consider the effects of temporal delay in a neural feedback system with excitation and inhibition. The topology of our model system reflects the anatomy of the avian isthmic circuitry, a feedback structure found in all classes of vertebrates. We show that the system is capable of performing a `winner-take-all' selection rule for certain combinations of excitatory and inhibitory feedback. In particular, we show that when the time delays are sufficiently large a system with local inhibition and global excitation can function as a `winner-take-all' network and exhibit oscillatory dynamics. We demonstrate how the origin of the oscillations can be attributed to the finite delays through a linear stability analysis.Comment: 8 pages, 6 figure

Spatio-temporal patterns in coral reef communities of the Spermonde Archipelago, 2012-2014, I: Comprehensive reef monitoring of water and benthic indicators reflect changes in reef health

Pollution, fishing, and outbreaks of predators can heavily impact coastal coral reef ecosystems, leading to decreased water quality and benthic community shifts. To determine the main environmental drivers of coral reef status in the Spermonde Archipelago, Indonesia, we monitored environmental variables and coral reef benthic community structure along an on-to-offshore gradient annually from 2012 to 2014. Findings revealed that concentrations of phosphate, chlorophyll a-like fluorescence, suspended particulate matter, and light attenuation significantly decreased from on-to-offshore, while concentrations of dissolved O2 and values of water pH significantly increased on-to-offshore. Nitrogen stable isotope signatures of sediment and an exemplary common brown alga were significantly enriched nearshore, identifying wastewater input from the city of Makassar as primary N source. In contrast to the high temporal variability in water quality, coral reef benthic community cover did not show strong temporal, but rather, spatial patterns. Turf algae was the dominant group next to live coral, and was negatively correlated to live coral, crustose coralline algae (CCA), rubble and hard substrate. Variation in benthic cover along the gradient was explained by water quality variables linked to trophic status and physico-chemical variables. As an integrated measure of reef status and structural complexity, the benthic index, based on the ratio of relative cover of live coral and CCA to other coral reef organisms, and reef rugosity were determined. The benthic index was consistently low nearshore and increased offshore, with high variability in the midshelf sites across years. Reef rugosity was also lowest nearshore and increased further offshore. Both indices dropped in 2013, increasing again in 2014, indicating a period of acute disturbance and recovery within the study and suggesting that the mid-shelf reefs are more resilient to disturbance than nearshore reefs. We thus recommend using these two indices with a selected number of environmental variables as an integral part of future reef monitoring

Models of Somatic Hypermutation Targeting and Substitution Based on Synonymous Mutations from High-Throughput Immunoglobulin Sequencing Data

Analyses of somatic hypermutation (SHM) patterns in B cell immunoglobulin (Ig) sequences contribute to our basic understanding of adaptive immunity, and have broad applications not only for understanding the immune response to pathogens, but also to determining the role of SHM in autoimmunity and B cell cancers. Although stochastic, SHM displays intrinsic biases that can confound statistical analysis, especially when combined with the particular codon usage and base composition in Ig sequences. Analysis of B cell clonal expansion, diversification, and selection processes thus critically depends on an accurate background model for SHM micro-sequence targeting (i.e., hot/cold-spots) and nucleotide substitution. Existing models are based on small numbers of sequences/mutations, in part because they depend on data from non-coding regions or non-functional sequences to remove the confounding influences of selection. Here, we combine high-throughput Ig sequencing with new computational analysis methods to produce improved models of SHM targeting and substitution that are based only on synonymous mutations, and are thus independent of selection. The resulting “S5F” models are based on 806,860 Synonymous mutations in 5-mer motifs from 1,145,182 Functional sequences and account for dependencies on the adjacent four nucleotides (two bases upstream and downstream of the mutation). The estimated profiles can explain almost half of the variance in observed mutation patterns, and clearly show that both mutation targeting and substitution are significantly influenced by neighboring bases. While mutability and substitution profiles were highly conserved across individuals, the variability across motifs was found to be much larger than previously estimated. The model and method source code are made available at http://clip.med.yale.edu/SH