39 research outputs found
Human Integrin α3ÎČ1 Regulates TLR2 Recognition of Lipopeptides from Endosomal Compartments
Toll-like receptor (TLR)-2/TLR1 heterodimers recognize bacterial lipopeptides and initiate the production of inflammatory mediators. Adaptors and co-receptors that mediate this process, as well as the mechanisms by which these adaptors and co-receptors function, are still being discovered.Using shRNA, blocking antibodies, and fluorescent microscopy, we show that U937 macrophage responses to the TLR2/1 ligand, Pam(3)CSK(4), are dependent upon an integrin, α(3)ÎČ(1). The mechanism for integrin α(3)ÎČ(1) involvement in TLR2/1 signaling is through its role in endocytosis of lipopeptides. Using inhibitors of endosomal acidification/maturation and physical tethering of the ligand, we show that the endocytosis of Pam(3)CSK(4) is necessary for the complete TLR2/1-mediated pro-inflammatory cytokine response. We also show that TLR2/1 signaling from the endosome results in the induction of different inflammatory mediators than TLR2/1 signaling from the plasma membrane.Here we identify integrin α(3)ÎČ(1) as a novel regulator for the recognition of bacterial lipopeptides. We demonstrate that induction of a specific subset of cytokines is dependent upon integrin α(3)ÎČ(1)-mediated endocytosis of the ligand. In addition, we address an ongoing controversy regarding endosomal recognition of bacterial lipopeptides by demonstrating that TLR2/1 signals from within endosomal compartments as well as the plasma membrane, and that downstream responses may differ depending upon receptor localization. We propose that the regulation of endosomal TLR2/1 signaling by integrin α(3)ÎČ(1) serves as a mechanism for modulating inflammatory responses
Spontaneous Reaction Silencing in Metabolic Optimization
Metabolic reactions of single-cell organisms are routinely observed to become
dispensable or even incapable of carrying activity under certain circumstances.
Yet, the mechanisms as well as the range of conditions and phenotypes
associated with this behavior remain very poorly understood. Here we predict
computationally and analytically that any organism evolving to maximize growth
rate, ATP production, or any other linear function of metabolic fluxes tends to
significantly reduce the number of active metabolic reactions compared to
typical non-optimal states. The reduced number appears to be constant across
the microbial species studied and just slightly larger than the minimum number
required for the organism to grow at all. We show that this massive spontaneous
reaction silencing is triggered by the irreversibility of a large fraction of
the metabolic reactions and propagates through the network as a cascade of
inactivity. Our results help explain existing experimental data on
intracellular flux measurements and the usage of latent pathways, shedding new
light on microbial evolution, robustness, and versatility for the execution of
specific biochemical tasks. In particular, the identification of optimal
reaction activity provides rigorous ground for an intriguing knockout-based
method recently proposed for the synthetic recovery of metabolic function.Comment: 34 pages, 6 figure
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The transiting exoplanet community early release science program for JWST
The transiting exoplanet community early release science program for JWST
The James Webb Space Telescope (JWST) presents the opportunity to transform
our understanding of planets and the origins of life by revealing the
atmospheric compositions, structures, and dynamics of transiting exoplanets in
unprecedented detail. However, the high-precision, time-series observations
required for such investigations have unique technical challenges, and prior
experience with other facilities indicates that there will be a steep learning
curve when JWST becomes operational. In this paper we describe the science
objectives and detailed plans of the Transiting Exoplanet Community Early
Release Science (ERS) Program, which is a recently approved program for JWST
observations early in Cycle 1. The goal of this project, for which the obtained
data will have no exclusive access period, is to accelerate the acquisition and
diffusion of technical expertise for transiting exoplanet observations with
JWST, while also providing a compelling set of representative datasets that
will enable immediate scientific breakthroughs. The Transiting Exoplanet
Community ERS Program will exercise the time-series modes of all four JWST
instruments that have been identified as the consensus highest priorities,
observe the full suite of transiting planet characterization geometries
(transits, eclipses, and phase curves), and target planets with host stars that
span an illustrative range of brightnesses. The observations in this program
were defined through an inclusive and transparent process that had
participation from JWST instrument experts and international leaders in
transiting exoplanet studies. Community engagement in the project will be
centered on a two-phase Data Challenge that culminates with the delivery of
planetary spectra, time-series instrument performance reports, and open-source
data analysis toolkits in time to inform the agenda for Cycle 2 of the JWST
mission