Serum metabolomic signatures of fatty acid oxidation defects differentiate host-response subphenotypes of acute respiratory distress syndrome

BACKGROUND: Fatty acid oxidation (FAO) defects have been implicated in experimental models of acute lung injury and associated with poor outcomes in critical illness. In this study, we examined acylcarnitine profiles and 3-methylhistidine as markers of FAO defects and skeletal muscle catabolism, respectively, in patients with acute respiratory failure. We determined whether these metabolites were associated with host-response ARDS subphenotypes, inflammatory biomarkers, and clinical outcomes in acute respiratory failure. METHODS: In a nested case-control cohort study, we performed targeted analysis of serum metabolites of patients intubated for airway protection (airway controls), Class 1 (hypoinflammatory), and Class 2 (hyperinflammatory) ARDS patients (N = 50 per group) during early initiation of mechanical ventilation. Relative amounts were quantified by liquid chromatography high resolution mass spectrometry using isotope-labeled standards and analyzed with plasma biomarkers and clinical data. RESULTS: Of the acylcarnitines analyzed, octanoylcarnitine levels were twofold increased in Class 2 ARDS relative to Class 1 ARDS or airway controls (P = 0.0004 and \u3c 0.0001, respectively) and was positively associated with Class 2 by quantile g-computation analysis (P = 0.004). In addition, acetylcarnitine and 3-methylhistidine were increased in Class 2 relative to Class 1 and positively correlated with inflammatory biomarkers. In all patients within the study with acute respiratory failure, increased 3-methylhistidine was observed in non-survivors at 30 days (P = 0.0018), while octanoylcarnitine was increased in patients requiring vasopressor support but not in non-survivors (P = 0.0001 and P = 0.28, respectively). CONCLUSIONS: This study demonstrates that increased levels of acetylcarnitine, octanoylcarnitine, and 3-methylhistidine distinguish Class 2 from Class 1 ARDS patients and airway controls. Octanoylcarnitine and 3-methylhistidine were associated with poor outcomes in patients with acute respiratory failure across the cohort independent of etiology or host-response subphenotype. These findings suggest a role for serum metabolites as biomarkers in ARDS and poor outcomes in critically ill patients early in the clinical course

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

SummaryRIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective “hybrid” RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies

Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.

BackgroundGeneral translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.ResultsHere, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.ConclusionsOur work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell

Conflict and Astroturfing in Niyamgiri: The Importance of National Advocacy Networks in Anti-Corporate Social Movements

Traditional models of transnational advocacy networks (TANs) and stakeholder management do not capture the nuance and dynamics of (counter-)organising processes around anti-corporate mobilisation. Based on the case of a resistance movement against a planned bauxite mine on tribal land in India, we develop a process theory of interactions between local, national and international actors within transnational advocacy networks. These encounters are not always friendly and are often characterised by conflict between actors with disparate goals and interests. We highlight the importance of national advocacy networks (NANs) in anti-corporate social movements and describe the conflicts and disruptions that result from ignoring them. Our findings also point to the role of corporate counter-mobilisation strategies in shaping resistance movements. Our narrative revolves around a particular focal actor in the anti-mining campaign: a young tribal man who emerged as a passionate spokesperson of the movement, but later became a supporter of the controversial mine. Our findings contribute to a richer understanding of the processes underlying transnational and national anti-corporate mobilisation

Mobilizing Against GM Crops in India, South Africa and Brazil

This paper explores the national and transnational character of mobilization against GM crops in India, South Africa and Brazil in the ten-year period to 2005. By examining the contexts and practices of mobilization across the three countries, and in particular the complex, often fraught, local and global connections, the paper examines the diverse mobilizations that have occurred. The paper argues that to understand these processes, particular national political and economic contexts must be appreciated, alongside how the GM debates articulate with other foci for activism and the complex and often fragile nature of alliances that make up activist networks. The paper shows how the debate about GM crops has become a much wider one: about the future of agriculture and small-scale farmers, about corporate control and property rights and about the rules of global trade. In sum, a debate not just about the pros and cons of a particular set of technologies, but about politics and values and the future of agrarian society.ESR

Isolation of Flow and Nonflow Correlations by Two- and Four-Particle Cumulant Measurements of Azimuthal Harmonics in sNN=\sqrt{s_{_{\rm NN}}} = 200 GeV Au+Au Collisions

A data-driven method was applied to measurements of Au+Au collisions at $\sqrt{s_{_{\rm NN}}} =$ 200 GeV made with the STAR detector at RHIC to isolate pseudorapidity distance $\Delta\eta$-dependent and $\Delta\eta$-independent correlations by using two- and four-particle azimuthal cumulant measurements. We identified a component of the correlation that is $\Delta\eta$-independent, which is likely dominated by anisotropic flow and flow fluctuations. It was also found to be independent of $\eta$ within the measured range of pseudorapidity $|\eta|<1$. The relative flow fluctuation was found to be $34\% \pm 2\% (stat.) \pm 3\% (sys.)$ for particles of transverse momentum $p_{T}$ less than $2$ GeV/$c$. The $\Delta\eta$-dependent part may be attributed to nonflow correlations, and is found to be $5\% \pm 2\% (sys.)$ relative to the flow of the measured second harmonic cumulant at $|\Delta\eta| > 0.7$

Beam energy dependent two-pion interferometry and the freeze-out eccentricity of pions in heavy ion collisions at STAR

We present results of analyses of two-pion interferometry in Au+Au collisions at $\sqrt{s_{NN}}$ = 7.7, 11.5, 19.6, 27, 39, 62.4 and 200 GeV measured in the STAR detector as part of the RHIC Beam Energy Scan program. The extracted correlation lengths (HBT radii) are studied as a function of beam energy, azimuthal angle relative to the reaction plane, centrality, and transverse mass ($m_{T}$) of the particles. The azimuthal analysis allows extraction of the eccentricity of the entire fireball at kinetic freeze-out. The energy dependence of this observable is expected to be sensitive to changes in the equation of state. A new global fit method is studied as an alternate method to directly measure the parameters in the azimuthal analysis. The eccentricity shows a monotonic decrease with beam energy that is qualitatively consistent with the trend from all model predictions and quantitatively consistent with a hadronic transport model.Comment: 27 pages; 27 figure

Measurements of D0D^{0} and D∗D^{*} Production in pp + pp Collisions at s\sqrt{s} = 200 GeV

We report measurements of charmed-hadron ($D^{0}$, $D^{*}$) production cross sections at mid-rapidity in $p$ + $p$ collisions at a center-of-mass energy of 200 GeV by the STAR experiment. Charmed hadrons were reconstructed via the hadronic decays $D^{0}\rightarrow K^{-}\pi^{+}$, $D^{*+}\rightarrow D^{0}\pi^{+}\rightarrow K^{-}\pi^{+}\pi^{+}$ and their charge conjugates, covering the $p_T$ range of 0.6$-$2.0 GeV/$c$ and 2.0$-$6.0 GeV/$c$ for $D^{0}$ and $D^{*+}$, respectively. From this analysis, the charm-pair production cross section at mid-rapidity is $d\sigma/dy|_{y=0}^{c\bar{c}}$ = 170 $\pm$ 45 (stat.) $^{+38}_{-59}$ (sys.) $\mu$b. The extracted charm-pair cross section is compared to perturbative QCD calculations. The transverse momentum differential cross section is found to be consistent with the upper bound of a Fixed-Order Next-to-Leading Logarithm calculation.Comment: 15 pages, 16 figures. Revised version submitted to Phys. Rev.

Charged-to-neutral correlation at forward rapidity in Au+Au collisions at sNN\sqrt{s_{NN}}=200 GeV

Event-by-event fluctuations of the ratio of inclusive charged to photon multiplicities at forward rapidity in Au+Au collision at $\sqrt{s_{NN}}$=200 GeV have been studied. Dominant contribution to such fluctuations is expected to come from correlated production of charged and neutral pions. We search for evidences of dynamical fluctuations of different physical origins. Observables constructed out of moments of multiplicities are used as measures of fluctuations. Mixed events and model calculations are used as baselines. Results are compared to the dynamical net-charge fluctuations measured in the same acceptance. A non-zero statistically significant signal of dynamical fluctuations is observed in excess to the model prediction when charged particles and photons are measured in the same acceptance. We find that, unlike dynamical net-charge fluctuation, charge-neutral fluctuation is not dominated by correlation due to particle decay. Results are compared to the expectations based on the generic production mechanism of pions due to isospin symmetry, for which no significant (<1%) deviation is observed.Comment: 14 pages, 6 figure