Supplementary Material for: Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis

<b><i>Purpose:</i></b> We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. <b><i>Methods:</i></b> Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce <i>Escherichia coli</i> endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. <b><i>Results:</i></b> We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced <i>E. coli</i> endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). <b><i>Conclusions:</i></b> Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock

Supplementary Material for: TNFAIP2 Inhibits Early TNFa-Induced NF-κB Signaling and Decreases Survival in Septic Shock Patients

During septic shock, tumor necrosis factor alpha (TNFa) is an early response gene and induces a plethora of genes and signaling pathways. To identify robust signals in genes reliably upregulated by TNFa, we first measured microarray gene expression in vitro and searched methodologically comparable, publicly available data sets to identify concordant signals. Using tag single-nucleotide polymorphisms in the genes common to all data sets, we identified a genetic variant of the <i>TNFAIP2</i> gene, rs8126, associated with decreased 28-day survival and increased organ dysfunction in an adult cohort in the Vasopressin and Septic Shock Trial. Similar to this cohort, we found that an association with rs8126 and increased organ dysfunction is replicated in a second cohort of septic shock patients in the St. Paul's Hospital Intensive Care Unit. We found that TNFAIP2 inhibits NF-κB activity, impacting the downstream cytokine interleukin (IL)-8. The minor G allele of TNFAIP2 rs8126 resulted in greater TNFAIP2 expression, decreased IL-8 production and was associated with decreased survival in patients experiencing septic shock. These data suggest that TNFAIP2 is a novel inhibitor of NF-κB that acts as an autoinhibitor of the TNFa response during septic shock

Oligocene uplift of the Western Greater Caucasus: an effect of initial Arabia–Eurasia collision

The Greater Caucasus is Europe's largest mountain belt. Significant uncertainties remain over the evolution of the range, largely due to a lack of primary field data. This work demonstrates that depositional systems within the Oligocene–Early Miocene Maykop Series on either side of the Western Greater Caucasus (WGC) display a similar provenance and divergent palaeocurrents away from the range, constraining a minimum age for the subaerial uplift of the range as early Early Oligocene. An Eocene–Oligocene hiatus, basal Oligocene olistostromes and a marked increase in nannofossil reworking also point to initial deformation in the earliest Oligocene. The initial uplift of the WGC occurred during the final assembly of the Tethysides to its south. Uplift commenced after the Late Eocene final suturing of northern Neotethys and during the initial collision of Arabia with the southern accreted margin of Eurasia. This suggests that compressional deformation was rapidly transferred across the collision zone from the indenting Arabian plate to its northern margin.<br/

A labeled argumentation framework

To increase the expressivity of an argumentation formalism, we propose adding meta-level information to the arguments in the form of labels representing quantifiable data such as reliability degree, strength measure, skill, time availability, or any other feature about arguments. The extra information attached to an argument is then used in the acceptability determination process.We present a Labeled Argumentation Framework (LAF), combining the knowledge representation capabilities provided by the Argument Interchange Format (AIF) with an Algebra of Argumentation Labels, enabling us to handle the labels associated with the arguments. These labels are propagated through an argumentative graph according to the relations of support, conflict, and aggregation between arguments. Through this process we obtain final labels attached to the arguments that are useful to determine their acceptability.Fil: Budan, Maximiliano Celmo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Ciencia e Ingeniería de la Computación. Laboratorio de Investigación y Desarrollo en Inteligencia Artificial; Argentina. Universidad Nacional de Santiago del Estero; ArgentinaFil: Gomez Lucero, Mauro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Sur. Departamento de Ciencia e Ingeniería de la Computación. Laboratorio de Investigación y Desarrollo en Inteligencia Artificial; ArgentinaFil: Viglizzo, Ignacio Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Ciencia e Ingeniería de la Computación. Laboratorio de Investigación y Desarrollo en Inteligencia Artificial; Argentina. Universidad Nacional del Sur. Departamento de Matemática; ArgentinaFil: Simari, Guillermo Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Sur. Departamento de Ciencia e Ingeniería de la Computación. Laboratorio de Investigación y Desarrollo en Inteligencia Artificial; Argentin

The replacement of a native freshwater amphipod by an invader: roles for environmental degradation and intraguild predation

We assessed the extent to which an invader, Gammarus pulex (Crustacea: Amphipoda), has replaced a native, Gammarus duebeni celticus, over a 13-year period in a European river system and some of the abiotic and biotic factors that could account for this. Between 1988 and 2001, 56% of mixed-species sites had become invader-only sites, whereas no mixed sites had become native only again. The native dominated areas of higher dissolved oxygen and water quality, with the reciprocal true for the invader. Field transplant experiments revealed that native survivorship was lower in areas where it had been replaced than in areas where the invader does not yet occur. In invader-only areas, native survivorship was lower than that of the invader when kept separately and lowest when both species were kept together. We also observed predation of the native by the invader. Laboratory oxygen manipulation experiments revealed that at 30% saturation, the native's survivorship was two thirds that of the invader. We conclude that decreasing water quality favours replacement of the native by the invader.9 page(s

Probabilistic Logic with Strong Independence

Abstract. This papers investigates the manipulation of statements of strong independence in probabilistic logic. Inference methods based on polynomial programming are presented for strong independence, both for unconditional and conditional cases. We also consider graph-theoretic representations, where each node in a graph is associated with a Boolean variable and edges carry a Markov condition. The resulting model generalizes Bayesian networks, allowing probabilistic assessments and logical constraints to be mixed.