Stimulated Whole Blood Cytokine Release as a Biomarker of Immunosuppression in the Critically Ill

Objective: Reduced ex vivo lipopolysaccharide (LPS) stimulated whole blood pro-inflammatory cytokine release is a hallmark of immunosuppression in the critically ill and predicts adverse clinical outcomes. No standard technique for performing the assay currently exists. The impact of methodological heterogeneity was determined. Design, Setting, Subjects, and Interventions: Clinical experimental study set in a research laboratory. Venous blood from 5 to 10 healthy volunteers/experiment (total participant group: 18 subjects, 72% men, mean age 32) was stimulated ex vivo to evaluate the effect of variables identified via literature review on tumor necrosis factor-α (TNFα) release. These included sample handling, stimulation technique, and incubation conditions. Reporting convention was additionally assessed. Main Results: Measured TNFα release was significantly altered by source of LPS, concentration of LPS employed, duration and temperature of incubation prior to supernatant aspiration, and predilution of blood (repeated measures ANOVA, all P < 0.01). Sample handling prior to stimulation (anticoagulant employed, time to LPS addition, and storage temperature) also caused significant alterations in TNFα release. Considerable interindividual variation was observed (range 1,024–4,649 pg/mL, mean 2,339 pg/mL). Normalization by monocyte count and pretreatment with a cyclooxygenase inhibitor (indomethacin 10 μM) reduced the coefficient of variation from 47.17% to 32.09%. Conclusions: Inconsistency in interlaboratory methodology and reporting impairs interpretation, comparability, and reproducibility of the ex vivo LPS-stimulated whole blood cytokine release assay. A standardized validated technique is required. The advent of trials of immunoadjuvant agents renders this a clinical imperative

Levi umbilical surfaces in complex space

We define a complex connection on a real hypersurface of \C^{n+1} which is naturally inherited from the ambient space. Using a system of Codazzi-type equations, we classify connected real hypersurfaces in \C^{n+1}, $n\ge 2$, which are Levi umbilical and have non zero constant Levi curvature. It turns out that such surfaces are contained either in a sphere or in the boundary of a complex tube domain with spherical section.Comment: 18 page

Emergent simplicity in microbial community assembly

Published in final edited form as: Science. 2018 August 03; 361(6401): 469–474. doi:10.1126/science.aat1168.A major unresolved question in microbiome research is whether the complex taxonomic architectures observed in surveys of natural communities can be explained and predicted by fundamental, quantitative principles. Bridging theory and experiment is hampered by the multiplicity of ecological processes that simultaneously affect community assembly in natural ecosystems. We addressed this challenge by monitoring the assembly of hundreds of soil- and plant-derived microbiomes in well-controlled minimal synthetic media. Both the community-level function and the coarse-grained taxonomy of the resulting communities are highly predictable and governed by nutrient availability, despite substantial species variability. By generalizing classical ecological models to include widespread nonspecific cross-feeding, we show that these features are all emergent properties of the assembly of large microbial communities, explaining their ubiquity in natural microbiomes.The funding for this work partly results from a Scialog Program sponsored jointly by the Research Corporation, for Science Advancement and. the Gordon and Betty Moore Foundation through grants to Yale University and Boston University by the Research Corporation and by the Simons Foundation. This work was also supported by a young; investigator award from the Human Frontier Science Program to A.S. (RGY0077/2016) and by NIH NIGMS grant 1R35GM119461 and a Simons Investigator as in the Mathematical Modeling of Living Systems (MMLS) to P.M.; D.S. and J.E.G. additionally acknowledge funding from the Defense Advanced Research Projects Agency (purchase request no. HR0011515303, contract no.. HR0011-15-0-0091), the U.S. Department of Energy (DE-SC0012627), the NIH (T32GM100842, 5R01DE024468, R01GM121950, and Sub_P30DK036836_P&F), the National Science Foundation (1457695), the Human Frontier Science Program (RGP0020/2016) and the Boston University Interdisciplinary Biomedical Research Office. (Research Corporation, for Science Advancement; Gordon and Betty Moore Foundation; Boston University by the Research Corporation; Simons Foundation.; RGY0077/2016 - uman Frontier Science Program; 1R35GM119461 - NIH NIGMS grant; Simons Investigator as in the Mathematical Modeling of Living Systems (MMLS); HR0011515303 - Defense Advanced Research Projects Agency; HR0011-15-0-0091 - Defense Advanced Research Projects Agency; T32GM100842 - NIH; 5R01DE024468 - NIH; R01GM121950 - NIH; ub_P30DK036836 - NIH; 1457695 - National Science Foundation; RGP0020/2016 - Human Frontier Science Program; Boston University Interdisciplinary Biomedical Research Office)Accepted manuscrip

Mixing by polymers: experimental test of decay regime of mixing

By using high molecular weight fluorescent passive tracers with different diffusion coefficients and by changing the fluid velocity we study dependence of a characteristic mixing length on the Peclet number, $Pe$, which controls the mixing efficiency. The mixing length is found to be related to $Pe$ by a power law, $L_{mix}\propto Pe^{0.26\pm 0.01}$, and increases faster than expected for an unbounded chaotic flow. Role of the boundaries in the mixing length abnormal growth is clarified. The experimental findings are in a good quantitative agreement with the recent theoretical predictions.Comment: 4 pages,5 figures. accepted for publication in PR

The Finite Field Kakeya Problem

A Besicovitch set in AG(n,q) is a set of points containing a line in every direction. The Kakeya problem is to determine the minimal size of such a set. We solve the Kakeya problem in the plane, and substantially improve the known bounds for n greater than 4.Comment: 13 page

Cellular Automaton for Realistic Modelling of Landslides

A numerical model is developed for the simulation of debris flow in landslides over a complex three dimensional topography. The model is based on a lattice, in which debris can be transferred among nearest neighbors according to established empirical relationships for granular flows. The model is then validated by comparing a simulation with reported field data. Our model is in fact a realistic elaboration of simpler ``sandpile automata'', which have in recent years been studied as supposedly paradigmatic of ``self-organized criticality''. Statistics and scaling properties of the simulation are examined, and show that the model has an intermittent behavior.Comment: Revised version (gramatical and writing style cleanup mainly). Accepted for publication by Nonlinear Processes in Geophysics. 16 pages, 98Kb uuencoded compressed dvi file (that's the way life is easiest). Big (6Mb) postscript figures available upon request from [email protected] / [email protected]

Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation

Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or tissue damage-associated molecular motifs, common biochemical pathways lead to conserved yet variable physiological and immunological alterations. Dissection and delineation of the determinants and mechanisms underlying phenotypic variance in response is expected to yield novel therapeutic advances. Intravenous (IV) administration of endotoxin (gram-negative bacterial lipopolysaccharide), a specific Toll-like receptor 4 agonist, represents an in vivo model of systemic inflammation in man. National Institutes for Health Clinical Center Reference Endotoxin (CCRE, Escherichia coli O:113:H10:K negative) is employed to reliably and reproducibly generate vascular, hematological, endocrine, immunological and organ-specific functional effects that parallel, to varying degrees, those seen in the early stages of pathological states. Alteration of dose (0.06 - 4 ng/kg) and time-scale of exposure (bolus vs. infusion) allows replication of either acute or chronic inflammation and a range of severity to be elicited, with higher doses (2 - 4 ng/kg) frequently being used to create a 'sepsis-like' state. Established and novel medicinal compounds may additionally be administered prior to or post endotoxin exposure to appreciate their effect on the inflammatory cascade. Despite limitations in scope and generalizability, human IV endotoxin challenge offers a unique platform to gain mechanistic insights into inducible physiological responses and inflammatory pathways. Rationally employed it may aid translation of this knowledge into therapeutic innovations

Variety of idempotents in nonassociative algebras

In this paper, we study the variety of all nonassociative (NA) algebras from the idempotent point of view. We are interested, in particular, in the spectral properties of idempotents when algebra is generic, i.e. idempotents are in general position. Our main result states that in this case, there exist at least $n-1$ nontrivial obstructions (syzygies) on the Peirce spectrum of a generic NA algebra of dimension $n$. We also discuss the exceptionality of the eigenvalue $\lambda=\frac12$ which appears in the spectrum of idempotents in many classical examples of NA algebras and characterize its extremal properties in metrised algebras.Comment: 27 pages, 1 figure, submitte

Monte-Carlo simulation of events with Drell-Yan lepton pairs from antiproton-proton collisions

The complete knowledge of the nucleon spin structure at leading twist requires also addressing the transverse spin distribution of quarks, or transversity, which is yet unexplored because of its chiral-odd nature. Transversity can be best extracted from single-spin asymmetries in fully polarized Drell-Yan processes with antiprotons, where valence contributions are involved anyway. Alternatively, in single-polarized Drell-Yan the transversity happens convoluted with another chiral-odd function, which is likely to be responsible for the well known (and yet unexplained) violation of the Lam-Tung sum rule in the corresponding unpolarized cross section. We present Monte-Carlo simulations for the unpolarized and single-polarized Drell-Yan $\bar{p} p^{(\uparrow)} \to \mu^+ \mu^- X$ at different center-of-mass energies in both configurations where the antiproton beam hits a fixed proton target or it collides on another proton beam. The goal is to estimate the minimum number of events needed to extract the above chiral-odd distributions from future measurements at the HESR ring at GSI. It is important to study the feasibility of such experiments at HESR in order to demonstrate that interesting spin physics can be explored already using unpolarized antiprotons.Comment: Deeply revised text with improved discussion of kinematics and results; added one table; 12 figures. Accepted for publication in Phys. Rev.

q-breathers in Discrete Nonlinear Schroedinger lattices

$q$-breathers are exact time-periodic solutions of extended nonlinear systems continued from the normal modes of the corresponding linearized system. They are localized in the space of normal modes. The existence of these solutions in a weakly anharmonic atomic chain explained essential features of the Fermi-Pasta-Ulam (FPU) paradox. We study $q$-breathers in one- two- and three-dimensional discrete nonlinear Sch\"{o}dinger (DNLS) lattices -- theoretical playgrounds for light propagation in nonlinear optical waveguide networks, and the dynamics of cold atoms in optical lattices. We prove the existence of these solutions for weak nonlinearity. We find that the localization of $q$-breathers is controlled by a single parameter which depends on the norm density, nonlinearity strength and seed wave vector. At a critical value of that parameter $q$-breathers delocalize via resonances, signaling a breakdown of the normal mode picture and a transition into strong mode-mode interaction regime. In particular this breakdown takes place at one of the edges of the normal mode spectrum, and in a singular way also in the center of that spectrum. A stability analysis of $q$-breathers supplements these findings. For three-dimensional lattices, we find $q$-breather vortices, which violate time reversal symmetry and generate a vortex ring flow of energy in normal mode space.Comment: 19 pages, 9 figure