Exhaustion of Nucleation in a Closed System

We determine the distribution of cluster sizes that emerges from an initial phase of homogeneous aggregation with conserved total particle density. The physical ingredients behind the predictions are essentially classical: Super-critical nuclei are created at the Zeldovich rate, and before the depletion of monomers is significant, the characteristic cluster size is so large that the clusters undergo diffusion limited growth. Mathematically, the distribution of cluster sizes satisfies an advection PDE in "size-space". During this creation phase, clusters are nucleated and then grow to a size much larger than the critical size, so nucleation of super-critical clusters at the Zeldovich rate is represented by an effective boundary condition at zero size. The advection PDE subject to the effective boundary condition constitutes a "creation signaling problem" for the evolving distribution of cluster sizes during the creation era. Dominant balance arguments applied to the advection signaling problem show that the characteristic time and cluster size of the creation era are exponentially large in the initial free-energy barrier against nucleation, G_*. Specifically, the characteristic time is proportional to exp(2 G_*/ 5 k_B T) and the characteristic number of monomers in a cluster is proportional to exp(3G_*/5 k_B T). The exponentially large characteristic time and cluster size give a-posteriori validation of the mathematical signaling problem. In a short note, Marchenko obtained these exponentials and the numerical pre-factors, 2/5 and 3/5. Our work adds the actual solution of the kinetic model implied by these scalings, and the basis for connection to subsequent stages of the aggregation process after the creation era.Comment: Greatly shortened paper. Section on growth model removed. Added a section analyzing the error in the solution of the integral equation. Added reference

Experimental metrics for detection of detailed balance violation

We report on the measurement of detailed balance violation in a coupled, noise-driven linear electronic circuit consisting of two nominally identical RC elements that are coupled via a variable capacitance. The state variables are the time-dependent voltages across each of the two primary capacitors, and the system is driven by independent noise sources in series with each of the resistances. From the recorded time histories of these two voltages, we quantify violations of detailed balance by three methods: 1) explicit construction of the probability current density, 2) by constructing the time-dependent stochastic area, and 3) by constructing statistical fluctuation loops. In comparing the three methods, we find that the stochastic area is relatively simple to implement, computationally inexpensive, and provides a highly sensitive means for detecting violations of detailed balance.Comment: 12 pages, 6 figures, this version contains additional material relative to the previous on

Rotating spiral wave solutions of reaction-diffusion equations

We resolve the question of existence of regular rotating spiral waves as a consequence of only the processes of chemical reaction and molecular diffusion. We prove rigorously the existence of these waves as solutions of reaction-diffusion equations, and we exhibit them by means of numerical computations in several concrete cases. Existence is proved via the Schauder fixed point theorem applied to a class of functions with sufficient structure that, in fact, important constructive properties such as asymptotic representations and frequency of rotation are obtained

Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber