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"Carter, John D."
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Inactivation of DAP12 in PMN Inhibits TREM1-Mediated Activation in Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12's tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling pathways. While both TREM1 and DAP12 have been shown to be important activators of RA pathogenesis, their activity in PMNs or the importance of DAP12 as a possible therapeutic target have not been shown. Here we corroborate, using primary RA specimens, that isolated PMNs have an increased proportion of both TREM1 and DAP12 compared to normal healthy control isolated PMNs both at the protein and gene expression levels. This increased expression is highly functional with increased activation of ERK and MAPKs, secretion of IL-8 and RANTES and cytotoxicity of target cells. Importantly, based on our hypothesis of an imbalance of activating and inhibitory signaling in the pathogenesis of RA we demonstrate that inhibition of the DAP12 signaling pathway inactivates these important inflammatory cells.
Journal Article
The Eagle has landed : 50 years of lunar science fiction
\"In celebration of the 50th anniversary of the Apollo 11 landing, the endlessly-mysterious moon is explored in this reprint short science fiction anthology from award-winning editor and anthologist Neil Clarke ... On July 20, 1969, mankind made what had only years earlier seemed like an impossible leap forward: when Apollo 11 became the first manned mission to land on the moon, and Neil Armstrong the first person to step foot on the lunar surface. While there have only been a handful of new missions since, the fascination with our planet's satellite continues, and generations of writers and artists have imagined the endless possibilities of lunar life. From adventures in the vast gulf of space between the earth and the moon, to journeys across the light face to the dark side, to the establishment of permanent residences on its surface, science fiction has for decades given readers bold and forward-thinking ideas about our nearest interstellar neighbor and what it might mean to humankind, both now and in our future. [This book] collects the best stories written in the fifty years since mankind first stepped foot on the lunar surface, serving as a shining reminder that the moon is and always has been our most visible and constant example of all the infinite possibility of the wider universe\"-- Provided by publisher.
BOOK
The spatial Whitham equation
The Whitham equation is a non-local, nonlinear partial differential equation that models the temporal evolution of spatial profiles of surface displacement of water waves. However, many laboratory and field measurements record time series at fixed spatial locations. To directly model data of this type, it is desirable to have equations that model the spatial evolution of time series. The spatial Whitham (sWhitham) equation, proposed as the spatial generalization of the Whitham equation, fills this need. In this paper, we study this equation and apply it to water-wave experiments on shallow and deep water. We compute periodic travelling-wave solutions to the sWhitham equation and examine their properties, including their stability. Results for small-amplitude solutions align with known results for the Whitham equation. This suggests that the systems are consistent in the weakly nonlinear regime. At larger amplitudes, there are some discrepancies. Notably, the sWhitham equation does not appear to admit cusped solutions of maximal wave height. In the second part, we compare predictions from the temporal and spatial Korteweg–de Vries and Whitham equations with measurements from laboratory experiments. We show that the sWhitham equation accurately models measurements of tsunami-like waves of depression, waves of elevation, and solitary waves on shallow water. Its predictions also compare favourably with experimental measurements of waves of depression and elevation on deep water. Accuracy is increased by adding a phenomenological damping term. Finally, we show that neither the sWhitham nor the temporal Whitham equation accurately models the evolution of wave packets on deep water.
Journal Article
Fully dispersive Boussinesq models with uneven bathymetry
Three weakly nonlinear but fully dispersive Whitham–Boussinesq systems for uneven bathymetry are studied. The derivation and discretization of one system is presented. The numerical solutions of all three are compared with wave gauge measurements from a series of laboratory experiments conducted by Dingemans (Comparison of computations with Boussinesq-like models and laboratory measurements. Delft Hydraulics memo H168412, 1994). The results show that although the models are mathematically similar, their accuracy varies dramatically.
Journal Article
Treating reactive arthritis: insights for the clinician
There are two main forms of reactive arthritis (ReA): postvenereal and postdysentery. Chlamydia trachomatis (Ct) is the major causative organism of the postvenereal type; Salmonella, Shigella, Campylobacter, and Yersinia are the major triggers for the postenteric type. All of these causative organisms have been shown to traffic to the synovium in affected individuals. However, one important difference is that the chlamydial organisms have been shown to be viable, whereas, in general, the postenteric organisms are not. Although estimates vary widely, it is felt that 30-50% of all cases of ReA become chronic and the remainder resolve spontaneously within weeks to months. These important differences need to be considered when reviewing the available therapeutic outcomes data. There is a relative paucity of prospective clinical trial data assessing various treatment strategies. A large breadth of clinical experience demonstrates that nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are efficacious, but there have only been two rather small trials assessing NSAIDs and none with corticosteroids. Disease modifying drugs are sometimes utilized in more severe or chronic cases, but only sulfasalazine (SSZ) has been studied. Anti-tumor necrosis factor (TNF) therapy has proved remarkably efficacious with other types of spondyloarthritides, but there is very little data to support their use in ReA; theoretical concerns also exist with this drug class in ReA, specifically. Finally, antibiotics have been studied in several trials. A thorough analysis of these trials reveals equivocal results with a possible particular benefit in postchlamydial ReA. These data are reviewed with an emphasis on postchlamydial and postenteric ReA.
Journal Article
Stability of Periodic, Traveling-Wave Solutions to the Capillary Whitham Equation
Recently, the Whitham and capillary Whitham equations were shown to accurately model the evolution of surface waves on shallow water. In order to gain a deeper understanding of these equations, we compute periodic, traveling-wave solutions for both and study their stability. We present plots of a representative sampling of solutions for a range of wavelengths, wave speeds, wave heights, and surface tension values. Finally, we discuss the role these parameters play in the stability of these solutions.
Journal Article
Transverse instabilities of deep-water solitary waves
The dynamics of a one-dimensional slowly modulated, nearly monochromatic localized wave train in deep water is described by a one-dimensional soliton solution of a two-dimensional nonlinear Schrödinger (NLS) equation. In this paper, the instability of such a wave train with respect to transverse perturbations is examined numerically in the context of the NLS equation, using Hill's method. A variety of instabilities are obtained and discussed. Among these, we show that the solitary wave is susceptible to an oscillatory instability (complex growth rate) due to perturbations with arbitrarily short wavelength. Further, there is a cut-off on the instability with real growth rates. We show analytically that the nature of this cut-off is different from what is claimed in previous works.
Journal Article
Experimental evidence of stable wave patterns on deep water
Recent predictions from competing theoretical models have disagreed about the stability/instability of bi-periodic patterns of surface waves on deep water. We present laboratory experiments to address this controversy. Growth rates of modulational perturbations are compared to predictions from: (i) inviscid coupled nonlinear Schrödinger (NLS) equations, according to which the patterns are unstable and (ii) dissipative coupled NLS equations, according to which they are linearly stable. For bi-periodic wave patterns of small amplitude and nearly permanent form, we find that the dissipative model predicts the experimental observations more accurately. Hence, our experiments support the claim that these bi-periodic wave patterns are linearly stable in the presence of damping. For bi-periodic wave patterns of large enough amplitude or subject to large enough perturbations, both models fail to predict accurately the observed behaviour, which includes frequency downshifting.
Journal Article