Neutrophils are known to extrude decondensed chromatin, thus forming NETs (neutrophil extracellular traps). These structures immobilize pathogens, thereby preventing their spreading, and are also ...adorned with antimicrobial molecules. NETs can also influence pathogenesis in chronic inflammation, autoimmunity, and cancer. Despite the importance of NETs, the molecular mechanisms underlying their formation, as well as the upstream signaling pathways involved, are only partially understood. Likewise, current methodological approaches to quantify NETs suffer from significant drawbacks, not the least being the inclusion of a significant non-specific signal. In this study, we used novel, fluorescent polymers that only bind extruded chromatin, allowing a specific and standardized quantification of NETosis. This allowed us to reliably rank the relative potency of various physiologic NET inducers. In neutrophils activated with such stimuli, inhibition of the Syk or PI3K pathways blocked NETosis by acting upon late events in NET formation. Inhibition of the TAK1, p38 MAPK, or MEK pathways also hindered NETosis, but by acting on early events. By contrast, inhibiting PKC, Src family kinases, or JNK failed to prevent NETosis; cycloheximide or actinomycin D were also ineffective. Expectedly, NET formation was deeply compromised following inhibition of the NADPH oxidase in PMA-activated neutrophils, but was found to be ROS-independent in response to physiological agonists. Conversely, we show for the first time in human neutrophils that selective inhibition of PAD4 potently prevents NETosis by all stimuli tested. Our data substantially extends current knowledge of the signaling pathways controlling NETosis, and reveals how they affect early or late stages of the phenomenon. In view of the involvement of NETs in several pathologies, our findings also identify molecular targets that could be exploited for therapeutic intervention.
This paper blends recent research on hierarchy and democratization to examine the theoretical and empirical costs of treating regime type exogenously in the literature most identified with studying ...its impact on international politics. It argues that the apparent peace among democratic states that emerges in the aftermath of World War I is not caused by domestic institutional attributes normally associated with democracy. Instead, this peace is an artifact of historically specific great power settlements. These settlements shape subsequent aggregate patterns of military conflict by altering the organizational configuration of the system in three critical ways—by creating new states, by altering hierarchical orders, and by influencing regime type in states. These claims are defended with a series of tests that show first how the statistical relationship between democracy and peace has exhibited substantial variation across great power orders; second, that this statistical relationship breaks down with theoretically motivated research design changes; and third, that great powers foster peace and similar regime types within their hierarchical orders. In short, the relationship between democracy and peace is spurious. The international political order is still built and managed by great powers.
Factorial Survey Analysis (FSA) is an analytical tool that presents respondents with fictional situations ("vignettes") to be rated or judged. In this paper we study the use of FSA in labour market ...sociology, with a particular focus on employer-based surveys, and what they can teach us about hiring preferences. FSA is useful in this context as it targets employers directly and comes close to a causal design. This review article seeks to pinpoint the contributions FSA has made to the field, identify its limits and propose topics in which it may be useful.
We introduce FASTPM, a highly scalable approximated particle mesh (PM) N-body solver, which implements the PM scheme enforcing correct linear displacement (1LPT) evolution via modified kick and drift ...factors. Employing a two-dimensional domain decomposing scheme, FASTPM scales extremely well with a very large number of CPUs. In contrast to Comoving-Lagrangian (COLA) approach, we do not require to split the force or track separately the 2LPT solution, reducing the code complexity and memory requirements. We compare FASTPM with different number of steps (N sub( s)) and force resolution factor (B) against three benchmarks: halo mass function from friends-of-friends halo finder; halo and dark matter power spectrum; and cross-correlation coefficient (or stochasticity), relative to a high-resolution TREEPM simulation. We show that the modified time stepping scheme reduces the halo stochasticity when compared to COLA with the same number of steps and force resolution. While increasing N sub( s) and B improves the transfer function and cross-correlation coefficient, for many applications FASTPM achieves sufficient accuracy at low N sub( s) and B. For example, N sub( s) = 10 and B = 2 simulation provides a substantial saving (a factor of 10) of computing time relative to N sub( s) = 40, B = 3 simulation, yet the halo benchmarks are very similar at z = 0. We find that for abundance matched haloes the stochasticity remains low even for N sub( s) = 5. FASTPM compares well against less expensive schemes, being only 7 (4) times more expensive than 2LPT initial condition generator for N sub( s) = 10 (N sub( s) = 5). Some of the applications where FASTPM can be useful are generating a large number of mocks, producing non-linear statistics where one varies a large number of nuisance or cosmological parameters, or serving as part of an initial conditions solver.
To characterize the microbiota of the cerebrospinal fluid (CSF) from children with hydrocephalus at the time of initial surgical intervention.
CSF was obtained at initial surgical intervention. One ...aliquot was stored in skim milk-tryptone-glucose-glycerol (STGG) medium and the second was unprocessed; both were then stored at -70°C. Bacterial growth for CSF samples stored in STGG were subsequently characterized using aerobic and anaerobic culture on blood agar and MALDI-TOF sequencing. All unprocessed CSF samples underwent 16S quantitative polymerase chain reaction (qPCR) sequencing, and a subset underwent standard clinical microbiological culture. CSF with culture growth (either after storage in STGG or standard clinical) were further analyzed using whole-genome amplification sequencing (WGAS).
11/66 (17%) samples stored in STGG and 1/36 (3%) that underwent standard clinical microbiological culture demonstrated bacterial growth. Of the organisms present, 8 were common skin flora and 4 were potential pathogens; only 1 was also qPCR positive. WGAS findings and STGG culture findings were concordant for only 1 sample, identifying Staphylococcus epidermidis. No significant difference in time to second surgical intervention was observed between the STGG culture-positive and negative groups.
Using high sensitivity methods, we detected the presence of bacteria in a subset of CSF samples at the time of first surgery. Therefore, the true presence of bacteria in CSF of children with hydrocephalus cannot be ruled out, though our findings may suggest these bacteria are contaminants or false positives of the detection methods. Regardless of origin, the detection of microbiota in the CSF of these children may not have any clinical significance.
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