Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against bacterial pathogens. Recent evidence suggests that PMN apoptosis facilitates resolution of ...inflammation during bacterial infection. Although progress has been made toward understanding apoptosis in neutrophils, very little is known about transcriptional regulation of this process during bacterial infection. To gain insight into the molecular processes that facilitate resolution of infection, we measured global changes in PMN gene expression during phagocytosis of a diverse group of bacterial pathogens. Genes encoding key effectors of apoptosis were up-regulated, and receptors critical to innate immune function were down-regulated during apoptosis induced by phagocytosis of Burkholderia cepacia, Borrelia hermsii, Listeria monocytogenes, Staphylococcus aureus, and Streptococcus pyogenes. Importantly, we identified genes that comprise a common apoptosis differentiation program in human PMNs after phagocytosis of pathogenic bacteria. Unexpectedly, phagocytosis of Str. pyogenes induced changes in neutrophil gene expression not observed with other pathogens tested, including down-regulation of 21 genes involved in responses to IFN. Compared with other bacteria, PMN apoptosis was significantly accelerated by Str. pyogenes and was followed by necrosis. Thus, we hypothesize that there are two fundamental outcomes for the interaction of bacterial pathogens with neutrophils: (i) phagocytosis of bacteria induces an apoptosis differentiation program in human PMNs that contributes to resolution of bacterial infection, or (ii) phagocytosis of microorganisms such as Str. pyogenes alters the apoptosis differentiation program in neutrophils, resulting in pathogen survival and disease.
We present first results from radio observations with the Murchison Widefield Array seeking to constrain the power spectrum of 21 cm brightness temperature fluctuations between the redshifts of 11.6 ...and 17.9 (113 and 75 MHz). 3 h of observations were conducted over two nights with significantly different levels of ionospheric activity. We use these data to assess the impact of systematic errors at low frequency, including the ionosphere and radio-frequency interference, on a power spectrum measurement. We find that after the 1–3 h of integration presented here, our measurements at the Murchison Radio Observatory are not limited by RFI, even within the FM band, and that the ionosphere does not appear to affect the level of power in the modes that we expect to be sensitive to cosmology. Power spectrum detections, inconsistent with noise, due to fine spectral structure imprinted on the foregrounds by reflections in the signal-chain, occupy the spatial Fourier modes where we would otherwise be most sensitive to the cosmological signal. We are able to reduce this contamination using calibration solutions derived from autocorrelations so that we achieve an sensitivity of 104 mK on comoving scales k ≲ 0.5 h Mpc−1. This represents the first upper limits on the 21 cm power spectrum fluctuations at redshifts 12 ≲ z ≲ 18 but is still limited by calibration systematics. While calibration improvements may allow us to further remove this contamination, our results emphasize that future experiments should consider carefully the existence of and their ability to calibrate out any spectral structure within the EoR window.
The nature and extent of interindividual and temporal variation in gene expression patterns in specific cells and tissues is an important and relatively unexplored issue in human biology. We surveyed ...variation in gene expression patterns in peripheral blood from 75 healthy volunteers by using cDNA microarrays. Characterization of the variation in gene expression in healthy tissue is an essential foundation for the recognition and interpretation of the changes in these patterns associated with infections and other diseases, and peripheral blood was selected because it is a uniquely accessible tissue in which to examine this variation in patients or healthy volunteers in a clinical setting. Specific features of interindividual variation in gene expression patterns in peripheral blood could be traced to variation in the relative proportions of specific blood cell subsets; other features were correlated with gender, age, and the time of day at which the sample was taken. An analysis of multiple sequential samples from the same individuals allowed us to discern donor-specific patterns of gene expression. These data help to define human individuality and provide a database with which disease-associated gene expression patterns can be compared.
ABSTRACT We present the 21 cm power spectrum analysis approach of the Murchison Widefield Array Epoch of Reionization project. In this paper, we compare the outputs of multiple pipelines for the ...purpose of validating statistical limits cosmological hydrogen at redshifts between 6 and 12. Multiple independent data calibration and reduction pipelines are used to make power spectrum limits on a fiducial night of data. Comparing the outputs of imaging and power spectrum stages highlights differences in calibration, foreground subtraction, and power spectrum calculation. The power spectra found using these different methods span a space defined by the various tradeoffs between speed, accuracy, and systematic control. Lessons learned from comparing the pipelines range from the algorithmic to the prosaically mundane; all demonstrate the many pitfalls of neglecting reproducibility. We briefly discuss the way these different methods attempt to handle the question of evaluating a significant detection in the presence of foregrounds.
We present a self-consistent three-dimensional Monte-Carlo radiative transfer model of the stellar and dust emission in the Milky-Way, and have computed synthetic observations of the 3.6 to 100 ...μm emission in the Galactic mid-plane. To compare the model to observations, we use the GLIMPSE, MIPSGAL, and IRAS surveys to construct total emission spectra, as well as longitude and latitude profiles for the emission. The distribution of stars and dust is taken from the SKY model, and the dust emissivities include an approximation of the emission from polycyclic aromatic hydrocarbons (PAHs) in addition to thermal emission. The model emission is in broad agreement with the observations, but a few modifications are needed to obtain a good fit. Firstly, by adjusting the model to include two major and two minor spiral arms rather than four equal spiral arms, the fit to the longitude profiles for |ℓ| > 30° can be improved. Secondly, introducing a deficit in the dust distribution in the inner Galaxy results in a better fit to the shape of the IRAS longitude profiles at 60 and 100 μm. With these modifications, the model fits the observed profiles well, although it systematically under-estimates the 5.8 and 8.0 μm fluxes. One way to resolve this discrepancy is to increase the abundance of PAH molecules by 50% compared to the original model, although we note that changes to the dust distribution or radiation field may provide alternative solutions. Finally, we use the model to quantify which stellar populations contribute the most to the heating of different dust types and which stellar populations and dust types contribute the most to the emission at different wavelengths.
We introduce the Fast Holographic Deconvolution method for analyzing interferometric radio data. Our new method is an extension of A-projection/software-holography/forward modeling analysis ...techniques and shares their precision deconvolution and wide-field polarimetry, while being significantly faster than current implementations that use full direction-dependent antenna gains. Using data from the MWA 32 antenna prototype, we demonstrate the effectiveness and precision of our new algorithm. Fast Holographic Deconvolution may be particularly important for upcoming 21 cm cosmology observations of the Epoch of Reionization and Dark Energy where foreground subtraction is intimately related to the precision of the data reduction.
Polymorphonuclear leukocytes (PMNs or neutrophils) are the most prominent cellular component of the innate immune system in humans and produce an array of potent cytotoxic molecules. It is important ...that neutrophils undergo constitutive (spontaneous) apoptosis as a mechanism to facilitate normal cell turnover and immune system homeostasis. Conversely, several proinflammatory cytokines, including granulocyte macrophage‐colony stimulating factor (GM‐CSF), prolong neutrophil survival. The molecular mechanisms that regulate PMN apoptosis or survival remain incompletely defined. To that end, we compared global gene expression in human neutrophils during spontaneous apoptosis with that in cells cultured with human GM‐CSF. Genes encoding proteins that inhibit apoptosis, such as myeloid cell leukemia sequence 1, caspase 8 and Fas‐associated via death domain‐like apoptosis regulator (CFLAR), B cell chronic lymphocytic leukemia/lymphoma 2 (BCL2)/adenovirus E1B 19 kDa‐interacting protein 2 (BNIP2), and serum/glucocorticoid‐regulated kinase (SGK), were down‐regulated coincident with neutrophil apoptosis. In contrast, those encoding apoptosis inhibitor 5, BCL2‐like 1, BNIP2, CFLAR, SGK, and tumor necrosis factor α‐induced protein 8 were up‐regulated in PMNs cultured with GM‐CSF. Correspondingly, GM‐CSF delayed PMN apoptosis (P<0.03), increased cell viability (P<0.03), and prolonged neutrophil phagocytic capacity (P<0.05). Prolonged functional capacity was paralleled by striking up‐regulation of proinflammatory genes and proteins, including CD14, CD24, CD66, and human leukocyte antigen‐DR. In addition, expression of SGK protein diminished during PMN apoptosis but was restored by culture with GM‐CSF, suggesting SGK is involved in leukocyte survival. These studies provide a global view of the molecular events that regulate neutrophil survival and apoptosis.
Transmission of plague by fleas depends on infection of the proventricular valve in the insect's foregut by a dense aggregate of Yersinia pestis. Proventricular infection requires the Y. pestis hemin ...storage (hms) genes; here, we show that the hms genes are also required to produce an extracellular matrix and a biofilm in vitro, supporting the hypothesis that a transmissible infection in the flea depends on the development of a biofilm on the hydrophobic, acellular surface of spines that line the interior of the proventriculus. The development of biofilm and proventricular infection did not depend on the 3 Y. pestis quorum-sensing systems. The extracellular matrix enveloping the Y. pestis biofilm in the flea appeared to incorporate components from the flea's blood meal, and bacteria released from the biofilm were more resistant to human polymorphonuclear leukocytes than were in vitro-grown Y. pestis. Enabling arthropod-borne transmission represents a novel function of a bacterial biofilm.
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