120 research outputs found
The Inflammatory Response to Double Stranded DNA in Endothelial Cells Is Mediated by NFκB and TNFα
Endothelial cells represent an important barrier between the intravascular compartment and extravascular tissues, and therefore serve as key sensors, communicators, and amplifiers of danger signals in innate immunity and inflammation. Double stranded DNA (dsDNA) released from damaged host cells during injury or introduced by pathogens during infection, has emerged as a potent danger signal. While the dsDNA-mediated immune response has been extensively studied in immune cells, little is known about the direct and indirect effects of dsDNA on the vascular endothelium. In this study we show that direct dsDNA stimulation of endothelial cells induces a potent proinflammatory response as demonstrated by increased expression of ICAM1, E-selectin and VCAM1, and enhanced leukocyte adhesion. This response was dependent on the stress kinases JNK and p38 MAPK, required the activation of proinflammatory transcription factors NFκB and IRF3, and triggered the robust secretion of TNFα for sustained secondary activation of the endothelium. DNA-induced TNFα secretion proved to be essential in vivo, as mice deficient in the TNF receptor were unable to mount an acute inflammatory response to dsDNA. Our findings suggest that the endothelium plays an active role in mediating dsDNA-induced inflammatory responses, and implicate its importance in establishing an acute inflammatory response to sterile injury or systemic infection, where host or pathogen derived dsDNA may serve as a danger signal.United States. Dept. of Defense (CDMRP Predoctoral Training Award)National Institutes of Health (U.S.) (NIH BioMEMS Resource Center Grant P41 EB-002503)National Institutes of Health (U.S.) (NIH Grant RO1AI063795)Shriners Hospital for Childre
Genome wide array-CGH and qPCR analysis for the identification of genome defects in Williams’ syndrome patients in Saudi Arabia
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Detection of cosmic structures using the bispectrum phase. II. First results from application to cosmic reionization using the Hydrogen Epoch of Reionization Array
Characterizing the epoch of reionization (EoR) at via the
redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern
astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the IGM brightness temperature. From this limited data, at we infer "" upper limits on the IGM brightness temperature to be "pseudo" mK at Mpc (data-limited) and
"pseudo" mK at
Mpc (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues
Enhanced prefrontal serotonin 5-HT1A currents in a mouse model of Williams-Beuren syndrome with low innate anxiety
Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously (Gtf2ird1+/−) or homozygously (Gtf2ird1−/−) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1−/− mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1−/− mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1−/− mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT1A receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT1A receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT1A receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT1A-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1−/− mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines
Imaging and Modeling Data from the Hydrogen Epoch of Reionization Array
We analyze data from the Hydrogen Epoch of Reionization Array. This is the
third in a series of papers on the closure phase delay-spectrum technique
designed to detect the HI 21cm emission from cosmic reionization. We present
the details of the data and models employed in the power spectral analysis, and
discuss limitations to the process. We compare images and visibility spectra
made with HERA data, to parallel quantities generated from sky models based on
the GLEAM survey, incorporating the HERA telescope model. We find reasonable
agreement between images made from HERA data, with those generated from the
models, down to the confusion level. For the visibility spectra, there is broad
agreement between model and data across the full band of MHz. However,
models with only GLEAM sources do not reproduce a roughly sinusoidal spectral
structure at the tens of percent level seen in the observed visibility spectra
on scales MHz on 29 m baselines. We find that this structure is
likely due to diffuse Galactic emission, predominantly the Galactic plane,
filling the far sidelobes of the antenna primary beam. We show that our current
knowledge of the frequency dependence of the diffuse sky radio emission, and
the primary beam at large zenith angles, is inadequate to provide an accurate
reproduction of the diffuse structure in the models. We discuss implications
due to this missing structure in the models, including calibration, and in the
search for the HI 21cm signal, as well as possible mitigation techniques
Understanding the HERA Phase i receiver system with simulations and its impact on the detectability of the EoR delay power spectrum
The detection of the Epoch of Reionization (EoR) delay power spectrum using a
"foreground avoidance method" highly depends on the instrument chromaticity.
The systematic effects induced by the radio-telescope spread the foreground
signal in the delay domain, which contaminates the EoR window theoretically
observable. Applied to the Hydrogen Epoch of Reionization Array (HERA), this
paper combines detailed electromagnetic and electrical simulations in order to
model the chromatic effects of the instrument, and quantify its frequency and
time responses. In particular, the effects of the analogue receiver,
transmission cables, and mutual coupling are included. These simulations are
able to accurately predict the intensity of the reflections occurring in the
150-m cable which links the antenna to the back-end. They also show that
electromagnetic waves can propagate from one dish to another one through large
sections of the array due to mutual coupling. The simulated system time
response is attenuated by a factor after a characteristic delay which
depends on the size of the array and on the antenna position. Ultimately, the
system response is attenuated by a factor after 1400 ns because of the
reflections in the cable, which corresponds to characterizable
-modes above 0.7 at 150 MHz. Thus, this new
study shows that the detection of the EoR signal with HERA Phase I will be more
challenging than expected. On the other hand, it improves our understanding of
the telescope, which is essential to mitigate the instrument chromaticity
Automated Detection of Antenna Malfunctions in Large-N Interferometers: A case study With the Hydrogen Epoch of Reionization Array
We present a framework for identifying and flagging malfunctioning antennas in large radio
interferometers. We outline two distinct categories of metrics designed to detect outliers along known failure
modes of large arrays: cross-correlation metrics, based on all antenna pairs, and auto-correlation metrics, based
solely on individual antennas. We define and motivate the statistical framework for all metrics used, and present
tailored visualizations that aid us in clearly identifying new and existing systematics. We implement these
techniques using data from 105 antennas in the Hydrogen Epoch of Reionization Array (HERA) as a case study.
Finally, we provide a detailed algorithm for implementing these metrics as flagging tools on real data sets
Molecular imaging of rheumatoid arthritis by radiolabelled monoclonal antibodies: new imaging strategies to guide molecular therapies
The closing of the last century opened a wide variety of approaches for inflammation imaging and treatment of patients with rheumatoid arthritis (RA). The introduction of biological therapies for the management of RA started a revolution in the therapeutic armamentarium with the development of several novel monoclonal antibodies (mAbs), which can be murine, chimeric, humanised and fully human antibodies. Monoclonal antibodies specifically bind to their target, which could be adhesion molecules, activation markers, antigens or receptors, to interfere with specific inflammation pathways at the molecular level, leading to immune-modulation of the underlying pathogenic process. These new generation of mAbs can also be radiolabelled by using direct or indirect method, with a variety of nuclides, depending upon the specific diagnostic application. For studying rheumatoid arthritis patients, several monoclonal antibodies and their fragments, including anti-TNF-α, anti-CD20, anti-CD3, anti-CD4 and anti-E-selectin antibody, have been radiolabelled mainly with 99mTc or 111In. Scintigraphy with these radiolabelled antibodies may offer an exciting possibility for the study of RA patients and holds two types of information: (1) it allows better staging of the disease and diagnosis of the state of activity by early detection of inflamed joints that might be difficult to assess; (2) it might provide a possibility to perform ‘evidence-based biological therapy’ of arthritis with a view to assessing whether an antibody will localise in an inflamed joint before using the same unlabelled antibody therapeutically. This might prove particularly important for the selection of patients to be treated since biological therapies can be associated with severe side-effects and are considerably expensive. This article reviews the use of radiolabelled mAbs in the study of RA with particular emphasis on the use of different radiolabelled monoclonal antibodies for therapy decision-making and follow-up
Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, Bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals—but not all—develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease
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