985 research outputs found
Chromatin accessibility maps of chronic lymphocytic leukemia identify subtypespecific epigenome signatures and associated transcription regulatory networks
Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay. These data were further complemented by ChIPmentation and RNA-seq profiling in ten samples. Based on this dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status – which distinguishes the two major subtypes of CLL – was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic regulatory differences between these two disease subtypes. In summary, we found widespread heterogeneity in the CLL chromatin landscape, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research
Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies
From SOMAmer-Based Biomarker Discovery to Diagnostic and Clinical Applications: A SOMAmer-Based, Streamlined Multiplex Proteomic Assay
Recently, we reported a SOMAmer-based, highly multiplexed assay for the purpose of biomarker identification. To enable seamless transition from highly multiplexed biomarker discovery assays to a format suitable and convenient for diagnostic and life-science applications, we developed a streamlined, plate-based version of the assay. The plate-based version of the assay is robust, sensitive (sub-picomolar), rapid, can be highly multiplexed (upwards of 60 analytes), and fully automated. We demonstrate that quantification by microarray-based hybridization, Luminex bead-based methods, and qPCR are each compatible with our platform, further expanding the breadth of proteomic applications for a wide user community
A New Era in Extragalactic Background Light Measurements: The Cosmic History of Accretion, Nucleosynthesis and Reionization
(Brief Summary) What is the total radiative content of the Universe since the
epoch of recombination? The extragalactic background light (EBL) spectrum
captures the redshifted energy released from the first stellar objects,
protogalaxies, and galaxies throughout cosmic history. Yet, we have not
determined the brightness of the extragalactic sky from UV/optical to
far-infrared wavelengths with sufficient accuracy to establish the radiative
content of the Universe to better than an order of magnitude. Among many
science topics, an accurate measurement of the EBL spectrum from optical to
far-IR wavelengths, will address: What is the total energy released by stellar
nucleosynthesis over cosmic history? Was significant energy released by
non-stellar processes? Is there a diffuse component to the EBL anywhere from
optical to sub-millimeter? When did first stars appear and how luminous was the
reionization epoch? Absolute optical to mid-IR EBL spectrum to an
astrophysically interesting accuracy can be established by wide field imagingat
a distance of 5 AU or above the ecliptic plane where the zodiacal foreground is
reduced by more than two orders of magnitude.Comment: 7 pages; Science White Paper for the US Astro 2010-2020 Decadal
Survey. If interested in further community-wide efforts on this topic please
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Follow-up observations at 16 and 33 GHz of extragalactic sources from WMAP 3-year data: I - Spectral properties
We present follow-up observations of 97 point sources from the Wilkinson
Microwave Anisotropy Probe (WMAP) 3-year data, contained within the New
Extragalactic WMAP Point Source (NEWPS) catalogue between declinations of -4
and +60 degrees; the sources form a flux-density-limited sample complete to 1.1
Jy (approximately 5 sigma) at 33 GHz. Our observations were made at 16 GHz
using the Arcminute Microkelvin Imager (AMI) and at 33 GHz with the Very Small
Array (VSA). 94 of the sources have reliable, simultaneous -- typically a few
minutes apart -- observations with both telescopes. The spectra between 13.9
and 33.75 GHz are very different from those of bright sources at low frequency:
44 per cent have rising spectra (alpha < 0.0), where flux density is
proportional to frequency^-alpha, and 93 per cent have spectra with alpha <
0.5; the median spectral index is 0.04. For the brighter sources, the agreement
between VSA and WMAP 33-GHz flux densities averaged over sources is very good.
However, for the fainter sources, the VSA tends to measure lower values for the
flux densities than WMAP. We suggest that the main cause of this effect is
Eddington bias arising from variability.Comment: 12 pages, 13 figures, submitted to MNRA
Aptamer-based multiplexed proteomic technology for biomarker discovery
Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine
Chromosome-scale genome assembly of the brown anole (Anolis sagrei), an emerging model species
Rapid technological improvements are democratizing access to high quality, chromosome-scale genome assemblies. No longer the domain of only the most highly studied model organisms, now non-traditional and emerging model species can be genome-enabled using a combination of sequencing technologies and assembly software. Consequently, old ideas built on sparse sampling across the tree of life have recently been amended in the face of genomic data drawn from a growing number of high-quality reference genomes. Arguably the most valuable are those long-studied species for which much is already known about their biology; what many term emerging model species. Here, we report a highly complete chromosome-scale genome assembly for the brown anole, Anolis sagrei – a lizard species widely studied across a variety of disciplines and for which a high-quality reference genome was long overdue. This assembly exceeds the vast majority of existing reptile and snake genomes in contiguity (N50 = 253.6 Mb) and annotation completeness. Through the analysis of this genome and population resequence data, we examine the history of repetitive element accumulation, identify the X chromosome, and propose a hypothesis for the evolutionary history of fusions between autosomes and the X that led to the sex chromosomes of A. sagrei
Factors affecting the determination of threshold doses for allergenic foods: How much is too much?
Background: Ingestion of small amounts of an offending food can elicit adverse reactions in individuals with IgE-mediated food allergies. The threshold dose for provocation of such reactions is often considered to be zero. However, because of various practical limitations in food production and processing, foods may occasionally contain trace residues of the offending food. Are these very low, residual quantities hazardous to allergic consumers? How much of the offending food is too much? Very little quantitative information exists to allow any risk assessments to be conducted by the food industry. Objective: We sought to determine whether the quality and quantity of existing clinical data on threshold doses for commonly allergenic foods were sufficient to allow consensus to be reached on establishment of threshold doses for specific foods. Methods: In September 1999,12 clinical allergists and other interested parties were invited to participate in a roundtable conference to share existing data on threshold doses and to discuss clinical approaches that would allow the acquisition of that information. Results: Considerable data were identified in clinical files relating to the threshold doses for peanut, cows\u27 milk, and egg; limited data were available for other foods, such as fish and mustard. Conclusions: Because these data were often obtained by means of different protocols, the estimation of a threshold dose was very difficult. Development of a standardized protocol for clinical experiments to allow determination of the threshold dose is needed
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