DNA double-strand breaks (DSBs) can arise from multiple sources, including exposure to ionizing radiation. The repair of DSBs involves both posttranslational modification of nucleosomes and ...concentration of DNA-repair proteins at the site of damage. Consequently, nucleosome packing and chromatin architecture surrounding the DSB may limit the ability of the DNA-damage response to access and repair the break. Here, we review early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB, thereby facilitating mammalian DSB repair.
The affective dimension of pain is made up of feelings of unpleasantness and emotions associated with future implications, termed secondary affect. Experimental and clinical studies show serial ...interactions between pain sensation intensity, pain unpleasantness, and secondary affect. These pain dimensions and their interactions relate to a central network of brain structures that processes nociceptive information both in parallel and in series. Spinal pathways to limbic structures and medial thalamic nuclei provide direct inputs to brain areas involved in affect. Another source is from spinal pathways to somatosensory thalamic and cortical areas and then through a corticolimbic pathway. The latter integrates nociceptive input with contextual information and memory to provide cognitive mediation of pain affect. Both direct and corticolimbic pathways converge on the same anterior cingulate cortical and subcortical structures whose function may be to establish emotional valence and response priorities.
We tracked over time the conductance switching of single and bundled phenylene ethynylene oligomers isolated in matrices of alkanethiolate monolayers. The persistence times for isolated and bundled ...molecules in either the ON or OFF switch state range from seconds to tens of hours. When the surrounding matrix is well ordered, the rate at which the inserted molecules switch is low. Conversely, when the surrounding matrix is poorly ordered, the inserted molecules switch more often. We conclude that the switching is a result of conformational changes in the molecules or bundles, rather than electrostatic effects of charge transfer.
Outcomes of 3309 thoracoabdominal aortic aneurysm repairs Coselli, Joseph S., MD; LeMaire, Scott A., MD; Preventza, Ourania, MD ...
The Journal of thoracic and cardiovascular surgery,
05/2016, Letnik:
151, Številka:
5
Journal Article
Recenzirano
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Abstract Objective Since the pioneering era of E. Stanley Crawford, our multimodal strategy for thoracoabdominal aortic aneurysm repair has evolved. We describe our approximately 3-decade ...single-practice experience regarding 3309 thoracoabdominal aortic aneurysm repairs and identify predictors of early death and other adverse postoperative outcomes. Methods We analyzed retrospective (1986-2006) and prospective data (2006-2014) obtained from patients (2043 male; median age, 67 59-73 years) who underwent 914 Crawford extent I, 1066 extent II, 660 extent III, and 669 extent IV thoracoabdominal aortic aneurysm repairs, of which 723 (21.8%) were urgent or emergency. Repairs were performed to treat degenerative aneurysm (64.2%) or aortic dissection (35.8%). The outcomes examined included operative death (ie, 30-day or in-hospital death) and permanent stroke, paraplegia, paraparesis, and renal failure necessitating dialysis, as well as adverse event, a composite of these outcomes. Results There were 249 operative deaths (7.5%). Permanent paraplegia and paraparesis occurred after 97 (2.9%) and 81 (2.4%) repairs, respectively. Of 189 patients (5.7%) with permanent renal failure, 107 died in the hospital. Permanent stroke was relatively uncommon (n = 74; 2.2%). The rate of the composite adverse event (n = 478; 14.4%) was highest after extent II repair (n = 203; 19.0%) and lowest after extent IV repair (n = 67; 10.2%; P < .0001). Estimated postoperative survival was 83.5% ± 0.7% at 1 year, 63.6% ± 0.9% at 5 years, 36.8% ± 1.0% at 10 years, and 18.3% ± 0.9% at 15 years. Conclusions Repairing thoracoabdominal aortic aneurysms poses substantial risks, particularly when the entire thoracoabdominal aorta (extent II) is replaced. Nonetheless, our data suggest that thoracoabdominal aortic aneurysm repair, when performed at an experienced center, can produce respectable outcomes.
Disks of gas and dust surrounding young stars are the birthplace of planets. However, the direct detection of protoplanets forming within disks has proved elusive to date. We present the detection of ...a large, localized deviation from Keplerian velocity in the protoplanetary disk surrounding the young star HD 163296. The observed velocity pattern is consistent with the dynamical effect of a two-Jupiter-mass planet orbiting at a radius 260 au from the star.
Mutations in ADAR, which encodes the ADAR1 RNA-editing enzyme, cause Aicardi-Goutières syndrome (AGS), a severe autoimmune disease associated with an aberrant type I interferon response. How ADAR1 ...prevents autoimmunity remains incompletely defined. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered a MDA5-MAVS-independent function for ADAR1 in the development of multiple organs. We showed that the p150 isoform of ADAR1 uniquely regulated the MDA5 pathway, whereas both the p150 and p110 isoforms contributed to development. Abrupt deletion of ADAR1 in adult mice revealed that both of these functions were required throughout life. Our findings delineate genetically separable roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations.
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•ADAR1 is a specific negative regulator of the MDA5-MAVS antiviral response•A substantial fraction of ADAR1-controlled gene expression is MAVS independent•ADAR1 is essential for multi-organ development•ADAR1 isoforms independently contribute to regulation of MDA5 and developmental pathways
ADAR mutations cause Aicardi-Goutières syndrome, a severe human autoimmune disease, but how ADAR1 regulates autoimmunity remains unknown. Stetson and colleagues reveal two functions for ADAR1: prevention of MDA5- and MAVS-dependent autoimmunity and control of multi-organ development.
Chromatin remodeling during DNA double-strand break (DSB) repair is required to facilitate access to and repair of DSBs. This remodeling requires increased acetylation of histones and a shift in ...nucleosome organization to create open, relaxed chromatin domains. However, the underlying mechanism driving changes in nucleosome structure at DSBs is poorly defined. Here, we demonstrate that histone H2A.Z is exchanged onto nucleosomes at DSBs by the p400 remodeling ATPase. H2A.Z exchange at DSBs shifts the chromatin to an open conformation and is required for acetylation and ubiquitination of histones and for loading of the brca1 complex. H2A.Z exchange also restricts single-stranded DNA production by nucleases and is required for loading of the Ku70/Ku80 DSB repair protein. H2A.Z exchange therefore promotes specific patterns of histone modification and reorganization of the chromatin architecture, leading to the assembly of a chromatin template that is an efficient substrate for the DSB repair machinery.
► H2A.Z is exchanged onto nucleosomes at DSBs by the p400 remodeling ATPase ► H2A.Z exchange creates open, relaxed chromatin domains at DSBs ► H2A.Z exchange promotes histone acetylation and chromatin ubiquitination ► H2A.Z restricts end resection and promotes correct processing of damaged chromatin
Speciation generally involves a three-step process--range expansion, range fragmentation and the development of reproductive isolation between spatially separated populations. Speciation relies on ...cycling through these three steps and each may limit the rate at which new species form. We estimate phylogenetic relationships among all Himalayan songbirds to ask whether the development of reproductive isolation and ecological competition, both factors that limit range expansions, set an ultimate limit on speciation. Based on a phylogeny for all 358 species distributed along the eastern elevational gradient, here we show that body size and shape differences evolved early in the radiation, with the elevational band occupied by a species evolving later. These results are consistent with competition for niche space limiting species accumulation. Even the elevation dimension seems to be approaching ecological saturation, because the closest relatives both inside the assemblage and elsewhere in the Himalayas are on average separated by more than five million years, which is longer than it generally takes for reproductive isolation to be completed; also, elevational distributions are well explained by resource availability, notably the abundance of arthropods, and not by differences in diversification rates in different elevational zones. Our results imply that speciation rate is ultimately set by niche filling (that is, ecological competition for resources), rather than by the rate of acquisition of reproductive isolation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prediction of metabolic changes that result from genetic or environmental perturbations has several important applications, including diagnosing metabolic disorders and discovering novel drug ...targets. A cardinal challenge in obtaining accurate predictions is the integration of transcriptional regulatory networks with the corresponding metabolic network. We propose a method called probabilistic regulation of metabolism (PROM) that achieves this synthesis and enables straightforward, automated, and quantitative integration of high-throughput data into constraint-based modeling, making it an ideal tool for constructing genome-scale regulatory-metabolic network models for less-studied organisms. PROM introduces probabilities to represent gene states and gene-transcription factor interactions. By using PROM, we constructed an integrated regulatory-metabolic network for the model organism, Escherichia coli, and demonstrated that our method based on automated inference is more accurate and comprehensive than the current state of the art, which is based on manual curation of literature. After validating the approach, we used PROM to build a genome-scale integrated metabolic-regulatory model for Mycobacterium tuberculosis, a critically important human pathogen. This study incorporated data from more than 1,300 microarrays, 2,000 transcription factor-target interactions regulating 3,300 metabolic reactions, and 1,905 KO phenotypes for E. coli and M. tuberculosis. PROM identified KO phenotypes with accuracies as high as 95%, and predicted growth rates quantitatively with correlation of 0.95. Importantly, PROM represents the successful integration of a top-down reconstructed, statistically inferred regulatory network with a bottom-up reconstructed, biochemically detailed metabolic network, bridging two important classes of systems biology models that are rarely combined quantitatively.
We report the first detections of the repeating fast radio burst source FRB 121102 above 5.2 GHz. Observations were performed using the 4-8 GHz receiver of the Robert C. Byrd Green Bank Telescope ...with the Breakthrough Listen digital backend. We present the spectral, temporal, and polarization properties of 21 bursts detected within the first 60 minutes of a total of 6 hr of observations. These observations comprise the highest burst density yet reported in the literature, with 18 bursts being detected in the first 30 minutes. A few bursts clearly show temporal sub-structure with distinct spectral properties. These sub-structures superimpose to provide an enhanced peak signal-to-noise ratio at higher trial dispersion measures. Broad features occur in ∼1 GHz wide subbands that typically differ in peak frequency between bursts within the band. Finer-scale structures (∼10-50 MHz) within these bursts are consistent with the structure expected from Galactic diffractive interstellar scintillation. The bursts exhibit nearly 100% linear polarization, and a large average rotation measure of 9.359 0.012 × 104 rad m−2 (in the observer's frame). No circular polarization was found for any burst. We measure an approximately constant polarization position angle in the 13 brightest bursts. The peak flux densities of the reported bursts have average values (0.2 0.1 Jy) similar to those seen at lower frequencies (<3 GHz), while the average burst widths (0.64 0.46 ms) are relatively narrower.
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