In this work, we present the first experimental upper limits on the presence of stochastic gravitational waves in a frequency band with frequencies above 1 THz. We exclude gravitational waves in the ...frequency bands from
2.7
-
14
×
10
14
Hz and
5
-
12
×
10
18
Hz down to a characteristic amplitude of
h
c
min
≈
6
×
10
-
26
and
h
c
min
≈
5
×
10
-
28
at 95% confidence level, respectively. To obtain these results, we used data from existing facilities that have been constructed and operated with the aim of detecting weakly interacting slim particles, pointing out that these facilities are also sensitive to gravitational waves by graviton to photon conversion in the presence of a magnetic field. The principle applies to all experiments of this kind, with prospects of constraining (or detecting), for example, gravitational waves from light primordial black-hole evaporation in the early universe.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatocyte cell death via apoptosis and necrosis are major hallmarks of ethanol‐induced liver injury. However, inhibition of apoptosis is not sufficient to prevent ethanol‐induced hepatocyte injury ...or inflammation. Because receptor‐interacting protein kinase (RIP) 3–mediated necroptosis, a nonapoptotic cell death pathway, is implicated in a variety of pathological conditions, we tested the hypothesis that ethanol‐induced liver injury is RIP3‐dependent and RIP1‐independent. Increased expression of RIP3 was detected in livers of mice after chronic ethanol feeding, as well as in liver biopsies from patients with alcoholic liver disease. Chronic ethanol feeding failed to induce RIP3 in the livers of cytochrome P450 2E1 (CYP2E1)‐deficient mice, indicating CYP2E1‐mediated ethanol metabolism is critical for RIP3 expression in response to ethanol feeding. Mice lacking RIP3 were protected from ethanol‐induced steatosis, hepatocyte injury, and expression of proinflammatory cytokines. In contrast, RIP1 expression in mouse liver remained unchanged following ethanol feeding, and inhibition of RIP1 kinase by necrostatin‐1 did not attenuate ethanol‐induced hepatocyte injury. Ethanol‐induced apoptosis, assessed by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling–positive nuclei and accumulation of cytokeratin‐18 fragments in the liver, was independent of RIP3. Conclusion: CYP2E1‐dependent RIP3 expression induces hepatocyte necroptosis during ethanol feeding. Ethanol‐induced hepatocyte injury is RIP3‐dependent, but independent of RIP1 kinase activity; intervention of this pathway could be targeted as a potential therapeutic strategy. (HEPATOLOGY 2013)
Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional ...prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD+) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD+ pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD+ can be prophylactic or therapeutic in HCC.
•URI causes NAD+ depletion-dependent DNA damage leading to HCC development•Restoring NAD+ pools in vivo protects from DNA damage and HCC•URI inhibits AhR/ER transcriptional activity-mediated de novo NAD+ synthesis•URI-mediated de novo NAD+ synthesis inhibition may occur in human HCC
Tummala et al. show that overexpression of URI in mouse liver inhibits NAD+ metabolism, thereby causing DNA damage and tumorigenesis. Importantly, restoring NAD+ pools prevents DNA damage and tumor formation. URI expression in human HCC correlates negatively with L-tryptophan catabolism and patient survival.
Distinct DNA methylomes of newborns and centenarians Heyn, Holger; Li, Ning; Ferreira, Humberto J. ...
Proceedings of the National Academy of Sciences - PNAS,
06/2012, Letnik:
109, Številka:
26
Journal Article
Recenzirano
Odprti dostop
Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we ...performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine—phosphate—guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.
Context.
Large field-of-view imaging and polarimetry instruments operating at millimetre and sub-millimetre wavelengths are fundamental tools to understand the role of magnetic fields in channelling ...filament material into prestellar cores, providing unique insight in the physics of galactic star-forming regions. Among other topics, at extra-galactic scales, polarisation observations of Active Galactic Nuclei (AGNs) will allow us to constrain the possible physical conditions of the emitting plasma from the jets and/or explore the physics of dust inside supernova remnants. The kilo-pixel New IRAM KIDs Array 2 (NIKA2) camera, installed today at the Institut de Radioastronomie Millimétrique (IRAM) 30-m telescope, represents one of the best tools available to astronomers to produce simultaneous intensity and polarimetry maps over large fields at 260 GHz (1.15 mm).
Aims.
The polarisation measurement, in NIKA and NIKA2, is achieved by rapidly modulating the total incoming polarisation. In the end, this allows one to safely isolate the small science signal from the large, un-polarised, and strongly variable, atmospheric background.
Methods.
The polarisation modulation is achieved by inserting a fast rotating half-wave plate (HWP) in the optical beam. In order to allow wide field-of-view observations, the plate has to be large, with a diameter of 250 mm. The modulation of the polarised signal at 12 Hz also requires the waveplate to be sufficiently light. In addition, this key optical element has to exhibit optimal electromagnetic characteristics in terms of transmission and differential phase-shift. For this purpose, three metamaterial HWPs have been developed using the mesh-filter technology. The knowledge acquired in developing the first two single-band HWPs was used to achieve the more challenging performance requirements of the last dual-band HWP. The first and the third waveplates met the requirements for both the NIKA and NIKA2 instruments.
Results.
We first illustrate the design, the technical developments, the fabrication, and laboratory characterisation of the three mesh-HWPs. The deployment of two such elements in the NIKA and NIKA2 instruments at the 30-metre telescope is then described. We conclude with representative examples of astrophysical maps integrating polarimetry.
Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the ...disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes-most of which are not differentially expressed-exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences.
Rap1 is a component of the shelterin complex at mammalian telomeres, but its in vivo role in telomere biology has remained largely unknown to date. Here we show that Rap1 deficiency is dispensable ...for telomere capping but leads to increased telomere recombination and fragility. We generated cells and mice deleted for Rap1; mice with Rap1 deletion in stratified epithelia were viable but had shorter telomeres and developed skin hyperpigmentation in adulthood. By performing chromatin immunoprecipitation coupled with ultrahigh-throughput sequencing, we found that Rap1 binds to both telomeres and to extratelomeric sites through the (TTAGGG)(2) consensus motif. Extratelomeric Rap1-binding sites were enriched at subtelomeric regions, in agreement with preferential deregulation of subtelomeric genes in Rap1-deficient cells. More than 70% of extratelomeric Rap1-binding sites were in the vicinity of genes, and 31% of the genes deregulated in Rap1-null cells contained Rap1-binding sites, suggesting a role for Rap1 in transcriptional control. These findings place a telomere protein at the interface between telomere function and transcriptional regulation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We study the propagation of a specific class of instrumental systematics to the reconstruction of the
B
-mode power spectrum of the cosmic microwave background (CMB). We focus on the non-idealities ...of the half-wave plate (HWP), a polarization modulator that is to be deployed by future CMB experiments, such as the phase-A satellite mission LiteBIRD. We study the effects of non-ideal HWP properties, such as transmittance, phase shift, and cross-polarization. To this end, we developed a simple, yet stand-alone end-to-end simulation pipeline adapted to LiteBIRD. We analyzed the effects of a possible mismatch between the measured frequency profiles of HWP properties (used in the mapmaking stage of the pipeline) and the actual profiles (used in the sky-scanning step). We simulated single-frequency, CMB-only observations to emphasize the effects of non-idealities on the BB power spectrum. We also considered multi-frequency observations to account for the frequency dependence of HWP properties and the contribution of foreground emission. We quantified the systematic effects in terms of a bias Δ
r
on the tensor-to-scalar ratio,
r
, with respect to the ideal case without systematic effects. We derived the accuracy requirements on the measurements of HWP properties by requiring Δ
r
< 10
−5
(1% of the expected LiteBIRD sensitivity on
r
). Our analysis is introduced by a detailed presentation of the mathematical formalism employed in this work, including the use of the Jones and Mueller matrix representations.
Telomeric RNAs (TERRAs) are UUAGGG repeat-containing RNAs that are transcribed from the subtelomere towards the telomere. The precise genomic origin of TERRA has remained elusive. Using a ...whole-genome RNA-sequencing approach, we identify novel mouse transcripts arising mainly from the subtelomere of chromosome 18, and to a lesser extend chromosome 9, that resemble TERRA in several key aspects. Those transcripts contain UUAGGG-repeats and are heterogeneous in size, fluctuate in abundance in a TERRA-like manner during the cell cycle, are bound by TERRA RNA-binding proteins and are regulated in a manner similar to TERRA in response to stress and the induction of pluripotency. These transcripts are also found to associate with nearly all chromosome ends and downregulation of the transcripts that originate from chromosome 18 causes a reduction in TERRA abundance. Interestingly, downregulation of either chromosome 18 transcripts or TERRA results in increased number of telomere dysfunction-induced foci, suggesting a protective role at telomeres.
PDF
