All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears ...the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We update the all-sky Planck catalogue of 1227 clusters and cluster candidates (PSZ1) published in March 2013, derived from detections of the Sunyaev–Zeldovich (SZ) effect using the first 15.5 months ...of Planck satellite observations. As an addendum, we deliver an updated version of the PSZ1 catalogue, reporting the further confirmation of 86 Planck-discovered clusters. In total, the PSZ1 now contains 947 confirmed clusters, of which 214 were confirmed as newly discovered clusters through follow-up observations undertaken by the Planck Collaboration. The updated PSZ1 contains redshifts for 913 systems, of which 736 (~ 80.6%) are spectroscopic, and associated mass estimates derived from the Yz mass proxy. We also provide a new SZ quality flag for the remaining 280 candidates. This flag was derived from a novel artificial neural-network classification of the SZ signal. Based on this assessment, the purity of the updated PSZ1 catalogue is estimated to be 94%. In this release, we provide the full updated catalogue and an additional readme file with further information on the Planck SZ detections.
Planck 2015 results Adam, R; Ade, P A R; Aghanim, N ...
Astronomy and astrophysics (Berlin),
10/2016, Letnik:
594
Journal Article
Recenzirano
Odprti dostop
This paper describes the processing applied to the cleaned, time-ordered information obtained from the Planck High Frequency Instrument (HFI) with the aim of producing photometrically calibrated maps ...in temperature and (for the first time) in polarization. The data from the entire 2.5-year HFI mission include almost five full-sky surveys. HFI observes the sky over a broad range of frequencies, from 100 to 857GHz. To obtain the best accuracy on the calibration over such a large range, two different photometric calibration schemes have been used. The 545 and 857GHz data are calibrated using models of planetary atmospheric emission. The lower frequencies (from 100 to 353GHz) are calibrated using the time-variable cosmological microwave background dipole, which we call the orbital dipole. This source of calibration only depends on the satellite velocity with respect to the solar system. Using a CMB temperature of T sub(CMB)= 2.7255 + or - 0.0006 K, it permits an independent measurement of the amplitude of the CMB solar dipole (3364.3 + or - 1.5 muK), which is approximatively 1sigma higher than the WMAP measurement with a direction that is consistent between the two experiments. We describe the pipeline used to produce the maps ofintensity and linear polarization from the HFI timelines, and the scheme used to set the zero level of the maps a posteriori. We also summarize the noise characteristics of the HFI maps in the 2015 Planck data release and present some null tests to assess their quality. Finally, we discuss the major systematic effects and in particular the leakage induced by flux mismatch between the detectors that leads to spurious polarization signal.
Objective
To identify whether abnormal electroencephalography (EEG) connectivity is present before the onset of epileptic spasms (ES) in infants with tuberous sclerosis complex (TSC).
Methods
Scalp ...EEG recordings were collected prospectively in infants diagnosed with TSC in the first year of life. This study compared the earliest recorded EEG from infants prior to ES onset (n = 16) and from infants who did not develop ES (n = 28). Five minutes of stage II or quiet sleep was clipped and filtered into canonical EEG frequency bands. Mutual information values between each pair of EEG channels were compared directly and used as a weighted graph to calculate graph measures of global efficiency, characteristic path length, average clustering coefficient, and modularity.
Results
At the group level, infants who later developed ES had increased EEG connectivity in sleep. They had higher mutual information values between most EEG channels in all frequency bands adjusted for age. Infants who later developed ES had higher global efficiency and average clustering coefficients, shorter characteristic path lengths, and lower modularity across most frequency bands adjusted for age. This suggests that infants who went on to develop ES had increased local and long‐range EEG connectivity with less segregation of graph regions into distinct modules.
Significance
This study suggests that increased neural connectivity precedes clinical ES onset in a cohort of infants with TSC. Overconnectivity may reflect progressive pathologic network synchronization culminating in generalized ES. Further research is needed before scalp EEG connectivity measures can be used as a potential biomarker of ES risk and treatment response in pre‐symptomatic infants with TSC.
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•A fully-automated SISCAPA–MALDI-TOF-MS assay was developed for apoA-I and apoB-100.•The assay allowed processing and analysis of 96 samples in one day.•The imprecision (4 replicates, ...5days, 2 sera) was below 5% for both proteins.•Quantification of 93 patient sera agreed well with clinical immunoturbidimetry.•Analytical validation demonstrated selectivity and ruggedness of the assay.
A fully automated workflow was developed and validated for simultaneous quantification of the cardiovascular disease risk markers apolipoproteins A-I (apoA-I) and B-100 (apoB-100) in clinical sera. By coupling of stable-isotope standards and capture by anti-peptide antibodies (SISCAPA) for enrichment of proteotypic peptides from serum digests to matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS detection, the standardized platform enabled rapid, liquid chromatography-free quantification at a relatively high throughput of 96 samples in 12h. The average imprecision in normo- and triglyceridemic serum pools was 3.8% for apoA-I and 4.2% for apoB-100 (4 replicates over 5days). If stored properly, the MALDI target containing enriched apoA-1 and apoB-100 peptides could be re-analyzed without any effect on bias or imprecision for at least 7days after initial analysis. Validation of the workflow revealed excellent linearity for daily calibration with external, serum-based calibrators (R2 of 0.984 for apoA-I and 0.976 for apoB-100 as average over five days), and absence of matrix effects or interference from triglycerides, protein content, hemolysates, or bilirubins. Quantification of apoA-I in 93 normo- and hypertriglyceridemic clinical sera showed good agreement with immunoturbidimetric analysis (slope=1.01, R2=0.95, mean bias=4.0%). Measurement of apoB-100 in the same clinical sera using both methods, however, revealed several outliers in SISCAPA–MALDI-TOF-MS measurements, possibly as a result of the lower MALDI-TOF-MS signal intensity (slope=1.09, R2=0.91, mean bias=2.0%).
The combination of analytical performance, rapid cycle time and automation potential validate the SISCAPA–MALDI-TOF-MS platform as a valuable approach for standardized and high-throughput quantification of apoA-I and apoB-100 in large sample cohorts.
The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances β-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, ...which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 × 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.
Alexithymia is a personality trait characterized by difficulties identifying and describing feelings (DIF and DDF) and an externally oriented thinking (EOT) style. The primary aim of the present ...study was to investigate links between alexithymia and the evaluation of emotional scenes. We also investigated whether viewers’ evaluations of emotional scenes were better predicted by specific alexithymic traits or by individual differences in sensory processing sensitivity (SPS). Participants (
N
= 106) completed measures of alexithymia and SPS along with a task requiring speeded judgments of the pleasantness of 120 moderately arousing scenes. We did not replicate laterality effects previously described with the scene perception task. Compared to those with weak alexithymic traits, individuals with moderate-to-strong alexithymic traits were less likely to classify positively valenced scenes as pleasant and were less likely to classify scenes with (vs. without) implied motion (IM) in a way that was consistent with normative scene valence ratings. In addition, regression analyses confirmed that reporting strong EOT and a tendency to be easily overwhelmed by busy sensory environments negatively predicted classification accuracy for positive scenes, and that both DDF and EOT negatively predicted classification accuracy for scenes depicting IM. These findings highlight the importance of accounting for stimulus characteristics and individual differences in specific traits associated with alexithymia and SPS when investigating the processing of emotional stimuli. Learning more about the links between these individual difference variables may have significant clinical implications, given that alexithymia is an important, transdiagnostic risk factor for a wide range of psychopathologies.
Abstract
Cadmium exposure is ubiquitous and has been linked to diseases including cancers and reproductive defects. Since cadmium is nonmutagenic, it is thought to exert its gene dysregulatory ...effects through epigenetic reprogramming. Several studies have implicated germline exposure to cadmium in developmental reprogramming. However, most of these studies have focused on maternal exposure, while the impact on sperm fertility and disease susceptibility has received less attention. In this study, we used reduced representation bisulfite sequencing to comprehensively investigate the impact of chronic cadmium exposure on mouse spermatozoa DNA methylation. Adult male C57BL/J6 mice were provided water with or without cadmium chloride for 9 weeks. Sperm, testes, liver, and kidney tissues were collected at the end of the treatment period. Cadmium exposure was confirmed through gene expression analysis of metallothionein-1 and 2, 2 well-known cadmium-induced genes. Analysis of sperm DNA methylation changes revealed 1788 differentially methylated sites present at regulatory regions in sperm of mice exposed to cadmium compared with vehicle (control) mice. Furthermore, most of these differential methylation changes positively correlated with changes in gene expression at both the transcription initiation stage as well as the splicing levels. Interestingly, the genes targeted by cadmium exposure are involved in several critical developmental processes. Our results present a comprehensive analysis of the sperm methylome in response to chronic cadmium exposure. These data, therefore, highlight a foundational framework to study gene expression patterns that may affect fertility in the exposed individual as well as their offspring, through paternal inheritance.
Planck 2015 results Adam, R; Ade, P A R; Aghanim, N ...
Astronomy and astrophysics (Berlin),
10/2016, Letnik:
594
Journal Article
Recenzirano
Odprti dostop
Planck has mapped the microwave sky in temperature over nine frequency bands between 30 and 857GHz and in polarization over seven frequency bands between 30 and 353GHz in polarization. In this paper ...we consider the problem of diffuse astrophysical component separation, and process these maps within a Bayesian framework to derive an internally consistent set of full-sky astrophysical component maps. Component separation dedicated to cosmic microwave background (CMB) reconstruction is described in a companion paper. For the temperature analysis, we combine the Planck observations with the 9-yr Wilkinson Microwave Anisotropy Probe (WMAP) sky maps and the Haslam et al. 408MHz map, to derive a joint model of CMB, synchrotron, free-free, spinning dust, CO, line emission in the 94 and 100GHz channels, and thermal dust emission. Full-sky maps are provided for each component, with an angular resolution varying between 7.5 and 1deg. Global parameters (monopoles, dipoles, relative calibration, and bandpass errors) are fitted jointly with the sky model, and best-fit values are tabulated. For polarization, the model includes CMB, synchrotron, and thermal dust emission. These models provide excellent fits to the observed data, with rms temperature residuals smaller than 4muK over 93% of the sky for all Planck frequencies up to 353GHz, and fractional errors smaller than 1% in the remaining 7% of the sky. The main limitations of the temperature model at the lower frequencies are internal degeneracies among the spinning dust, free-free, and synchrotron components; additional observations from external low-frequency experiments will be essential to break these degeneracies. The main limitations of the temperature model at the higher frequencies are uncertainties in the 545 and 857GHz calibration and zero-points. For polarization, the main outstanding issues are instrumental systematics in the 100-353GHz bands on large angular scales in the form of temperature-to-polarization leakage, uncertainties in the analogue-to-digital conversion, and corrections for the very long time constant of the bolometer detectors, all of which are expected to improve in the near future.
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