| 1. |
- Niemi, MEK, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 2. |
- Adrian-Martinez, S., et al.
(författare)
-
A first search for coincident gravitational waves and high energy neutrinos using LIGO, Virgo and ANTARES data from 2007
- 2013
-
Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :6
-
Tidskriftsartikel (refereegranskat)abstract
- We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.
|
|
| 3. |
- Aasi, J., et al.
(författare)
-
Einstein@Home all-sky search for periodic gravitational waves in LIGO S5 data
- 2013
-
Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 87:4
-
Tidskriftsartikel (refereegranskat)abstract
- This paper presents results of an all-sky search for periodic gravitational waves in the frequency range [50, 1190] Hz and with frequency derivative range of similar to[-20, 1.1] x 10(-10) Hz s(-1) for the fifth LIGO science run (S5). The search uses a noncoherent Hough-transform method to combine the information from coherent searches on time scales of about one day. Because these searches are very computationally intensive, they have been carried out with the Einstein@Home volunteer distributed computing project. Postprocessing identifies eight candidate signals; deeper follow-up studies rule them out. Hence, since no gravitational wave signals have been found, we report upper limits on the intrinsic gravitational wave strain amplitude h(0). For example, in the 0.5 Hz-wide band at 152.5 Hz, we can exclude the presence of signals with h(0) greater than 7.6 x 10(-25) at a 90% confidence level. This search is about a factor 3 more sensitive than the previous Einstein@Home search of early S5 LIGO data.
|
|
| 4. |
- Aasi, J., et al.
(författare)
-
The characterization of Virgo data and its impact on gravitational-wave searches
- 2012
-
Ingår i: Classical and Quantum Gravity. - : IOP Publishing. - 1361-6382 .- 0264-9381. ; 29:15
-
Tidskriftsartikel (refereegranskat)abstract
- Between 2007 and 2010 Virgo collected data in coincidence with the LIGO and GEO gravitational-wave (GW) detectors. These data have been searched for GWs emitted by cataclysmic phenomena in the universe, by non-axisymmetric rotating neutron stars or from a stochastic background in the frequency band of the detectors. The sensitivity of GW searches is limited by noise produced by the detector or its environment. It is therefore crucial to characterize the various noise sources in a GW detector. This paper reviews the Virgo detector noise sources, noise propagation, and conversion mechanisms which were identified in the three first Virgo observing runs. In many cases, these investigations allowed us to mitigate noise sources in the detector, or to selectively flag noise events and discard them from the data. We present examples from the joint LIGO-GEO-Virgo GW searches to show how well noise transients and narrow spectral lines have been identified and excluded from the Virgo data. We also discuss how detector characterization can improve the astrophysical reach of GW searches.
|
|
| 5. |
- Evans, P. A., et al.
(författare)
-
Swift Follow-up Observations of Candidate Gravitational-wave Transient Events
- 2012
-
Ingår i: The Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 203:2
-
Tidskriftsartikel (refereegranskat)abstract
- We present the first multi-wavelength follow-up observations of two candidate gravitational-wave (GW) transient events recorded by LIGO and Virgo in their 2009-2010 science run. The events were selected with low latency by the network of GW detectors (within less than 10 minutes) and their candidate sky locations were observed by the Swift observatory (within 12 hr). Image transient detection was used to analyze the collected electromagnetic data, which were found to be consistent with background. Off-line analysis of the GW data alone has also established that the selected GW events show no evidence of an astrophysical origin; one of them is consistent with background and the other one was a test, part of a "blind injection challenge." With this work we demonstrate the feasibility of rapid follow-ups of GW transients and establish the sensitivity improvement joint electromagnetic and GW observations could bring. This is a first step toward an electromagnetic follow-up program in the regime of routine detections with the advanced GW instruments expected within this decade. In that regime, multi-wavelength observations will play a significant role in completing the astrophysical identification of GW sources. We present the methods and results from this first combined analysis and discuss its implications in terms of sensitivity for the present and future instruments.
|
|
| 6. |
- Aasi, J., et al.
(författare)
-
Parameter estimation for compact binary coalescence signals with the first generation gravitational-wave detector network
- 2013
-
Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 88:6
-
Tidskriftsartikel (refereegranskat)abstract
- Compact binary systems with neutron stars or black holes are one of the most promising sources for ground-based gravitational-wave detectors. Gravitational radiation encodes rich information about source physics; thus parameter estimation and model selection are crucial analysis steps for any detection candidate events. Detailed models of the anticipated waveforms enable inference on several parameters, such as component masses, spins, sky location and distance, that are essential for new astrophysical studies of these sources. However, accurate measurements of these parameters and discrimination of models describing the underlying physics are complicated by artifacts in the data, uncertainties in the waveform models and in the calibration of the detectors. Here we report such measurements on a selection of simulated signals added either in hardware or software to the data collected by the two LIGO instruments and the Virgo detector during their most recent joint science run, including a "blind injection'' where the signal was not initially revealed to the collaboration. We exemplify the ability to extract information about the source physics on signals that cover the neutron-star and black-hole binary parameter space over the component mass range 1M(circle dot)-25M(circle dot) and the full range of spin parameters. The cases reported in this study provide a snapshot of the status of parameter estimation in preparation for the operation of advanced detectors.
|
|
| 7. |
- Aasi, J., et al.
(författare)
-
Search for gravitational waves from binary black hole inspiral, merger, and ringdown in LIGO-Virgo data from 2009-2010
- 2013
-
Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 87:2
-
Tidskriftsartikel (refereegranskat)abstract
- We report a search for gravitational waves from the inspiral, merger and ringdown of binary black holes (BBH) with total mass between 25 and 100 solar masses, in data taken at the LIGO and Virgo observatories between July 7, 2009 and October 20, 2010. The maximum sensitive distance of the detectors over this period for a (20, 20)M-circle dot coalescence was 300 Mpc. No gravitational wave signals were found. We thus report upper limits on the astrophysical coalescence rates of BBH as a function of the component masses for nonspinning components, and also evaluate the dependence of the search sensitivity on component spins aligned with the orbital angular momentum. We find an upper limit at 90% confidence on the coalescence rate of BBH with nonspinning components of mass between 19 and 28M(circle dot) of 3:3 x 10(-7) mergers Mpc(-3) yr(-1).
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
- Willems, S. M., et al.
(författare)
-
Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
- 2017
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality. © The Author(s) 2017.
|
|
| 13. |
- Borges, A. H., et al.
(författare)
-
Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor-based Regimens for Initial Treatment of HIV Infection: A Systematic Review and Metaanalysis of Randomized Trials
- 2016
-
Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 63:2, s. 268-280
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. Methods. We searched databases to identify randomized trials that compared NNRTI-vs PI/r-based initial therapy. A meta-analysis calculated risk ratios (RRs) or mean differences (MDs), as appropriate. Primary outcome was death or progression to AIDS. Secondary outcomes were death, progression to AIDS, and treatment discontinuation. We calculated RR of virologic suppression and MD for an increase in CD4 cells at week 48. Results. We included 29 trials with 9047 participants. Death or progression to AIDS occurred in 226 participants in the NNRTI arm and in 221 in the PI/r arm (RR, 1.03; 95% confidence interval, .87-1.22; 12 trials; n = 3825), death in 205 participants in the NNRTI arm vs 198 in the PI/r arm (1.04; 0.86-1.25; 22 trials; n = 8311), and progression to AIDS in 140 participants in the NNRTI arm vs 144 in the PI/r arm (1.00; 0.80-1.25; 13 trials; n = 4740). Overall treatment discontinuation (1.12; 0.93-1.35; 24 trials; n = 8249) and from toxicity (1.21; 0.87-1.68; 21 trials; n = 6195) were comparable, but discontinuation due to virologic failure was more common with NNRTI (1.58; 0.91-2.74; 17 trials; n = 5371). At week 48, there was no difference between NNRTI and PI/r in virologic suppression (RR, 1.03; 0.98-1.09) or CD4(+) recovery (MD, -4.7 cells; -14.2 to 4.8). Conclusions. We found no difference in clinical and viro-immunologic outcomes between NNRTI-and PI/r-based therapy.
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Lobell, Anna, et al.
(författare)
-
Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts
- 2014
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
|
|
| 18. |
- Lutman, A. A., et al.
(författare)
-
Polarization control in an X-ray free-electron laser
- 2016
-
Ingår i: Nature Photonics. - : Springer Science and Business Media LLC. - 1749-4885 .- 1749-4893. ; 10:7, s. 468-472
-
Tidskriftsartikel (refereegranskat)abstract
- X-ray free-electron lasers are unique sources of high-brightness coherent radiation. However, existing devices supply only linearly polarized light, precluding studies of chiral dynamics. A device called the Delta undulator has been installed at the Linac Coherent Light Source (LCLS) to provide tunable polarization. With a reverse tapered planar undulator line to pre-microbunch the beam and the novel technique of beam diverting, hundreds of microjoules of circularly polarized X-ray pulses are produced at 500-1,200 eV. These X-ray pulses are tens of femtoseconds long, have a degree of circular polarization of 0.98(+0.02)(-0.04) at 707 eV and may be scanned in energy. We also present a new two-colour X-ray pump-X-ray probe operating mode for the LCLS. Energy differences of Delta E/E = 2.4% are supported, and the second pulse can be adjusted to any elliptical polarization. In this mode, the pointing, timing, intensity and wavelength of the two pulses can be modified.
|
|
| 19. |
|
|
| 20. |
- Burdett, Heidi L., et al.
(författare)
-
Dynamic photoinhibition exhibited by red coralline algae in the red sea
- 2014
-
Ingår i: BMC Plant Biology. - : BioMed Central. - 1471-2229. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Red coralline algae are critical components of tropical reef systems, and their success and development is, at least in part, dependent on photosynthesis. However, natural variability in the photosynthetic characteristics of red coralline algae is poorly understood. This study investigated diurnal variability in encrusting Porolithon sp. and free-living Lithophyllum kotschyanum. Measured parameters included: photosynthetic characteristics, pigment composition, thallus reflectance and intracellular concentrations of dimethylsulphoniopropionate (DMSP), an algal antioxidant that is derived from methionine, an indirect product of photosynthesis. L. kotschyanum thalli were characterised by a bleached topside and a pigmented underside.Results: Minimum saturation intensity and intracellular DMSP concentrations in Porolithon sp. were characterised by significant diurnal patterns in response to the high-light regime. A smaller diurnal pattern in minimum saturation intensity in the topside of L. kotschyanum was also evident. The overall reflectance of the topside of L. kotschyanum also exhibited a diurnal pattern, becoming increasingly reflective with increasing ambient irradiance. The underside of L. kotschyanum, which is shaded from ambient light exposure, exhibited a much smaller diurnal variability.Conclusions: This study highlights a number of dynamic photoinhibition strategies adopted by coralline algae, enabling them to tolerate, rather than be inhibited by, the naturally high irradiance of tropical reef systems; a factor that may become more important in the future under global change projections. In this context, this research has significant implications for tropical reef management planning and conservation monitoring, which, if natural variability is not taken into account, may become flawed. The information provided by this research may be used to inform future investigations into the contribution of coralline algae to reef accretion, ecosystem service provision and palaeoenvironmental reconstruction.
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
- Glinos, Dafni A., et al.
(författare)
-
Transcriptome variation in human tissues revealed by long-read sequencing
- 2022
-
Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 608:7922, s. 353-359
-
Tidskriftsartikel (refereegranskat)abstract
- Regulation of transcript structure generates transcript diversity and plays an important role in human disease(1-7). The advent oflong-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure(8-)(16). In this Article, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from Genotype-Tissue Expression (GTEx) tissues and cell lines, complementing the GTEx resource. We identified just over 70,000 novel transcripts for annotated genes, and validated the protein expression of 10% of novel transcripts. We developed a new computational package, LORALS, to analyse the genetic effects of rare and common variants on the transcriptome by allele-specific analysis of long reads. We characterized allele-specific expression and transcript structure events, providing new insights into the specific transcript alterations caused by common and rare genetic variants and highlighting the resolution gained from long-read data. We were able to perturb the transcript structure upon knockdown of PTBP1, an RNA binding protein that mediates splicing, thereby finding genetic regulatory effects that are modified by the cellular environment. Finally, we used this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns.
|
|
| 24. |
- Hartmann, G., et al.
(författare)
-
Circular dichroism measurements at an x-ray free-electron laser with polarization control
- 2016
-
Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 87:8
-
Tidskriftsartikel (refereegranskat)abstract
- A non-destructive diagnostic method for the characterization of circularly polarized, ultraintense, short wavelength free-electron laser (FEL) light is presented. The recently installed Delta undulator at the LCLS (Linac Coherent Light Source) at SLAC National Accelerator Laboratory (USA) was used as showcase for this diagnostic scheme. By applying a combined two-color, multi-photon experiment with polarization control, the degree of circular polarization of the Delta undulator has been determined. Towards this goal, an oriented electronic state in the continuum was created by non-resonant ionization of the O2 1s core shell with circularly polarized FEL pulses at hν 700 eV. An also circularly polarized, highly intense UV laser pulse with hν 3.1 eV was temporally and spatially overlapped, causing the photoelectrons to redistribute into so-called sidebands that are energetically separated by the photon energy of the UV laser. By determining the circular dichroism of these redistributed electrons using angle resolving electron spectroscopy and modeling the results with the strong-field approximation, this scheme allows to unambiguously determine the absolute degree of circular polarization of any pulsed, ultraintense XUV or X-ray laser source. © 2016 Author(s).
|
|
| 25. |
- Jelovsek, J Eric, et al.
(författare)
-
Predicting Risk of Pelvic Floor Disorders 12 and 20 Years after Delivery.
- 2018
-
Ingår i: American journal of obstetrics and gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 218:2
-
Tidskriftsartikel (refereegranskat)abstract
- Little progress has been made in preventing pelvic floor disorders despite their significant health and economic impact. Identifying women at risk remains a key element in targeting prevention and planning health resource allocation strategies. Although events around the time of childbirth are clinically recognized as important predictors, it is difficult to counsel women and intervene around the time of childbirth due to an inability to accurately convey a patient's risk in the presence of multiple risk factors and the long time lapse, often decades, between obstetric events and the onset of pelvic floor disorders later in life. Prediction models and scoring systems have been used in other areas of medicine to identify patients at risk for chronic diseases. Models have been developed for use before delivery that predict short-term risk of pelvic floor disorders after childbirth but no models predicting long-term risk exist.To use variables known before and during childbirth to develop and validate prognostic models estimating risks of these disorders 12 and 20 years after delivery.Obstetric variables were collected from two cohorts: 1) women who gave birth in the United Kingdom and New Zealand (n=3763) and 2) women from the Swedish Medical Birth Register (n=4991). Pelvic floor disorders were self-reported 12 years after childbirth in the UK/NZ cohort and 20 years after childbirth in the Swedish Register. The cohorts were split so that data during the first half of the cohort's time period were used to fit prediction models and validation was performed from the second half (temporal validation). As there is currently no consensus on how to best define pelvic floor disorders from a patient's perspective, we chose to fit the data for each model using multiple outcome definitions for prolapse, urinary incontinence, fecal incontinence, 1 or more pelvic floor disorder and 2 or more pelvic floor disorders. Model accuracy was measured: 1) by ranking an individual's risk among all subjects in the cohort (discrimination) using a concordance index and 2) by observing whether the predicted probability was too high or low (calibration) at a range of predicted probabilities using visual plots.Models were able to discriminate between women who developed bothersome symptoms or received treatment, at 12 and 20 years respectively, for: pelvic organ prolapse (concordance indices 0.570, 0.627), urinary incontinence (concordance indices 0.653, 0.689), fecal incontinence (concordance indices 0.618, 0.676), ≥1 pelvic floor disorders (concordance indices 0.639, 0.675) and ≥2 pelvic floor disorders (concordance indices 0.635, 0.619). The discriminatory ability of all models is shown in Table 2. Route of delivery and family history of each pelvic floor disorder were strong predictors in most models. Urinary incontinence before and during the index pregnancy was a strong predictor for developing all pelvic floor disorders in most models 12 years after delivery. The 12 and 20-year bothersome or treatment for prolapse models were accurate when providing predictions for risk from 0% to approximately 15%. The 12-year and 20-year primiparous model began to over-predict when risk rates reached 20%. When predicting bothersome symptoms or treatment for urinary incontinence, the 12-year models were accurate when predictions ranged from approximately 5% to 60% and 20-year primiparous models were accurate between 5% and 80%. For bothersome symptoms or treatment for fecal incontinence, the 12 and 20-year models were accurate between 1% and 15% risk and began to over-predict at rates above 15% and 20%, respectively.Models may provide an opportunity before birth to identify women at low risk of developing pelvic floor disorders and institute prevention strategies such as pelvic floor muscle training, weight control or elective cesarean section for women at higher risk. Models are provided at: http://riskcalc.org/UR_CHOICE/.
|
|
| 26. |
- Lappalainen, Tuuli, et al.
(författare)
-
From variant to function in human disease genetics
- 2021
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 373:6562, s. 1464-1468
-
Forskningsöversikt (refereegranskat)abstract
- Over the next decade, the primary challenge in human genetics will be to understand the biological mechanisms by which genetic variants influence phenotypes, including disease risk. Although the scale of this challenge is daunting, better methods for functional variant interpretation will have transformative consequences for disease diagnosis, risk prediction, and the development of new therapies. An array of new methods for characterizing variant impact at scale, using patient tissue samples as well as in vitro models, are already being applied to dissect variant mechanisms across a range of human cell types and environments. These approaches are also increasingly being deployed in clinical settings. We discuss the rationale, approaches, applications, and future outlook for characterizing the molecular and cellular effects of genetic variants.
|
|
| 27. |
- MacArthur, Katherine E., et al.
(författare)
-
Optimizing Experimental Conditions for Accurate Quantitative Energy-Dispersive X-ray Analysis of Interfaces at the Atomic Scale
- 2021
-
Ingår i: Microscopy and Microanalysis. - 1435-8115 .- 1431-9276. ; 27:3, s. 528-542
-
Tidskriftsartikel (refereegranskat)abstract
- The invention of silicon drift detectors has resulted in an unprecedented improvement in detection efficiency for energy-dispersive X-ray (EDX) spectroscopy in the scanning transmission electron microscope. The result is numerous beautiful atomic-scale maps, which provide insights into the internal structure of a variety of materials. However, the task still remains to understand exactly where the X-ray signal comes from and how accurately it can be quantified. Unfortunately, when crystals are aligned with a low-order zone axis parallel to the incident beam direction, as is necessary for atomic-resolution imaging, the electron beam channels. When the beam becomes localized in this way, the relationship between the concentration of a particular element and its spectroscopic X-ray signal is generally nonlinear. Here, we discuss the combined effect of both spatial integration and sample tilt for ameliorating the effects of channeling and improving the accuracy of EDX quantification. Both simulations and experimental results will be presented for a perovskite-based oxide interface. We examine how the scattering and spreading of the electron beam can lead to erroneous interpretation of interface compositions, and what approaches can be made to improve our understanding of the underlying atomic structure.
|
|
| 28. |
- Misulovin, Ziva, et al.
(författare)
-
Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome
- 2008
-
Ingår i: Chromosoma. - : Springer Science and Business Media LLC. - 0009-5915 .- 1432-0886. ; 117:1, s. 89-102
-
Tidskriftsartikel (refereegranskat)abstract
- The cohesin complex is a chromosomal component required for sister chromatid cohesion that is conserved from yeast to man. The similarly conserved Nipped-B protein is needed for cohesin to bind to chromosomes. In higher organisms, Nipped-B and cohesin regulate gene expression and development by unknown mechanisms. Using chromatin immunoprecipitation, we find that Nipped-B and cohesin bind to the same sites throughout the entire non-repetitive Drosophila genome. They preferentially bind transcribed regions and overlap with RNA polymerase II. This contrasts sharply with yeast, where cohesin binds almost exclusively between genes. Differences in cohesin and Nipped-B binding between Drosophila cell lines often correlate with differences in gene expression. For example, cohesin and Nipped-B bind the Abd-B homeobox gene in cells in which it is transcribed, but not in cells in which it is silenced. They bind to the Abd-B transcription unit and downstream regulatory region and thus could regulate both transcriptional elongation and activation. We posit that transcription facilitates cohesin binding, perhaps by unfolding chromatin, and that Nipped-B then regulates gene expression by controlling cohesin dynamics. These mechanisms are likely involved in the etiology of Cornelia de Lange syndrome, in which mutation of one copy of the NIPBL gene encoding the human Nipped-B ortholog causes diverse structural and mental birth defects.
|
|
| 29. |
- Rivas, Manuel A., et al.
(författare)
-
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
- 2016
-
Ingår i: Nature Communications. - London, United Kingdom : Nature Publishing Group. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
- Whiffin, N, et al.
(författare)
-
The effect of LRRK2 loss-of-function variants in humans
- 2020
-
Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:6, s. 869-877
-
Tidskriftsartikel (refereegranskat)abstract
- Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
|
|
