| 11. |
- Gharpure, Anant, et al.
(författare)
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Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor
- 2019
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Ingår i: Neuron. - : CELL PRESS. - 0896-6273 .- 1097-4199. ; 104:3, s. 501-
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Tidskriftsartikel (refereegranskat)abstract
- Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha 3 beta 4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha 3 beta 4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha 3 beta 4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.
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| 12. |
- Haycock, Philip C., et al.
(författare)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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Ingår i: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 13. |
- Kristan, Matej, et al.
(författare)
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The Visual Object Tracking VOT2016 Challenge Results
- 2016
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Ingår i: COMPUTER VISION - ECCV 2016 WORKSHOPS, PT II. - Cham : SPRINGER INT PUBLISHING AG. - 9783319488813 - 9783319488806 ; , s. 777-823
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Konferensbidrag (refereegranskat)abstract
- The Visual Object Tracking challenge VOT2016 aims at comparing short-term single-object visual trackers that do not apply pre-learned models of object appearance. Results of 70 trackers are presented, with a large number of trackers being published at major computer vision conferences and journals in the recent years. The number of tested state-of-the-art trackers makes the VOT 2016 the largest and most challenging benchmark on short-term tracking to date. For each participating tracker, a short description is provided in the Appendix. The VOT2016 goes beyond its predecessors by (i) introducing a new semi-automatic ground truth bounding box annotation methodology and (ii) extending the evaluation system with the no-reset experiment.
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| 14. |
- Luo, Xi, et al.
(författare)
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ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants
- 2019
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Ingår i: Blood Advances. - : AMER SOC HEMATOLOGY. - 2473-9529 .- 2473-9537. ; 3:20, s. 2962-2979
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Tidskriftsartikel (refereegranskat)abstract
- Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously classified as benign/likely benign, pathogenic/likely pathogenic, variant of unknown significance (VUS), or conflicting interpretations (CONF) in ClinVar. The application of RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the benefit of gene-specific criteria and sharing internal laboratory data.
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| 15. |
- Pirzkal, Norbert, et al.
(författare)
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A Two-dimensional Spectroscopic Study of Emission-line Galaxies in the Faint Infrared Grism Survey (FIGS). I. Detection Method and Catalog
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 868:1
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Tidskriftsartikel (refereegranskat)abstract
- We present the results from the application of a two-dimensional emission line detection method, EMission-line two-Dimensional (EM2D), to the near-infrared G102 grism observations obtained with the Wide-Field Camera 3 (WFC3) as part of the Cycle 22 Hubble Space Telescope Treasury Program: the Faint Infrared Grism Survey (FIGS). Using the EM2D method, we have assembled a catalog of emission line galaxies (ELGs) with resolved star formation from each of the four FIGS fields. Not only can one better assess the global properties of ELGs, but the EM2D method allows for the analysis and improved study of the individual emission-line region within each galaxy. This paper includes a description of the methodology, advantages, and the first results of the EM2D method applied to ELGs in FIGS. The advantage of 2D emission line measurements includes significant improvement of galaxy redshift measurements, approaching the level of accuracy seen in high-spectral-resolution data, but with greater efficiency; and the ability to identify and measure the properties of multiple sites of star formation and over scales of similar to 1 kpc within individual galaxies out to z similar to 4. The EM2D method also significantly improves the reliability of high-redshift (z similar to 7) Ly alpha detections. Coupled with the wide field of view and high efficiency of space-based grism observations, EM2D provides a noteworthy improvement on the physical parameters that can be extracted from grism observations.
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| 16. |
- Pirzkal, Norbert, et al.
(författare)
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FIGS-Faint Infrared Grism Survey : Description and Data Reduction
- 2017
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 846:1
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Tidskriftsartikel (refereegranskat)abstract
- The Faint Infrared Grism Survey (FIGS) is a deep Hubble Space Telescope (HST) WFC3/IR (Wide Field Camera 3 Infrared) slitless spectroscopic survey of four deep fields. Two fields are located in the Great Observatories Origins Deep Survey-North (GOODS-N) area and two fields are located in the Great Observatories Origins Deep Survey-South (GOODS-S) area. One of the southern fields selected is the Hubble Ultra Deep Field. Each of these four fields were observed using the WFC3/G102 grism (0.8 mu m-1.15 mu m continuous coverage) with a total exposure time of 40 orbits (approximate to 100 kilo-seconds) per field. This reaches a 3 sigma continuum depth of approximate to 26 AB magnitudes and probes emission lines to similar to 10(-17) erg s(-1) cm(-2). This paper details the four FIGS fields and the overall observational strategy of the project. A detailed description of the Simulation Based Extraction (SBE) method used to extract and combine over 10,000 spectra of over 2000 distinct sources brighter than m(F105W) = 26.5 mag is provided. High fidelity simulations of the observations is shown to significantly improve the background subtraction process, the spectral contamination estimates, and the final flux calibration. This allows for the combination of multiple spectra to produce a final high quality, deep, 1D spectra for each object in the survey.
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| 17. |
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| 18. |
- Ryan, L., et al.
(författare)
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Antimicrobial resistance and molecular epidemiology using whole-genome sequencing of Neisseria gonorrhoeae in Ireland, 2014-2016 : focus on extended-spectrum cephalosporins and azithromycin
- 2018
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Ingår i: European Journal of Clinical Microbiology and Infectious Diseases. - : Springer. - 0934-9723 .- 1435-4373. ; 37:9, s. 1661-1672
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Tidskriftsartikel (refereegranskat)abstract
- High-level resistance and treatment failures with ceftriaxone and azithromycin, the first-line agents for gonorrhoea treatment are reported and antimicrobial-resistant Neisseria gonorrhoeae is an urgent public health threat. Our aims were to determine antimicrobial resistance rates, resistance determinants and phylogeny of N. gonorrhoeae in Ireland, 2014-2016. Overall, 609 isolates from four University Hospitals were tested for susceptibility to extended-spectrum cephalosporins (ESCs) and azithromycin by the MIC Test Strips. Forty-three isolates were whole-genome sequenced based on elevated MICs. The resistance rate to ceftriaxone, cefixime, cefotaxime and azithromycin was 0, 1, 2.1 and 19%, respectively. Seven high-level azithromycin-resistant (HLAzi-R) isolates were identified, all susceptible to ceftriaxone. Mosaic penA alleles XXXIV, X and non-mosaic XIII, and G120K plus A121N/D/G (PorB1b), H105Y (MtrR) and A deletion (mtrR promoter) mutations, were associated with elevated ESC MICs. A2059G and C2611T mutations in 23S rRNA were associated with HLAzi-R and azithromycin MICs of 4-32 mg/L, respectively. The 43 whole-genome sequenced isolates belonged to 31 NG-MAST STs. All HLAzi-R isolates belonged to MLST ST1580 and some clonal clustering was observed; however, the isolates differed significantly from the published HLAzi-R isolates from the ongoing UK outbreak. There is good correlation between previously described genetic antimicrobial resistance determinants and phenotypic susceptibility categories for ESCs and azithromycin in N. gonorrhoeae. This work highlights the advantages and potential of whole-genome sequencing to be applied at scale in the surveillance of antibiotic resistant strains of N. gonorrhoeae, both locally and internationally.
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| 19. |
- Tilvi, V., et al.
(författare)
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FIRST RESULTS FROM THE FAINT INFRARED GRISM SURVEY (FIGS) : FIRST SIMULTANEOUS DETECTION OF Ly alpha EMISSION AND LYMAN BREAK FROM A GALAXY AT z=7.51
- 2016
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Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 827:1
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Tidskriftsartikel (refereegranskat)abstract
- Galaxies at high redshifts are a valuable tool for studying cosmic dawn, therefore it is crucial to reliably identify these galaxies. Here, we present an unambiguous and first simultaneous detection of both the Ly alpha emission and the Lyman break from a z = 7.512 +/- 0.004 galaxy, observed in the Faint Infrared Grism Survey (FIGS). These spectra, taken with the G102 grism on the Hubble Space Telescope (HST), show a significant emission line detection (6 sigma) in two observational position angles (PAs), with Lya line flux of 1.06 +/- 0.19 x 10(-17) erg s(-1) cm(-2). The line flux is nearly a factor of four higher than that in the archival MOSFIRE spectroscopic observations. This is consistent with other recent observations, implying that ground-based near-infrared spectroscopy underestimates the total emission line fluxes, and if confirmed, can have strong implications for reionization studies that are based on ground-based Ly alpha measurements. A 4 sigma detection of the NV line in one PA also suggests a weak active galactic nucleus (AGN), and if confirmed, would make this source the highest-redshift AGN yet found. These observations from HST thus clearly demonstrate the sensitivity of the FIGS survey, and the capability of grism spectroscopy for studying the epoch of reionization.
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| 20. |
- Walsh, Ryan, et al.
(författare)
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Activity Engagement and Everyday Technology Use Among Older Adults in an Urban Area
- 2018
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Ingår i: American Journal of Occupational Therapy. - : American Occupational Therapy Association. - 0272-9490 .- 1943-7676. ; 72:4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE. We investigated associations among activity engagement (AE), number of available and relevant everyday technologies, ability to use everyday technologies, and cognitive status among older adults in an urban area. METHOD. This cross-sectional study included 110 participants and used three assessments: the Frenchay Activities Index to measure AE, the Everyday Technology Use Questionnaire to measure the number of and ability to use available and relevant everyday technologies, and the Montreal Cognitive Assessment to measure cognitive status. Data analyses used a one-way analysis of variance and a multiple linear regression model. RESULTS. The number of available and relevant everyday technologies was significantly different (p < .001) among groups that varied in level of AE. Ability to use everyday technologies did not significantly differ among groups. Cognitive status did not explain level of AE when the number of available and relevant everyday technologies was considered. CONCLUSION. Increasing the accessibility of available and relevant everyday technologies among older adults in an urban area may increase AE.
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