| 1. |
- Berg, Danielle A., et al.
(författare)
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The COS Legacy Archive Spectroscopy Survey (CLASSY) Treasury Atlas
- 2022
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 261:2
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Tidskriftsartikel (refereegranskat)abstract
- Far-ultraviolet (FUV; ∼1200–2000 Å) spectra are fundamental to our understanding of star-forming galaxies, providing a unique window on massive stellar populations, chemical evolution, feedback processes, and reionization. The launch of the James Webb Space Telescope will soon usher in a new era, pushing the UV spectroscopic frontier to higher redshifts than ever before; however, its success hinges on a comprehensive understanding of the massive star populations and gas conditions that power the observed UV spectral features. This requires a level of detail that is only possible with a combination of ample wavelength coverage, signal-to-noise, spectral-resolution, and sample diversity that has not yet been achieved by any FUV spectral database. We present the Cosmic Origins Spectrograph Legacy Spectroscopic Survey (CLASSY) treasury and its first high-level science product, the CLASSY atlas. CLASSY builds on the Hubble Space Telescope (HST) archive to construct the first high-quality (S/N1500 Å ≳ 5/resel), high-resolution (R ∼ 15,000) FUV spectral database of 45 nearby (0.002 < z < 0.182) star-forming galaxies. The CLASSY atlas, available to the public via the CLASSY website, is the result of optimally extracting and coadding 170 archival+new spectra from 312 orbits of HST observations. The CLASSY sample covers a broad range of properties including stellar mass (6.2 < log M⋆(M⊙) < 10.1), star formation rate (−2.0 < log SFR (M⊙ yr−1) < +1.6), direct gas-phase metallicity (7.0 < 12+log(O/H) < 8.8), ionization (0.5 < O32 < 38.0), reddening (0.02 < E(B − V) < 0.67), and nebular density (10 < ne (cm−3) < 1120). CLASSY is biased to UV-bright star-forming galaxies, resulting in a sample that is consistent with the z ∼ 0 mass–metallicity relationship, but is offset to higher star formation rates by roughly 2 dex, similar to z ≳ 2 galaxies. This unique set of properties makes the CLASSY atlas the benchmark training set for star-forming galaxies across cosmic time.
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| 2. |
- Block, Keith I., et al.
(författare)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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| 3. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 4. |
- Stanaway, Jeffrey D., et al.
(författare)
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Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
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Tidskriftsartikel (refereegranskat)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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| 5. |
- Arellano-Cordova, Karla Z., et al.
(författare)
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CLASSY V : The Impact of Aperture Effects on the Inferred Nebular Properties of Local Star-forming Galaxies
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 935:2
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Tidskriftsartikel (refereegranskat)abstract
- Strong nebular emission lines are an important diagnostic tool for tracing the evolution of star-forming galaxies across cosmic time. However, different observational setups can affect these lines, and the derivation of the physical nebular properties. We analyze 12 local star-forming galaxies from the COS Legacy Spectroscopy SurveY (CLASSY) to assess the impact of using different aperture combinations on the determination of the physical conditions and gas-phase metallicity. We compare optical spectra observed with the Sloan Digital Sky Survey Data Release aperture, which has a 3'' diameter similar to COS, IFU, and long-slit spectra, including new LBT/MODS observations of five CLASSY galaxies. We calculate the reddening, electron densities and temperatures, metallicities, star formation rates, and equivalent widths (EWs). We find that measurements of the electron densities and temperatures, and metallicity remained roughly constant with aperture size, indicating that the gas conditions are relatively uniform for this sample. However, using IFU observations of three galaxies, we find that the E(B − V) values derived from the Balmer ratios decrease (by up to 53%) with increasing aperture size. The values change most significantly in the center of the galaxies, and level out near the COS aperture diameter of 2 5. We examine the relative contributions from the gas and stars using the Hα and [O iii] λ5007 EWs as a function of aperture light fraction, but find little to no variations within a given galaxy. These results imply that the optical spectra provide nebular properties appropriate for the far-UV CLASSY spectra, even when narrow 1 0 long-slit observations are used.
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| 6. |
- Ashuiev, Anton, et al.
(författare)
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Geometry and electronic structure of Yb(iii)[CH(SiMe3)2]3 from EPR and solid-state NMR augmented by computations
- 2024
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - 1463-9076 .- 1463-9084. ; 26:11, s. 8734-8747
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of paramagnetic compounds, in particular regarding the detailed conformation and electronic structure, remains a challenge, and – still today it often relies solely on the use of X-ray crystallography, thus limiting the access to electronic structure information. This is particularly true for lanthanide elements that are often associated with peculiar structural and electronic features in relation to their partially filled f-shell. Here, we develop a methodology based on the combined use of state-of-the-art magnetic resonance spectroscopies (EPR and solid-state NMR) and computational approaches as well as magnetic susceptibility measurements to determine the electronic structure and geometry of a paramagnetic Yb(III) alkyl complex, Yb(III)[CH(SiMe3)2]3, a prototypical example, which contains notable structural features according to X-ray crystallography. Each of these techniques revealed specific information about the geometry and electronic structure of the complex. Taken together, both EPR and NMR, augmented by quantum chemical calculations, provide a detailed and complementary understanding of such paramagnetic compounds. In particular, the EPR and NMR signatures point to the presence of three-centre–two-electron Yb-γ-Me-β-Si secondary metal–ligand interactions in this otherwise tri-coordinate metal complex, similarly to its diamagnetic Lu analogues. The electronic structure of Yb(III) can be described as a single 4f13 configuration, while an unusually large crystal-field splitting results in a thermally isolated ground Kramers doublet. Furthermore, the computational data indicate that the Yb–carbon bond contains some π-character, reminiscent of the so-called α-H agostic interaction.
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| 7. |
- Brugat, Thibaut, et al.
(författare)
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Antibody-independent mechanisms regulate the establishment of chronic Plasmodium infection
- 2017
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Ingår i: Nature Microbiology. - : Macmillan Publishers Ltd.. - 2058-5276. ; 2:4
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Tidskriftsartikel (refereegranskat)abstract
- Malaria is caused by parasites of the genus Plasmodium. All human-infecting Plasmodium species can establish long-lasting chronic infections(1-5), creating an infectious reservoir to sustain transmission(1,6). It is widely accepted that the maintenance of chronic infection involves evasion of adaptive immunity by antigenic variation(7). However, genes involved in this process have been identified in only two of five human-infecting species: Plasmodium falciparum and Plasmodium knowlesi. Furthermore, little is understood about the early events in the establishment of chronic infection in these species. Using a rodent model we demonstrate that from the infecting population, only a minority of parasites, expressing one of several clusters of virulence-associated pir genes, establishes a chronic infection. This process occurs in different species of parasites and in different hosts. Establishment of chronicity is independent of adaptive immunity and therefore different from the mechanism proposed for maintenance of chronic P. falciparum infections(7-9). Furthermore, we show that the proportions of parasites expressing different types of pir genes regulate the time taken to establish a chronic infection. Because pir genes are common to most, if not all, species of Plasmodium(10), this process may be a common way of regulating the establishment of chronic infections.
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| 8. |
- Böhme, Ulrike, et al.
(författare)
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Complete avian malaria parasite genomes reveal features associated with lineage-specific evolution in birds and mammals
- 2018
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory Press (CSHL). - 1088-9051 .- 1549-5469. ; 28:4, s. 547-560
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Tidskriftsartikel (refereegranskat)abstract
- Avian malaria parasites are prevalent around the world and infect a wide diversity of bird species. Here, we report the sequencing and analysis of high-quality draft genome sequences for two avian malaria species, Plasmodium relictum and Plasmodium gallinaceum. We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes. Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian Plasmodium species, and using amino acid divergence between species, we estimate the avian- and mammalian-infective lineages diverged in the order of 10 million years ago. Consistent with their phylogenetic position, we identify orthologs of genes that had previously appeared to be restricted to the clades of parasites containing Plasmodium falciparum and Plasmodium vivax, the species with the greatest impact on human health. From these orthologs, we explore differential diversifying selection across the genus and show that the avian lineage is remarkable in the extent to which invasion-related genes are evolving. The subtelomeres of the P. relictum and P. gallinaceum genomes contain several novel gene families, including an expanded surf multigene family. We also identify an expansion of reticulocyte binding protein homologs in P. relictum, and within these proteins, we detect distinct regions that are specific to nonhuman primate, humans, rodent, and avian hosts. For the first time in the Plasmodium lineage, we find evidence of transposable elements, including several hundred fragments of LTR-retrotransposons in both species and an apparently complete LTR-retrotransposon in the genome of P. gallinaceum.
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| 9. |
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| 10. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 11. |
- Gonzalez-Ericsson, Paula, et al.
(författare)
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The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers into breast cancer clinical trials and daily practice
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 250:5, s. 667-684
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
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| 12. |
- Kurien, Matthew, et al.
(författare)
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A nationwide population-based study on the risk of coma, ketoacidosis and hypoglycemia in patients with celiac disease and type 1 diabetes
- 2015
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Ingår i: Acta Diabetologica. - : Springer Milan. - 0940-5429 .- 1432-5233. ; 52:6, s. 1167-1174
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Tidskriftsartikel (refereegranskat)abstract
- Celiac disease (CD) may influence metabolic control in type 1 diabetes (T1D). This work examines whether CD in T1D influences hospital admissions due to coma, ketoacidosis and hypoglycemia.In population-based cohort study, individuals with CD were identified using biopsy data (1969-2008) from Sweden's 28 pathology departments. T1D was defined as a recorded diagnosis of T1D at age a parts per thousand currency sign30 years in the Swedish National Patient Register between 1964 and 2009. In total, 906 individuals had both T1D and CD and were matched for sex, age and calendar period with 4303 reference individuals. Through stratified Cox regression analysis, we modeled CD as a time-dependent covariate and estimated the risk of future coma, ketoacidosis and hypoglycemia, defined by relevant international classification of disease codes among T1D patients with and without CD.During follow-up, patients with both T1D and CD had 49 hospital admissions with diabetic coma, 91 episodes of ketoacidosis and 25 hypoglycemic events. Among patients with T1D, CD did not influence the risk of coma (adjusted HR 0.97; 95 % CI 0.72-1.32), ketoacidosis (adjusted HR 1.08; 95 % CI 0.86-1.34), or hypoglycemia (adjusted HR 1.34; 95 % CI 0.87-2.05). The absolute risk of coma was 621/100,000 person-years in T1D and CD (637 in controls). Corresponding figures for ketoacidosis were 1175/100,000 person-years in T1D and CD (1092 in controls) and for hypoglycemia 316/100,000 person-years (236 in controls). HRs for metabolic emergencies in T1D were similar in the first 5 years after T1D diagnosis as thereafter.Having a diagnosis of CD is unlikely to influence the risk of coma, ketoacidosis and hypoglycemia in T1D patients.
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| 13. |
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| 14. |
- Kurien, Matthew, et al.
(författare)
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Celiac Disease Increases Risk of Thyroid Disease in Patients With Type 1 Diabetes : A Nationwide Cohort Study
- 2016
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Ingår i: Diabetes Care. - Alexandria, USA : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 39:3, s. 371-375
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Both type 1 diabetes (T1D) and celiac disease (CD) have been linked to autoimmune thyroid disease (ATD). We examined if individuals with both T1D and CD were at a higher risk of ATD than those with only T1D.Research design and methods: This study was a nationwide population-based cohort study. We defined T1D as having an inpatient or a hospital-based outpatient diagnosis of T1D at age ≤30 years in the Swedish National Patient Register between 1964 and 2009. Data on CD were obtained through small intestinal biopsy reports showing villous atrophy (Marsh histopathology grade III) between 1969 and 2008 at any of the 28 pathology departments in Sweden. ATD included hyperthyreosis and hypothyreosis, defined according to the Swedish National Patient Register. We identified 947 individuals with T1D and biopsy-verified CD. These were matched to 4,584 control subjects with T1D but no CD diagnosis. Cox regression then estimated the risk of ATD.Results: Among T1D, CD was a risk factor for later ATD. During follow-up, 90 T1D+CD patients developed ATD (expected n = 54). Adjusting for sex, age, and calendar period, this corresponded to a hazard ratio (HR) of 1.67 (95% CI 1.32-2.11; P < 0.001). This excess risk was highest in those who had CD for 10 years or more (HR 2.22 [95% CI 1.49-3.23]). Risk increases were seen in both males and females. CD was a risk factor for both hypothyreosis (HR 1.66 [95% CI 1.30-2.12]) and hyperthyreosis (HR 1.72 [95% CI 0.95-3.11]).Conclusions: Among patients with T1D, CD is a risk factor for the later development of ATD.
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| 15. |
- Kurien, Matthew, et al.
(författare)
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Increased rate of abdominal surgery both before and after diagnosis of celiac disease
- 2017
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Ingår i: Digestive and Liver Disease. - : Elsevier. - 1590-8658 .- 1878-3562. ; 49:2, s. 147-151
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Tidskriftsartikel (refereegranskat)abstract
- Background: The detection of celiac disease (CD) is suboptimal.Aims: We hypothesized that misdiagnosis is leading to diagnostic delays, and examine this assertion by determining if patients have increased risk of abdominal surgery before CD diagnosis.Methods: Through biopsy reports from Sweden's 28 pathology departments we identified all individuals with CD (Marsh stage 3; n=29,096). Using hospital-based data on inpatient and outpatient surgery recorded in the Swedish Patient Register, we compared abdominal surgery (appendectomy, laparotomy, biliary tract surgery, and uterine surgery) with that in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression estimated odds ratios (ORs).Results: 4064 (14.0%) individuals with CD and 15,760 (10.9%) controls had a record of earlier abdominal surgery (OR=1.36, 95% CI=1.31-1.42). Risk estimates were highest in the first year after surgery (OR=2.00; 95% CI=1.79-2.22). Appendectomy, laparotomy, biliary tract surgery, and uterine surgery were all associated with having a later CD diagnosis. Of note, abdominal surgery was also more common after CD diagnosis (hazard ratio=1.34; 95% CI=1.29-1.39).Conclusions: There is an increased risk of abdominal surgery both before and after CD diagnosis. Surgical complications associated with CD may best explain these outcomes. Medical nihilism and lack of CD awareness may be contributing to outcomes.
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| 16. |
- Kurien, Matthew, et al.
(författare)
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Persistent mucosal damage and the risk of epilepsy in people with celiac disease
- 2018
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Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 25:3, s. 592-e38
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of CD patients have persistent villous atrophy (VA) on follow-up biopsy. This study's objective was to determine whether persistent VA on follow-up biopsy affects long-term epilepsy risk and epilepsy-related hospital emergency admissions.METHODS: Nationwide Cohort Study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA to those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant ICD codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures.RESULTS: Of 7590 people with CD who had a follow-up biopsy, VA was present in 43%. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.38-0.98). On stratified analysis this effect was primarily amongst males (HR 0.35; 95 CI 0.15-0.80). Among the 58 CD patients with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (HR 0.37; 95%CI 0.09-1.09).CONCLUSIONS: In a population-based study of CD individuals, persisting VA on follow up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. Mechanisms as to why persistent VA confers this benefit requires further exploration. This article is protected by copyright. All rights reserved.
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| 17. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 18. |
- Otto, Thomas D., et al.
(författare)
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A comprehensive evaluation of rodent malaria parasite genomes and gene expression
- 2014
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Ingår i: BMC Biology. - : BioMed Central. - 1741-7007. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rodent malaria parasites (RMP) are used extensively as models of human malaria. Draft RMP genomes have been published for Plasmodium yoelii, P. berghei ANKA (PbA) and P. chabaudi AS (PcAS). Although availability of these genomes made a significant impact on recent malaria research, these genomes were highly fragmented and were annotated with little manual curation. The fragmented nature of the genomes has hampered genome wide analysis of Plasmodium gene regulation and function.RESULTS: We have greatly improved the genome assemblies of PbA and PcAS, newly sequenced the virulent parasite P. yoelii YM genome, sequenced additional RMP isolates/lines and have characterized genotypic diversity within RMP species. We have produced RNA-seq data and utilised it to improve gene-model prediction and to provide quantitative, genome-wide, data on gene expression. Comparison of the RMP genomes with the genome of the human malaria parasite P. falciparum and RNA-seq mapping permitted gene annotation at base-pair resolution. Full-length chromosomal annotation permitted a comprehensive classification of all subtelomeric multigene families including the 'Plasmodium interspersed repeat genes' (pir). Phylogenetic classification of the pir family, combined with pir expression patterns, indicates functional diversification within this family.CONCLUSIONS: Complete RMP genomes, RNA-seq and genotypic diversity data are excellent and important resources for gene-function and post-genomic analyses and to better interrogate Plasmodium biology. Genotypic diversity between P. chabaudi isolates makes this species an excellent parasite to study genotype-phenotype relationships. The improved classification of multigene families will enhance studies on the role of (variant) exported proteins in virulence and immune evasion/modulation.
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| 19. |
- Reid, Adam J., et al.
(författare)
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Single-cell RNA-seq reveals hidden transcriptional variation in malaria parasites
- 2018
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Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell RNA-sequencing is revolutionising our understanding of seemingly homogeneous cell populations but has not yet been widely applied to single-celled organisms. Transcriptional variation in unicellular malaria parasites from the Plasmodium genus is associated with critical phenotypes including red blood cell invasion and immune evasion, yet transcriptional variation at an individual parasite level has not been examined in depth. Here, we describe the adaptation of a single-cell RNA-sequencing (scRNA-seq) protocol to deconvolute transcriptional variation for more than 500 individual parasites of both rodent and human malaria comprising asexual and sexual life-cycle stages. We uncover previously hidden discrete transcriptional signatures during the pathogenic part of the life cycle, suggesting that expression over development is not as continuous as commonly thought. In transmission stages, we find novel, sex-specific roles for differential expression of contingency gene families that are usually associated with immune evasion and pathogenesis.
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| 20. |
- Sanders, Donald B., et al.
(författare)
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Guidelines for single fiber EMG
- 2019
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Ingår i: Clinical Neurophysiology. - : ELSEVIER IRELAND LTD. - 1388-2457 .- 1872-8952. ; 130:8, s. 1417-1439
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Tidskriftsartikel (refereegranskat)abstract
- This document is the consensus of international experts on the current status of Single Fiber EMG (SFEMG)and the measurement of neuromuscular jitter with concentric needle electrodes (CNE - CN-jitter). The panel of authors was chosen based on their particular interests and previous publications within a specific area of SFEMG or CN-jitter. Each member of the panel was asked to submit a section on their particular area of interest and these submissions were circulated among the panel members for edits and comments. This process continued until a consensus was reached. Donald Sanders and Erik Stalberg then edited the final document.
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| 21. |
- Singer, Andrew C, et al.
(författare)
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Meeting Report : Risk Assessment of Tamiflu Use Under Pandemic Conditions
- 2008
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Ingår i: Environmental Health Perspectives. ; 116:11, s. 1563-7
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Tidskriftsartikel (refereegranskat)abstract
- On 3 October 2007, 40 participants with diverse expertise attended the workshop Tamiflu and the Environment: Implications of Use under Pandemic Conditions to assess the potential human health impact and environmental hazards associated with use of Tamiflu during an influenza pandemic. Based on the identification and risk-ranking of knowledge gaps, the consensus was that oseltamivir ethylester-phosphate (OE-P) and oseltamivir carboxylate (OC) were unlikely to pose an ecotoxicologic hazard to freshwater organisms. OC in river water might hasten the generation of OC-resistance in wildfowl, but this possibility seems less likely than the potential disruption that could be posed by OC and other pharmaceuticals to the operation of sewage treatment plants. The workgroup members agreed on the following research priorities: a) available data on the ecotoxicology of OE-P and OC should be published ; b) risk should be assessed for OC-contaminated river water generating OC-resistant viruses in wildfowl ; c) sewage treatment plant functioning due to microbial inhibition by neuraminidase inhibitors and other antimicrobials used during a pandemic should be investigated ; and d) realistic worst-case exposure scenarios should be developed. Additional modeling would be useful to identify localized areas within river catchments that might be prone to high pharmaceutical concentrations in sewage treatment plant effluent. Ongoing seasonal use of Tamiflu in Japan offers opportunities for researchers to assess how much OC enters and persists in the aquatic environment.
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| 22. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 23. |
- Stålberg, Erik, et al.
(författare)
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Standards for quantification of EMG and neurography
- 2019
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Ingår i: Clinical Neurophysiology. - : Elsevier BV. - 1388-2457 .- 1872-8952. ; 130:9, s. 1688-1729
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Forskningsöversikt (refereegranskat)abstract
- This document is an update and extension of ICCN Standards published in 1999. It is the consensus of experts on the current status of EMG and Neurography methods. A panel of authors from different countries with different approach to routines in neurophysiological methods was chosen based on their particular interest and previous publications. Each member of the panel submitted a section on their particular area of interest and these submissions were circulated among the panel members for edits and comments. This process continued until a consensus was reached. The document covers EMG topics such as conventional EMG, Macro EMG, applications of surface EMG and electrical impedance myography. Single Fiber EMG is not included, since it is the topic in a separate IFCN document. A neurography section covers topics such as motor and sensory neurography, F wave recordings, H-reflex, short segment recordings, CMAP scan and motor unit number methods. Other sections cover repetitive nerve stimulation and Pediatric electrodiagnostic testing. Each method includes a description of methodologies, pitfalls, and the use of reference values. Clinical applications accompany some of these sections.
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| 24. |
- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 25. |
- Taler, Sandra J., et al.
(författare)
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KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD
- 2013
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Ingår i: American Journal of Kidney Diseases. - : Elsevier BV. - 1523-6838 .- 0272-6386. ; 62:2, s. 201-213
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to <= 140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure <= 130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed. (C) 2013 by the National Kidney Foundation, Inc.
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