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- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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- Boen, Rune, et al.
(author)
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Beyond the global brain differences : intraindividual variability differences in 1q21.1 distal and 15q11.2 bp1-bp2 deletion carriers
- 2024
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In: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 95:2, s. 147-160
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Journal article (peer-reviewed)abstract
- Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
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8. |
- Kehoe, Laura, et al.
(author)
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Make EU trade with Brazil sustainable
- 2019
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Journal article (other academic/artistic)
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9. |
- Sønderby, Ida E., et al.
(author)
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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- 2021
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In: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1
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Journal article (peer-reviewed)abstract
- Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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10. |
- van der Meer, Dennis, et al.
(author)
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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
- 2020
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
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Journal article (peer-reviewed)abstract
- Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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11. |
- Belov, Vladimir, et al.
(author)
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Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures
- 2024
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In: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 14:1
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Journal article (peer-reviewed)abstract
- Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.
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14. |
- Jones, Benedict C, et al.
(author)
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To which world regions does the valence-dominance model of social perception apply?
- 2021
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In: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
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Journal article (peer-reviewed)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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15. |
- Van Hemelrijck, Mieke, et al.
(author)
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Reasons for Discontinuing Active Surveillance : Assessment of 21 Centres in 12 Countries in the Movember GAP3 Consortium
- 2019
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In: European Urology. - : Elsevier BV. - 0302-2838. ; 75:3, s. 523-531
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Journal article (peer-reviewed)abstract
- Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa). Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation. Design, setting, and participants: We compared data from 10 296 men on AS from 21 centres across 12 countries. Outcome measurements and statistical analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation. Results and limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4–28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0–13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5–2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4–2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5 yr, 4561 had follow-up for <5 yr, and 149 were lost to follow-up. Cumulative incidence of progression was 27.5% (95% CI: 26.4–28.6%) at 5 yr and 38.2% (95% CI: 36.7–39.9%) at 10 yr. A limitation is that not all centres were included due to limited information on the reason for discontinuation and limited follow-up. Conclusions: Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression. Patient summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5 yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS.
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16. |
- Charman, D. J., et al.
(author)
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Climate-related changes in peatland carbon accumulation during the last millennium
- 2013
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In: Biogeosciences. - : Copernicus GmbH. - 1726-4189. ; 10:2, s. 929-944
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Journal article (peer-reviewed)abstract
- Peatlands are a major terrestrial carbon store and a persistent natural carbon sink during the Holocene, but there is considerable uncertainty over the fate of peatland carbon in a changing climate. It is generally assumed that higher temperatures will increase peat decay, causing a positive feedback to climate warming and contributing to the global positive carbon cycle feedback. Here we use a new extensive database of peat profiles across northern high latitudes to examine spatial and temporal patterns of carbon accumulation over the past millennium. Opposite to expectations, our results indicate a small negative carbon cycle feedback from past changes in the long-term accumulation rates of northern peatlands. Total carbon accumulated over the last 1000 yr is linearly related to contemporary growing season length and photosynthetically active radiation, suggesting that variability in net primary productivity is more important than decomposition in determining long-term carbon accumulation. Furthermore, northern peatland carbon sequestration rate declined over the climate transition from the Medieval Climate Anomaly (MCA) to the Little Ice Age (LIA), probably because of lower LIA temperatures combined with increased cloudiness suppressing net primary productivity. Other factors including changing moisture status, peatland distribution, fire, nitrogen deposition, permafrost thaw and methane emissions will also influence future peatland carbon cycle feedbacks, but our data suggest that the carbon sequestration rate could increase over many areas of northern peatlands in a warmer future.
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17. |
- Breznau, Nate, et al.
(author)
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Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
- 2022
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:44
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Journal article (peer-reviewed)abstract
- This study explores how researchers analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each teams workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.
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18. |
- Hall, C. Michael, et al.
(author)
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Denying bogus skepticism in climate change and tourism research.
- 2015
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In: Tourism Management. - : Elsevier BV. - 0261-5177 .- 1879-3193. ; 47, s. 352-356
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Journal article (peer-reviewed)abstract
- This final response to the two climate change denial papers by Shani and Arad further highlights the inaccuracies, misinformation and errors in their commentaries. The obfuscation of scientific research and the consensus on anthropogenic climate change may have significant long-term negative consequences for better understanding the implications of climate change and climate policy for tourism and create confusion and delay in developing and implementing tourism sector responses.
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19. |
- Hall, C. Michael, et al.
(author)
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No time for smokescreen skepticism : A rejoinder to Shani and Arad
- 2015
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In: Tourism Management. - : Elsevier BV. - 0261-5177 .- 1879-3193. ; 47, s. 341-347
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Journal article (peer-reviewed)abstract
- Shani and Arad (2014) claimed that tourism scholars tend to endorse the most pessimistic assessments regarding climate change, and that anthropogenic climate change was a "fashionable" and "highly controversial scientific topic". This brief rejoinder provides the balance that is missing from such climate change denial and skepticism studies on climate change and tourism. Recent research provides substantial evidence that reports on anthropogenic climate change are accurate, and that human-induced greenhouse gas emissions, including from the tourism industry, play a significant role in climate change. Some positive net effects may be experienced by some destinations in the short-term, but in the long-term all elements of the tourism system will be impacted. The expansion of tourism emissions at a rate greater than efficiency gains means that it is increasingly urgent that the tourism sector acknowledge, accept and respond to climate change. Debate on tourism-related adaptation and mitigation measures is to be encouraged and welcomed. Climate change denial is not.
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20. |
- Knevel, R., et al.
(author)
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A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis
- 2013
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In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 65:3, s. 582-589
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Journal article (peer-reviewed)abstract
- Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. Results SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 x 104). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 x 105). Conclusion SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.
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21. |
- Knevel, R., et al.
(author)
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Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study
- 2012
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In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 71:10, s. 1651-1657
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Journal article (peer-reviewed)abstract
- Background Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in IL15 with the rate of joint destruction in RA. Method 1418 patients with 4885 x-ray sets of both hands and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty-five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis. Results Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09- fold rate of joint destruction compared to other patients (p = 4.0x10(-6), p = 3.8x10(-4), p = 5.0x10(-3), p = 5.0x10(-3) and p = 9.4x10(-3)). Discussion Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p < 0.001; rs7665842, p < 0.001; rs4371699, p = 0.01; rs6821171, p = 0.01). These SNPs were also significant after correction for multiple testing. Conclusion Genetic variants in IL-15 are associated with progression of joint destruction in RA.
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23. |
- Broeze, KA, et al.
(author)
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Chlamydia antibody testing and diagnosing tubal pathology in subfertile women : an individual patient data meta-analysis
- 2011
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In: Human Reproduction Update. - : Oxford University Press (OUP). - 1355-4786 .- 1460-2369. ; 17:3, s. 301-310
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Journal article (peer-reviewed)abstract
- BACKGROUND The Chlamydia IgG antibody test (CAT) shows considerable variations in reported estimates of test accuracy, partly because of the use of different assays and cut-off values. The aim of this study was to reassess the accuracy of CAT in diagnosing tubal pathology by individual patient data (IPD) meta-analysis for three different CAT assays. METHODS We approached authors of primary studies that used micro-immunofluorescence tests (MIF), immunofluorescence tests (IF) or enzyme-linked immunosorbent assay tests (ELISA). Using the obtained IPD, we performed pooled receiver operator characteristics analysis and logistic regression analysis with a random effects model to compare the three assays. Tubal pathology was defined as either any tubal obstruction or bilateral tubal obstruction. RESULTS We acquired data of 14 primary studies containing data of 6191 women, of which data of 3453 women were available for analysis. The areas under the curve for ELISA, IF and MIF were 0.64, 0.65 and 0.75, respectively (P-value < 0.001) for any tubal pathology and 0.66, 0.66 and 0.77, respectively (P-value = 0.01) for bilateral tubal pathology. CONCLUSIONS In Chlamydia antibody testing, MIF is superior in the assessment of tubal pathology. In the initial screen for tubal pathology MIF should therefore be the test of first choice.
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24. |
- De Hert, S, et al.
(author)
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Aprotinin: is it time to reconsider?
- 2015
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In: European journal of anaesthesiology. - 1365-2346. ; 32:9, s. 591-595
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Journal article (other academic/artistic)
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25. |
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26. |
- ODonnell, Michael, et al.
(author)
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Registered Replication Report: Dijksterhuis and van Knippenberg (1998)
- 2018
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In: Perspectives on Psychological Science. - : SAGE PUBLICATIONS LTD. - 1745-6916 .- 1745-6924. ; 13:2, s. 268-294
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Journal article (peer-reviewed)abstract
- Dijksterhuis and van Knippenberg (1998) reported that participants primed with a category associated with intelligence (professor) subsequently performed 13% better on a trivia test than participants primed with a category associated with a lack of intelligence (soccer hooligans). In two unpublished replications of this study designed to verify the appropriate testing procedures, Dijksterhuis, van Knippenberg, and Holland observed a smaller difference between conditions (2%-3%) as well as a gender difference: Men showed the effect (9.3% and 7.6%), but women did not (0.3% and -0.3%). The procedure used in those replications served as the basis for this multilab Registered Replication Report. A total of 40 laboratories collected data for this project, and 23 of these laboratories met all inclusion criteria. Here we report the meta-analytic results for those 23 direct replications (total N = 4,493), which tested whether performance on a 30-item general-knowledge trivia task differed between these two priming conditions (results of supplementary analyses of the data from all 40 labs, N = 6,454, are also reported). We observed no overall difference in trivia performance between participants primed with the professor category and those primed with the hooligan category (0.14%) and no moderation by gender.
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27. |
- Armus, Lee, et al.
(author)
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GOALS-JWST: Mid-infrared Spectroscopy of the Nucleus of NGC 7469
- 2023
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 942:2
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Journal article (peer-reviewed)abstract
- We present mid-infrared spectroscopic observations of the nucleus of the nearby Seyfert galaxy NGC 7469 taken with the MIRI instrument on the James Webb Space Telescope (JWST) as part of Directors Discretionary Time Early Release Science program 1328. The high-resolution nuclear spectrum contains 19 emission lines covering a wide range of ionization. The high-ionization lines show broad, blueshifted emission reaching velocities up to 1700 km s−1 and FWHM ranging from ∼500 to 1100 km s−1. The width of the broad emission and the broad-to-narrow line flux ratios correlate with ionization potential. The results suggest a decelerating, stratified, AGN-driven outflow emerging from the nucleus. The estimated mass outflow rate is 1-2 orders of magnitude larger than the current black hole accretion rate needed to power the AGN. Eight pure rotational H2 emission lines are detected with intrinsic widths ranging from FWHM ∼125 to 330 km s−1. We estimate a total mass of warm H2 gas of ∼1.2 × 107 M ⊙ in the central 100 pc. The PAH features are extremely weak in the nuclear spectrum, but a 6.2 μm PAH feature with an equivalent width of ∼0.07 μm and a flux of 2.7 × 10−17 W m−2 is detected. The spectrum is steeply rising in the mid-infrared, with a silicate strength of ∼0.02, significantly smaller than seen in most PG QSOs but comparable to other Seyfert 1s. These early MIRI mid-infrared IFU data highlight the power of JWST to probe the multiphase interstellar media surrounding actively accreting supermassive black holes.
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28. |
- Gallego-Sala, Angela V., et al.
(author)
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Latitudinal limits to the predicted increase of the peatland carbon sink with warming
- 2018
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In: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 8:10, s. 907-
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Journal article (peer-reviewed)abstract
- The carbon sink potential of peatlands depends on the balance of carbon uptake by plants and microbial decomposition. The rates of both these processes will increase with warming but it remains unclear which will dominate the global peatland response. Here we examine the global relationship between peatland carbon accumulation rates during the last millennium and planetary-scale climate space. A positive relationship is found between carbon accumulation and cumulative photosynthetically active radiation during the growing season for mid- to high-latitude peatlands in both hemispheres. However, this relationship reverses at lower latitudes, suggesting that carbon accumulation is lower under the warmest climate regimes. Projections under Representative Concentration Pathway (RCP)2.6 and RCP8.5 scenarios indicate that the present-day global sink will increase slightly until around AD 2100 but decline thereafter. Peatlands will remain a carbon sink in the future, but their response to warming switches from a negative to a positive climate feedback (decreased carbon sink with warming) at the end of the twenty-first century.
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29. |
- Lai, Thomas, et al.
(author)
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GOALS-JWST: Small Neutral Grains and Enhanced 3.3 μm PAH Emission in the Seyfert Galaxy NGC 7469
- 2023
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In: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 957:2
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Journal article (peer-reviewed)abstract
- We present James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec) integral field spectroscopy of the nearby luminous infrared galaxy NGC 7469. We take advantage of the high spatial/spectral resolution and wavelength coverage of JWST/NIRSpec to study the 3.3 μm neutral polycyclic aromatic hydrocarbon (PAH) grain emission on ∼200 pc scales. A clear change in the average grain properties between the star-forming ring and the central AGN is found. Regions in the vicinity of the AGN, with [Ne iii]/[Ne ii] > 0.25, tend to have larger grain sizes and lower aliphatic-to-aromatic (3.4/3.3) ratios, indicating that smaller grains are preferentially removed by photodestruction in the vicinity of the AGN. PAH emission at the nucleus is weak and shows a low 11.3/3.3 PAH ratio. We find an overall suppression of the total PAH emission relative to the ionized gas in the central 1 kpc region of the AGN in NGC 7469 compared to what has been observed with Spitzer on 3 kpc scales. However, the fractional 3.3 μm-to-total PAH power is enhanced in the starburst ring, possibly due to a variety of physical effects on subkiloparsec scales, including recurrent fluorescence of small grains or multiple photon absorption by large grains. Finally, the IFU data show that while the 3.3 μm PAH-derived star formation rate (SFR) in the ring is 27% higher than that inferred from the [Ne ii] and [Ne iii] emission lines, the integrated SFR derived from the 3.3 μm feature would be underestimated by a factor of 2 due to the deficit of PAHs around the AGN, as might occur if a composite system like NGC 7469 were to be observed at high redshift.
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30. |
- Lai, Thomas, et al.
(author)
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GOALS-JWST: Tracing AGN Feedback on the Star-forming Interstellar Medium in NGC 7469
- 2022
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 941:2
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Journal article (peer-reviewed)abstract
- We present James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) integral-field spectroscopy of the nearby merging, luminous infrared galaxy, NGC 7469. This galaxy hosts a Seyfert type-1.5 nucleus, a highly ionized outflow, and a bright, circumnuclear star-forming ring, making it an ideal target to study active galactic nucleus (AGN) feedback in the local universe. We take advantage of the high spatial/spectral resolution of JWST/ MIRI to isolate the star-forming regions surrounding the central active nucleus and study the properties of the dust and warm molecular gas on ∼100 pc scales. The starburst ring exhibits prominent polycyclic aromatic hydrocarbon (PAH) emission, with grain sizes and ionization states varying by only ∼30%, and a total star formation rate of 10–30 Me yr−1 derived from fine structure and recombination emission lines. Using pure rotational lines of H2 we detect 1.2 × 107 Me of warm molecular gas at a temperature higher than 200 K in the ring. All PAH bands get significantly weaker toward the central source, where larger and possibly more ionized grains dominate the emission, likely the result of the ionizing radiation and/or the fast wind emerging from the AGN. The small grains and warm molecular gas in the bright regions of the ring however display properties consistent with normal star-forming regions. These observations highlight the power of JWST to probe the inner regions of dusty, rapidly evolving galaxies for signatures of feedback and inform models that seek to explain the coevolution of supermassive black holes and their hosts.
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31. |
- Loisel, Julie, et al.
(author)
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A database and synthesis of northern peatland soil properties and Holocene carbon and nitrogen accumulation
- 2014
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In: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 24:9, s. 1028-1042
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Journal article (peer-reviewed)abstract
- Here, we present results from the most comprehensive compilation of Holocene peat soil properties with associated carbon and nitrogen accumulation rates for northern peatlands. Our database consists of 268 peat cores from 215 sites located north of 45 degrees N. It encompasses regions within which peat carbon data have only recently become available, such as the West Siberia Lowlands, the Hudson Bay Lowlands, Kamchatka in Far East Russia, and the Tibetan Plateau. For all northern peatlands, carbon content in organic matter was estimated at 42 +/- 3% (standard deviation) for Sphagnum peat, 51 +/- 2% for non-Sphagnum peat, and at 49 +/- 2% overall. Dry bulk density averaged 0.12 +/- 0.07 g/cm(3), organic matter bulk density averaged 0.11 +/- 0.05 g/cm(3), and total carbon content in peat averaged 47 +/- 6%. In general, large differences were found between Sphagnum and non-Sphagnum peat types in terms of peat properties. Time-weighted peat carbon accumulation rates averaged 23 +/- 2 (standard error of mean) g C/m(2)/yr during the Holocene on the basis of 151 peat cores from 127 sites, with the highest rates of carbon accumulation (25-28 g C/m(2)/yr) recorded during the early Holocene when the climate was warmer than the present. Furthermore, we estimate the northern peatland carbon and nitrogen pools at 436 and 10 gigatons, respectively. The database is publicly available at https://peatlands.lehigh.edu.
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32. |
- Rich, Jeffrey A., et al.
(author)
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GOALS-JWST: Pulling Back the Curtain on the AGN and Star Formation in VV 114
- 2023
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 944:2
-
Journal article (peer-reviewed)abstract
- We present results from the James Webb Space Telescope Director’s Discretionary Time Early Release Science program 1328 targeting the nearby, luminous infrared galaxy, VV 114. We use the MIRI and NIRSpec instruments to obtain integral-field spectroscopy of the heavily obscured eastern nucleus (V114E) and surrounding regions. The spatially resolved, high-resolution spectra reveal the physical conditions in the gas and dust over a projected area of 2-3 kpc that includes the two brightest IR sources, the NE and SW cores. Our observations show for the first time spectroscopic evidence that the SW core hosts an active galactic nucleus as evidenced by its very low 6.2 μm and 3.3 μm polycyclic aromatic hydrocarbon equivalent widths (0.12 and 0.017 μm, respectively) and mid- and near-IR colors. Our observations of the NE core show signs of deeply embedded star formation including absorption features due to aliphatic hydrocarbons, large quantities of amorphous silicates, as well as HCN due to cool gas along the line of sight. We detect elevated [Fe ii]/Pfα consistent with extended shocks coincident with enhanced emission from warm H2, far from the IR-bright cores and clumps. We also identify broadening and multiple kinematic components in both H2 and fine structure lines caused by outflows and previously identified tidal features.
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33. |
- Bianchin, Marina, et al.
(author)
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GOALS-JWST: Gas Dynamics and Excitation in NGC 7469 Revealed by NIRSpec
- 2024
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In: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 965:2
-
Journal article (peer-reviewed)abstract
- We present new JWST NIRSpec integral field spectroscopy (IFS) data for the luminous infrared galaxy NGC 7469, a nearby (70.6 Mpc) active galaxy with a Seyfert 1.5 nucleus that drives a highly ionized gas outflow and a prominent nuclear star-forming ring. Using the superb sensitivity and high spatial resolution of the JWST instrument NIRSpec IFS, we investigate the role of the Seyfert nucleus in the excitation and dynamics of the circumnuclear gas. Our analysis focuses on the [Fe ii], H2, and hydrogen recombination lines that trace the radiation/shocked-excited molecular and ionized interstellar medium around the active galactic nucleus (AGN). We investigate gas excitation through H2/Brγ and [Fe ii]/Paβ emission line ratios and find that photoionization by the AGN dominates within the central 300 pc of the galaxy except in a small region that shows signatures of shock-heated gas; these shock-heated regions are likely associated with a compact radio jet. In addition, the velocity field and velocity dispersion maps reveal complex gas kinematics. Rotation is the dominant feature, but we also identify noncircular motions consistent with gas inflows as traced by the velocity residuals and the spiral pattern in the Paα velocity dispersion map. The inflow is 2 orders of magnitude higher than the AGN accretion rate. The compact nuclear radio jet has enough power to drive the highly ionized outflow. This scenario suggests that the inflow and outflow are in a self-regulating feeding-feedback process, with a contribution from the radio jet helping to drive the outflow.
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34. |
- Bohn, Thomas, et al.
(author)
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GOALS-JWST: NIRCam and MIRI Imaging of the Circumnuclear Starburst Ring in NGC 7469
- 2023
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 942:2
-
Journal article (peer-reviewed)abstract
- We present James Webb Space Telescope (JWST) imaging of NGC 7469 with the Near-Infrared Camera and the Mid-InfraRed Instrument. NGC 7469 is a nearby, z = 0.01627, luminous infrared galaxy that hosts both a Seyfert Type-1.5 nucleus and a circumnuclear starburst ring with a radius of ∼0.5 kpc. The new near-infrared (NIR) JWST imaging reveals 66 star-forming regions, 37 of which were not detected by Hubble Space Telescope (HST) observations. Twenty-eight of the 37 sources have very red NIR colors that indicate obscurations up to A v ∼ 7 and a contribution of at least 25% from hot dust emission to the 4.4 μm band. Their NIR colors are also consistent with young (<5 Myr) stellar populations and more than half of them are coincident with the mid-infrared (MIR) emission peaks. These younger, dusty star-forming regions account for ∼6% and ∼17% of the total 1.5 and 4.4 μm luminosity of the starburst ring, respectively. Thanks to JWST, we find a significant number of young dusty sources that were previously unseen due to dust extinction. The newly identified 28 young sources are a significant increase compared to the number of HST-detected young sources (4-5). This makes the total percentage of the young population rise from ∼15% to 48%. These results illustrate the effectiveness of JWST in identifying and characterizing previously hidden star formation in the densest star-forming environments around active galactic nuclei (AGN).
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35. |
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36. |
- Evans, Aaron S., et al.
(author)
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GOALS-JWST: Hidden Star Formation and Extended PAH Emission in the Luminous Infrared Galaxy VV 114
- 2022
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 940:1
-
Journal article (peer-reviewed)abstract
- James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) images of the luminous infrared (IR) galaxy VV 114 are presented. This redshift ∼0.020 merger has a western component (VV 114W) rich in optical star clusters and an eastern component (VV 114E) hosting a luminous mid-IR nucleus hidden at UV and optical wavelengths by dust lanes. With MIRI, the VV 114E nucleus resolves primarily into bright NE and SW cores separated by 630 pc. This nucleus comprises 45% of the 15 μm light of VV 114, with the NE and SW cores having IR luminosities, L IR(8 − 1000 μm) ∼ 8 ± 0.8 × 1010 L ⊙ and ∼ 5 ± 0.5 × 1010 L ⊙, respectively, and IR densities, ΣIR ≳ 2 ± 0.2 × 1013 L ⊙ kpc−2 and ≳ 7 ± 0.7 × 1012 L ⊙ kpc−2, respectively—in the range of ΣIR for the Orion star-forming core and the nuclei of Arp 220. The NE core, previously speculated to have an active galactic nucleus (AGN), has starburst-like mid-IR colors. In contrast, the VV 114E SW core has AGN-like colors. Approximately 40 star-forming knots with L IR ∼ 0.02-5 × 1010 L ⊙ are identified, 28% of which have no optical counterpart. Finally, diffuse emission accounts for 40%-60% of the mid-IR emission. Mostly notably, filamentary polycyclic aromatic hydrocarbon (PAH) emission stochastically excited by UV and optical photons accounts for half of the 7.7 μm light of VV 114. This study illustrates the ability of JWST to detect obscured compact activity and distributed PAH emission in the most extreme starburst galaxies in the local universe.
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37. |
- Inami, H., et al.
(author)
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GOALS-JWST: Unveiling Dusty Compact Sources in the Merging Galaxy IIZw096
- 2022
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 940:1
-
Journal article (peer-reviewed)abstract
- We have used the Mid-InfraRed Instrument (MIRI) on the James Webb Space Telescope (JWST) to obtain the first spatially resolved, mid-infrared images of IIZw096, a merging luminous infrared galaxy (LIRG) at z = 0.036. Previous observations with the Spitzer Space Telescope suggested that the vast majority of the total IR luminosity (L IR) of the system originated from a small region outside of the two merging nuclei. New observations with JWST/MIRI now allow an accurate measurement of the location and luminosity density of the source that is responsible for the bulk of the IR emission. We estimate that 40%-70% of the IR bolometric luminosity, or 3-5 × 1011 L ⊙, arises from a source no larger than 175 pc in radius, suggesting a luminosity density of at least 3-5 × 1012 L ⊙ kpc−2. In addition, we detect 11 other star-forming sources, five of which were previously unknown. The MIRI F1500W/F560W colors of most of these sources, including the source responsible for the bulk of the far-IR emission, are much redder than the nuclei of local LIRGs. These observations reveal the power of JWST to disentangle the complex regions at the hearts of merging, dusty galaxies.
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38. |
- Linden, S. T., et al.
(author)
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GOALS-JWST: Revealing the Buried Star Clusters in the Luminous Infrared Galaxy VV 114
- 2023
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 944:2
-
Journal article (peer-reviewed)abstract
- We present the results of a James Webb Space Telescope NIRCam investigation into the young massive star cluster (YMC) population in the luminous infrared galaxy VV 114. We identify 374 compact YMC candidates with signal-to-noise ratios ≥ 3, 5, and 5 at F150W, F200W, and F356W, respectively. A direct comparison with our HST cluster catalog reveals that ∼20% of these sources are undetected at optical wavelengths. Based on yggdrasil stellar population models, we identify 17 YMC candidates in our JWST imaging alone with F150W - F200W and F200W - F356W colors suggesting they are all very young, dusty (A V = 5-15), and massive (105.8 < M ⊙ < 106.1). The discovery of these “hidden” sources, many of which are found in the “overlap” region between the two nuclei, quadruples the number of t < 3 Myr clusters and nearly doubles the number of t < 6 Myr clusters detected in VV 114. Now extending the cluster age distribution ( dN / d τ ∝ τ γ ) to the youngest ages, we find a slope of γ = −1.30 ± 0.39 for 106 < τ(yr) < 107, which is consistent with the previously determined value from 107 < τ(yr) < 108.5, and confirms that VV 114 has a steep age distribution slope for all massive star clusters across the entire range of cluster ages observed. Finally, the consistency between our JWST- and HST-derived age distribution slopes indicates that the balance between cluster formation and destruction has not been significantly altered in VV 114 over the last 0.5 Gyr.
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39. |
- Mol, Femke, et al.
(author)
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The ESEP study: salpingostomy versus salpingectomy for tubal ectopic pregnancy; the impact on future fertility: a randomised controlled trial.
- 2008
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In: BMC women's health. - London : Springer Science and Business Media LLC. - 1472-6874. ; 8
-
Journal article (peer-reviewed)abstract
- For most tubal ectopic pregnancies (EP) surgery is the treatment of first choice. Whether surgical treatment should be performed conservatively (salpingostomy) or radically (salpingectomy) in women wishing to preserve their reproductive capacity, is subject to debate. Salpingostomy preserves the tube, but bears the risks of both persistent trophoblast and repeat ipsilateral tubal EP. Salpingectomy, avoids these risks, but leaves only one tube for reproductive capacity. This study aims to reveal the trade-off between both surgical options: whether the potential advantage of salpingostomy, i.e. a better fertility prognosis as compared to salpingectomy, outweighs the potential disadvantages, i.e. persistent trophoblast and an increased risk for a repeat EP.
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40. |
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41. |
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42. |
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43. |
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44. |
- van Rhee, Koen P., et al.
(author)
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Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity
- 2024
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In: Journal of Clinical Pharmacology. - 0091-2700.
-
Journal article (peer-reviewed)abstract
- Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P <.001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.
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45. |
- Vivian, U., et al.
(author)
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GOALS-JWST: Resolving the Circumnuclear Gas Dynamics in NGC 7469 in the Mid-infrared
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 940:1
-
Journal article (peer-reviewed)abstract
- The nearby, luminous infrared galaxy NGC 7469 hosts a Seyfert nucleus with a circumnuclear star-forming ring and is thus the ideal local laboratory for investigating the starburst-AGN (active galactic nucleus) connection in detail. We present integral-field observations of the central 1.3 kpc region in NGC 7469 obtained with the JWST Mid-InfraRed Instrument. Molecular and ionized gas distributions and kinematics at a resolution of ∼100 pc over the 4.9-7.6 μm region are examined to study the gas dynamics influenced by the central AGN. The low-ionization [Fe ii] λ5.34 μm and [Ar ii] λ6.99 μm lines are bright on the nucleus and in the starburst ring, as opposed to H2 S(5) λ6.91 μm, which is strongly peaked at the center and surrounding ISM. The high-ionization [Mg v] line is resolved and shows a broad, blueshifted component associated with the outflow. It has a nearly face-on geometry that is strongly peaked on the nucleus, where it reaches a maximum velocity of −650 km s−1, and extends about 400 pc to the east. Regions of enhanced velocity dispersion in H2 and [Fe ii] ∼ 180 pc from the AGN that also show high L(H2)/L(PAH) and L([Fe ii])/L(Pfα) ratios to the W and N of the nucleus pinpoint regions where the ionized outflow is depositing energy, via shocks, into the dense interstellar medium between the nucleus and the starburst ring. These resolved mid-infrared observations of the nuclear gas dynamics demonstrate the power of JWST and its high-sensitivity integral-field spectroscopic capability to resolve feedback processes around supermassive black holes in the dusty cores of nearby luminous infrared galaxies.
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46. |
- Bartels, Ronald H M A, et al.
(author)
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External validation of a model to predict the survival of patients presenting with a spinal epidural metastasis.
- 2011
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In: Cancer metastasis reviews. - : Springer Science and Business Media LLC. - 1573-7233 .- 0167-7659. ; 30:2, s. 153-9
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Journal article (peer-reviewed)abstract
- The surgical treatment of spinal metastases is evolving. The major problem is the selection of patients who may benefit from surgical treatment. One of the criteria is an expected survival of at least 3 months. A prediction model has been previously developed. The present study has been performed in order to validate externally the model and to demonstrate that this model can be generalized to other institutions and other countries than the Netherlands. Data of 356 patients from five centers in Germany, Spain, Sweden, and the Netherlands who were treated for metastatic epidural spinal cord compression were collected. Hazard ratios in the test population corresponded with those of the developmental population. However, the observed and the expected survival were different. Analysis revealed that the baseline hazard function was significantly different. This tempted us to combine the data and develop a new prediction model. Estimating iteratively, a baseline hazard was composed. An adapted prediction model is presented. External validation of a prediction model revealed a difference in expected survival, although the relative contribution of the specific hazard ratios was the same as in the developmental population. This study emphasized the need to check the baseline hazard function in external validation. A new model has been developed using an estimated baseline hazard.
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47. |
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48. |
- Chirivi, RGS, et al.
(author)
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Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases
- 2021
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In: Cellular & molecular immunology. - : Springer Science and Business Media LLC. - 2042-0226 .- 1672-7681. ; 1718:126, s. 1528-1544
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Journal article (peer-reviewed)abstract
- Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
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49. |
- da Bandeira, Diana Sa, et al.
(author)
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PDGFR beta(+) cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
- 2022
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In: Cell Reports. - : CELL PRESS. - 2211-1247. ; 40:3
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Journal article (peer-reviewed)abstract
- Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFR beta signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFR beta is involved. Here, we show that PDGFR beta is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFR beta(+) cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFR beta(+) embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.
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50. |
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