| 1. |
- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
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- 2017
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In: Physical Review D. - 2470-0010 .- 2470-0029. ; 96:2
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Journal article (peer-reviewed)
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| 4. |
- Khatri, C, et al.
(author)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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In: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Journal article (peer-reviewed)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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| 5. |
- Vogel, Jacob W., et al.
(author)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 6. |
- Weiner, D. J., et al.
(author)
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
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Journal article (peer-reviewed)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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| 7. |
- Anney, R. J. L., et al.
(author)
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Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
- 2017
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In: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 8
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Journal article (peer-reviewed)abstract
- Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) < 1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P= 9 x10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental- related genes such as EXT1, ASTN2, MACROD2, and HDAC4.
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| 8. |
- Heywood, I., et al.
(author)
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Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event
- 2019
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 573:7773, s. 235-237
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Journal article (peer-reviewed)abstract
- The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Zhou, XP, et al.
(author)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 15. |
- de Graauw, Th., et al.
(author)
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The Herschel-Heterodyne Instrument for the Far-Infrared (HIFI)
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518, s. L6-
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Journal article (peer-reviewed)abstract
- Aims: This paper describes the Heterodyne Instrument for the Far-Infrared (HIFI) that was launched onboard ESA's Herschel Space Observatory in May 2009. Methods: The instrument is a set of 7 heterodyne receivers that are electronically tuneable, covering 480-1250 GHz with SIS mixers and the 1410-1910 GHz range with hot electron bolometer (HEB) mixers. The local oscillator (LO) subsystem comprises a Ka-band synthesizer followed by 14 chains of frequency multipliers and 2 chains for each frequency band. A pair of auto-correlators and a pair of acousto-optical spectrometers process the two IF signals from the dual-polarization, single-pixel front-ends to provide instantaneous frequency coverage of 2 × 4 GHz, with a set of resolutions (125 kHz to 1 MHz) that are better than 0.1 km s-1. Results: After a successful qualification and a pre-launch TB/TV test program, the flight instrument is now in-orbit and completed successfully the commissioning and performance verification phase. The in-orbit performance of the receivers matches the pre-launch sensitivities. We also report on the in-orbit performance of the receivers and some first results of HIFI's operations. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.
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| 16. |
- Gupta, H., et al.
(author)
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Detection of OH+ and H2O+ towards Orion KL
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521, s. L47-
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Journal article (peer-reviewed)abstract
- We report observations of the reactive molecular ions OH+, H2O+, and H3O+ towards Orion KL with Herschel/HIFI. All three N = 1-0 fine-structure transitions of OH+ at 909, 971, and 1033 GHz and both fine-structure components of the doublet ortho-H2O+ 111-000 transition at 1115 and 1139 GHz were detected; an upper limit was obtained for H3O+. OH+ and H2O+ are observed purely in absorption, showing a narrow component at the source velocity of 9 km s-1, and a broad blueshifted absorption similar to that reported recently for HF and para-H218O, and attributed to the low velocity outflow of Orion KL. We estimate column densities of OH+ and H2O+ for the 9 km s-1 component of 9 ± 3 × 1012 cm-2 and 7 ± 2 × 1012 cm-2, and those in the outflow of 1.9 ± 0.7 × 1013 cm-2 and 1.0 ± 0.3 × 1013 cm-2. Upper limits of 2.4 × 1012 cm-2 and 8.7 × 1012 cm-2 were derived for the column densities of ortho and para-H3O+ from transitions near 985 and 1657 GHz. The column densities of the three ions are up to an order of magnitude lower than those obtained from recent observations of W31C and W49N. The comparatively low column densities may be explained by a higher gas density despite the assumption of a very high ionization rate.
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| 17. |
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| 18. |
- Falster, Daniel, et al.
(author)
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AusTraits, a curated plant trait database for the Australian flora
- 2021
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In: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Journal article (peer-reviewed)abstract
- We introduce the AusTraits database - a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual- and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge.
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| 19. |
- Pinto, Dalila, et al.
(author)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
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Journal article (peer-reviewed)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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| 20. |
- Anney, Richard, et al.
(author)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Journal article (peer-reviewed)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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| 21. |
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| 22. |
- Chambers, John C., et al.
(author)
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Genetic loci influencing kidney function and chronic kidney disease
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 373-375
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Journal article (peer-reviewed)abstract
- Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
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| 23. |
- Lis, D. C., et al.
(author)
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Herschel/HIFI discovery of interstellar chloronium (H2Cl+)
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1
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Journal article (peer-reviewed)abstract
- We report the first detection of chloronium, H_2Cl^+, in the interstellar medium, using the HIFI instrument aboard the Herschel Space Observatory. The 2_12-1_01 lines of ortho-H\_2^35Cl^+ and ortho-H\_2^37Cl^+ are detected in absorption towards NGC 6334I, and the 1_11-0_00 transition of para-H\_2^35Cl^+ is detected in absorption towards NGC 6334I and Sgr B2(S). The H_2Cl^+ column densities are compared to those of the chemically-related species HCl. The derived HCl/H_2Cl^+ column density ratios, ~1-10, are within the range predicted by models of diffuse and dense photon dominated regions (PDRs). However, the observed H_2Cl^+ column densities, in excess of 10^13 cm^-2, are significantly higher than the model predictions. Our observations demonstrate the outstanding spectroscopic capabilities of HIFI for detecting new interstellar molecules and providing key constraints for astrochemical models.
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| 24. |
- Anney, Richard, et al.
(author)
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Individual common variants exert weak effects on the risk for autism spectrum disorders.
- 2012
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
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Journal article (peer-reviewed)abstract
- While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
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| 25. |
- Lis, D. C., et al.
(author)
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Herschel/HIFI measurements of the ortho/para ratio in water towards Sagittarius B2(M) and W31C
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L26 -
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Journal article (peer-reviewed)abstract
- We present Herschel/HIFI observations of the fundamental rotational transitions of ortho- and para-H216O and H218O in absorption towards Sagittarius B2(M) and W31C. The ortho/para ratio in water in the foreground clouds on the line of sight towards these bright continuum sources is generally consistent with the statistical high-temperature ratio of 3, within the observational uncertainties. However, somewhat unexpectedly, we derive a low ortho/para ratio of 2.35 +/- 0.35, corresponding to a spin temperature of similar to 27 K, towards Sagittarius B2(M) at velocities of the expanding molecular ring. Water molecules in this region appear to have formed with, or relaxed to, an ortho/para ratio close to the value corresponding to the local temperature of the gas and dust.
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| 26. |
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| 27. |
- Casey, Jillian P, et al.
(author)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
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In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
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Journal article (peer-reviewed)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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| 28. |
- Rolffs, R., et al.
(author)
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Reversal of infall in SgrB2(M) revealed by Herschel/HIFI observations of HCN lines at THz frequencies
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L46 -
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Journal article (peer-reviewed)abstract
- Aims. To investigate the accretion and feedback processes in massive star formation, we analyze the shapes of emission lines from hot molecular cores, whose asymmetries trace infall and expansion motions. Methods. The high-mass star forming region SgrB2(M) was observed with Herschel/HIFI (HEXOS key project) in various lines of HCN and its isotopologues, complemented by APEX data. The observations are compared to spherically symmetric, centrally heated models with density power-law gradient and different velocity fields (infall or infall+expansion), using the radiative transfer code RATRAN. Results. The HCN line profiles are asymmetric, with the emission peak shifting from blue to red with increasing J and decreasing line opacity (HCN to (HCN)-C-13). This is most evident in the HCN 12-11 line at 1062 GHz. These line shapes are reproduced by a model whose velocity field changes from infall in the outer part to expansion in the inner part. Conclusions. The qualitative reproduction of the HCN lines suggests that infall dominates in the colder, outer regions, but expansion dominates in the warmer, inner regions. We are thus witnessing the onset of feedback in massive star formation, starting to reverse the infall and finally disrupting the whole molecular cloud. To obtain our result, the THz lines uniquely covered by HIFI were critically important.
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| 29. |
- Comito, C., et al.
(author)
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Herschel observations of deuterated water towards Sgr B2(M)
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521, s. L38-
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Journal article (peer-reviewed)abstract
- Observations of HDO are an important complement for studies of water, because they give strong constraints on the formation processes - grain surfaces versus energetic process in the gas phase, e. g. in shocks. The HIFI observations of multiple transitions of HDO in Sgr B2(M) presented here allow the determination of the HDO abundance throughout the envelope, which has not been possible before with ground-based observations only. The abundance structure has been modeled with the spherical Monte Carlo radiative transfer code RATRAN, which also takes radiative pumping by continuum emission from dust into account. The modeling reveals that the abundance of HDO rises steeply with temperature from a low abundance (2.5 x 10(-11)) in the outer envelope at temperatures below 100 K through a medium abundance (1.5 x 10(-9)) in the inner envelope/outer core at temperatures between 100 and 200 K, and finally a high abundance (3.5 x 10(-9)) at temperatures above 200 K in the hot core.
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| 30. |
- Falgarone, E., et al.
(author)
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CH+(1-0) and 13CH+(1-0) absorption lines in the direction of massive star-forming regions
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1
-
Journal article (peer-reviewed)abstract
- We report the detection of the ground-state rotational transition of the methylidyne cation CH+ and its isotopologue (CH+)-C-13 toward the remote massive star-forming regions W33A, W49N, and W51 with the HIFI instrument onboard the Herschel satellite. Both lines are seen only in absorption against the dust continuum emission of the star-forming regions. The CH+ absorption is saturated over almost the entire velocity ranges sampled by the lines-of-sight that include gas associated with the star-forming regions (SFR) and Galactic foreground material. The CH+ column densities are inferred from the optically thin components. A lower limit of the isotopic ratio [(CH+)-C-12]/[(CH+)-C-13]> 35.5 is derived from the absorptions of foreground material toward W49N. The column density ratio, N(CH+)/N(HCO+), is found to vary by at least a factor 10, between 4 and > 40, in the Galactic foreground material. Line-of-sight 12CH+ average abundances relative to total hydrogen are estimated. Their average value, N(CH+)/NH > 2.6 x 10(-8), is higher than that observed in the solar neighborhood and confirms the high abundances of CH+ in the Galactic interstellar medium. We compare this result to the predictions of turbulent dissipation regions (TDR) models and find that these high abundances can be reproduced for the inner Galaxy conditions. It is remarkable that the range of predicted N(CH+)/ N(HCO+) ratios, from 1 to similar to 50, is comparable to that observed.
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| 31. |
- Roelfsema, P. R., et al.
(author)
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In-orbit performance of Herschel-HIFI
- 2012
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 537
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Journal article (peer-reviewed)abstract
- Aims: In this paper the calibration and in-orbit performance of the Heterodyne Instrument for the Far-Infrared (HIFI) is described.Methods: The calibration of HIFI is based on a combination of ground and in-flight tests. Dedicated ground tests to determine those instrument parameters that can only be measured accurately using controlled laboratory stimuli were carried out in the instrument level test (ILT) campaign. Special in-flight tests during the commissioning phase (CoP) and performance verification (PV) allowed the determination of the remaining instrument parameters. The various instrument observing modes, as specified in astronomical observation templates (AOTs), were validated in parallel during PV by observing selected celestial sources.Results: The initial calibration and in-orbit performance of HIFI has been established. A first estimate of the calibration budget is given. The overall in-flight instrument performance agrees with the original specification. Issues remain at only a few frequencies. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.
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| 32. |
- Szatmari, Peter, et al.
(author)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
-
Journal article (peer-reviewed)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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| 33. |
- Leffa, D. T., et al.
(author)
-
Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults
- 2023
-
In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 28:3, s. 1248-1255
-
Journal article (peer-reviewed)abstract
- Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-beta (A beta) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau(181)), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain A beta deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau(181) levels and frontoparietal atrophy in CU A beta-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in A beta-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of A beta pathology.
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| 34. |
- Fuchs, A., et al.
(author)
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Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization
- 2018
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
-
Journal article (peer-reviewed)abstract
- Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.
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| 35. |
- Lefloch, B., et al.
(author)
-
The CHESS spectral survey of star forming regions : Peering into the protostellar shock L1157-B1. II. Shock dynamics
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518, s. L113-
-
Journal article (peer-reviewed)abstract
- Context. The outflow driven by the low-mass class 0 protostar L1157 is the prototype of the so-called chemically active outflows. The bright bowshock B1 in the southern outflow lobe is a privileged testbed of magneto-hydrodynamical (MHD) shock models, for which dynamical and chemical processes are strongly interdependent. Aims: We present the first results of the unbiased spectral survey of the L1157-B1 bowshock, obtained in the framework of the key program “Chemical HErschel Surveys of star forming regions” (CHESS). The main aim is to trace the warm and chemically enriched gas and to infer the excitation conditions in the shock region. Methods: The CO 5-4 and o-H2O 110-101 lines have been detected at high-spectral resolution in the unbiased spectral survey of the HIFI-band 1b spectral window (555-636 GHz), presented by Codella et al. in this volume. Complementary ground-based observations in the submm window help establish the origin of the emission detected in the main-beam of HIFI and the physical conditions in the shock. Results: Both lines exhibit broad wings, which extend to velocities much higher than reported up to now. We find that the molecular emission arises from two regions with distinct physical conditions : an extended, warm (100 K), dense (3 × 105 cm-3) component at low-velocity, which dominates the water line flux in Band 1; a secondary component in a small region of B1 (a few arcsec) associated with high-velocity, hot (>400 K) gas of moderate density ((1.0-3.0) × 104 cm-3), which appears to dominate the flux of the water line at 179μm observed with PACS. The water abundance is enhanced by two orders of magnitude between the low- and the high-velocity component, from 8 × 10-7 up to 8 × 10-5. The properties of the high-velocity component agree well with the predictions of steady-state C-shock models. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.
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| 36. |
- Pinto, Dalila, et al.
(author)
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Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
- 2014
-
In: American journal of human genetics. - : Elsevier BV. - 1537-6605 .- 0002-9297. ; 94:5, s. 677-694
-
Journal article (peer-reviewed)abstract
- Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0× 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7× 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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| 37. |
- Vastel, C., et al.
(author)
-
Ortho-to-para ratio of interstellar heavy water
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L31 -
-
Journal article (peer-reviewed)abstract
- Context. Despite the low elemental deuterium abundance in the Galaxy, enhanced molecular D/H ratios have been found in the environments of low-mass star-forming regions, and in particular the Class 0 protostar IRAS 16293-2422. Aims. The CHESS (Chemical HErschel Surveys of Star forming regions) key program aims to study the molecular complexity of the interstellar medium. The high sensitivity and spectral resolution of the Herschel/HIFI instrument provide a unique opportunity to observe the fundamental 1(1,1)-0(0,0) transition of the ortho-D2O molecule, which is inaccessible from the ground, and determine the ortho-to-para D2O ratio. Methods. We detected the fundamental transition of the ortho-D2O molecule at 607.35 GHz towards IRAS 16293-2422. The line is seen in absorption with a line opacity of 0.62 +/- 0.11 (1 sigma). From the previous ground-based observations of the fundamental 1(1,0)-1(0,1) transition of para-D2O seen in absorption at 316.80 GHz, we estimate a line opacity of 0.26 +/- 0.05 (1 sigma). Results. We show that the observed absorption is caused by the cold gas in the envelope of the protostar. Using these new observations, we estimate for the first time the ortho-to-para D2O ratio to be lower than 2.6 at a 3 sigma level of uncertainty, which should be compared with the thermal equilibrium value of 2:1.
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| 38. |
- Gonzalez-Alfonso, E., et al.
(author)
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Herschel observations of water vapour in Markarian 231
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518:Article Number: L43
-
Journal article (peer-reviewed)abstract
- The Ultra luminous infrared galaxy (ULIRG) Mrk 231 reveals up to seven rotational lines of water (H2O) in emission, including a very high-lying (Eupper = 640 K) line detected at a 4 sigma level, within the Herschel/SPIRE wavelength range (190
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| 39. |
- Graham, J. B., et al.
(author)
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The Malmo polymorphism of coagulation factor IX, an immunologic polymorphism due to dimorphism of residue 148 that is in linkage disequilibrium with two other F.IX polymorphisms
- 1988
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In: American Journal of Human Genetics. - 0002-9297. ; 42:4, s. 573-580
-
Journal article (peer-reviewed)abstract
- A mouse monoclonal antibody (MAB 9,9) to coagulation factor IX (F.IX) detects a polymorphism in the plasma of normal people. Its epitope has been narrowed down to <6 amino acids in the activation peptide of the X-linked F.IX protein. The activation peptide contains a dimorphism - Thr:Ala - at position 148 of the protein. Using synthetic oligonucleotides, we have demonstrated that (1) the F.IX which reacts with 9.9 has Thr at position 148 and (2) that which does not has Ala. Positive reactors (148(thr)) are designated Malmo A, and negative reactors (148(ala)) are designated Malmo B. The plasma levels of AA women are indistinguishable from those of A men, and both B men and BB women are null against MAB 9.9. The plasma level of Malmo A in AB women is approximately half that of AA women, and 'lyonization' is clearly operating in the heterozygotes. The dimorphism is in strong linkage disequilibrium with two other intragenic RFLPs, TaqI and XmnI. Furthermore, intragenic crossing-over - including double crossing-over - appears to have occurred between the three sites. Seven of the eight possible haplotypes have been identified, five in men and two others in women. The immunoassay that identifies ~50% of the AB women in the pool of Malmo A females with 95% confidence identifies men unambiguously as A or B. The assay would be very useful for population-genetic studies of the Malmo epitope if the studies were limited to men.
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| 40. |
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| 41. |
- Lüscher, Bernhard, et al.
(author)
-
ADP-ribosyltransferases, an update on function and nomenclature
- 2022
-
In: The FEBS Journal. - : John Wiley & Sons. - 1742-464X .- 1742-4658. ; 289:23, s. 7399-7410
-
Journal article (peer-reviewed)abstract
- ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.
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| 42. |
- Meijerink, R., et al.
(author)
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Evidence for CO Shock Excitation in NGC 6240 from Herschel SPIRE Spectroscopy
- 2013
-
In: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 762:2, s. L16-L20
-
Journal article (peer-reviewed)abstract
- We present Herschel SPIRE FTS spectroscopy of the nearby luminous infrared galaxy NGC 6240. In total 20 linesare detected, including CO J = 4−3 through J = 13−12, 6 H2O rotational lines, and [C i] and [N ii] fine-structurelines. The CO to continuum luminosity ratio is 10 times higher in NGC 6240 than Mrk 231. Although the COladdersof NGC 6240 and Mrk 231 are very similar, UV and/or X-ray irradiation are unlikely to be responsible for theexcitation of the gas in NGC 6240.We applied both C and J shock models to the H2 v = 1–0 S(1) and v = 2–1 S(1)lines and the CO rotational ladder. The CO ladder is best reproduced by amodel with shock velocity vs = 10 km s−1and a pre-shock density nH = 5 × 104 cm−3. We find that the solution best fitting the H2 lines is degenerate. The shock velocities and number densities range between vs = 17–47 km s−1 and nH = 107–5×104 cm−3, respectively.The H2 lines thus need a much more powerful shock than the CO lines.We deduce that most of the gas is currently moderately stirred up by slow (10 km s−1) shocks while only a small fraction (1%) of the interstellar mediumis exposed to the high-velocity shocks. This implies that the gas is rapidly losing its highly turbulent motions. We argue that a high CO line-to-continuum ratio is a key diagnostic for the presence of shocks.
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| 43. |
- Privon, G., et al.
(author)
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EXCITATION MECHANISMS FOR HCN(1-0) AND HCO+ (1-0) IN GALAXIES FROM THE GREAT OBSERVATORIES ALL-SKY LIRG SURVEY
- 2015
-
In: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 814:1
-
Journal article (peer-reviewed)abstract
- We present new Institut de Radioastronomie Millimetrique (TRAM) 30 m spectroscopic observations of the similar to 88 GHz band, including emission from the CCH (N = 1 -> 0) multiplet, HCN (J = 1 -> 0), HCO (J = 1 -> 0), and HNC (J = 1 -> 0), for a sample of 58 local luminous and ultraluminous infrared galaxies from the Great Observatories All-sky LIRG Survey (GOALS). By combining our new TRAM data with literature data and Spitzer /IRS spectroscopy, we study the correspondence between these putative tracers of dense gas and the relative contribution of active galactic nuclei (AGNs) and star formation to the mid-infrared luminosity of each system. We find the HCN (1-0) emission to be enhanced in AGN-dominated systems (L'(HCN(1 0))/ L'(HCO+(1-o))) = 1.84), compared to composite and starburst-dominated systems (L'HCN(1413/(1-0)) = 1.14, and 0.88, respectively). However, some composite and starburst systems have LH/ CN (1 0) /LH/ CO (1 0) ratios comparable to those of AGNs, indicating that enhanced HCN emission is not uniquely associated with energetically dominant AGNs. After removing AGN-dominated systems from the sample, we find a linear relationship (within the uncertainties) between logio(L'(HCN(1-0))) and log(10)(LIR), consistent with most previous findings. Lc N(1 0) /LIR, typically interpreted as the dense-gas depletion time, appears to have no systematic trend with LIR for our sample of luminous and ultraluminous infrared galaxies, and has significant scatter. The galaxyintegrated L'(HCN(1-0)) and L'(HCO+(1-0)) emission do not appear to have a simple interpretation in terms of the AGN dominance or the star formation rate, and are likely determined by multiple processes, including density and radiative effects.
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| 44. |
- van der Werf, P.P., et al.
(author)
-
Black hole accretion and star formation as drivers of gas excitation and chemistry in Markarian 231
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518:Article Number: L42
-
Journal article (peer-reviewed)abstract
- We present a full high resolution SPIRE FTS spectrum of the nearby ultraluminous infrared galaxy Mrk 231. In total 25 lines are detected, including CO J = 5-4 through J = 13-12, 7 rotational lines of H2O, 3 of OH+ and one line each of H2O+, CH+, and HF. We find that the excitation of the CO rotational levels up to J = 8 can be accounted for by UV radiation from star formation. However, the approximately flat luminosity distribution of the CO lines over the rotational ladder above J = 8 requires the presence of a separate source of excitation for the highest CO lines. We explore X-ray heating by the accreting supermassive black hole in Mrk 231 as a source of excitation for these lines, and find that it can reproduce the observed luminosities. We also consider a model with dense gas in a strong UV radiation field to produce the highest CO lines, but find that this model strongly overpredicts the hot dust mass in Mrk 231. Our favoured model consists of a star forming disk of radius 560 pc, containing clumps of dense gas exposed to strong UV radiation, dominating the emission of CO lines up to J = 8. X-rays from the accreting supermassive black hole in Mrk 231 dominate the excitation and chemistry of the inner disk out to a radius of 160 pc, consistent with the X-ray power of the AGN in Mrk 231. The extraordinary luminosity of the OH+ and H2O+ lines reveals the signature of X-ray driven excitation and chemistry in this region.
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| 45. |
- Codella, C., et al.
(author)
-
The CHESS spectral survey of star forming regions : Peering into the protostellar shock L1157-B1. I. Shock chemical complexity
- 2010
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518, s. L112-
-
Journal article (peer-reviewed)abstract
- We present the first results of the unbiased survey of the L1157-B1 bow shock, obtained with HIFI in the framework of the key program Chemical HErschel Survey of Star forming regions (CHESS). The L1157 outflow is driven by a low-mass Class 0 protostar and is considered the prototype of the so-called chemically active outflows. The bright blue-shifted bow shock B1 is the ideal laboratory for studying the link between the hot (~1000-2000 K) component traced by H2 IR-emission and the cold (~10-20 K) swept-up material. The main aim is to trace the warm gas chemically enriched by the passage of a shock and to infer the excitation conditions in L1157-B1. A total of 27 lines are identified in the 555-636 GHz region, down to an average 3σ level of 30 mK. The emission is dominated by CO(5-4) and H2O(110-101) transitions, as discussed by Lefloch et al. in this volume. Here we report on the identification of lines from NH3, H2CO, CH3OH, CS, HCN, and HCO+. The comparison between the profiles produced by molecules released from dust mantles (NH3, H2CO, CH3OH) and that of H2O is consistent with a scenario in which water is also formed in the gas-phase in high-temperature regions where sputtering or grain-grain collisions are not efficient. The high excitation range of the observed tracers allows us to infer, for the first time for these species, the existence of a warm (≥200 K) gas component coexisting in the B1 bow structure with the cold and hot gas detected from ground. Herschel is an ESA space observatory with science instruments provided by European-led principal Investigator consortia and with important participation from NASA.Table 1 is only available in electronic form at http://www.aanda.org
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| 46. |
- Fisher, Oliver M., et al.
(author)
-
High Expression of Cathepsin E in Tissues but Not Blood of Patients with Barrett's Esophagus and Adenocarcinoma
- 2015
-
In: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1534-4681 .- 1068-9265. ; 22:7, s. 2431-2438
-
Journal article (peer-reviewed)abstract
- Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia-dysplasia-neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett's esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Median CTSE mRNA expression levels were a parts per thousand yen1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27-1.26, p = 0.17). CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues.
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| 47. |
- Fisher, O M, et al.
(author)
-
MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma.
- 2015
-
In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 112:8, s. 1384-1391
-
Journal article (peer-reviewed)abstract
- Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC.
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| 48. |
- Lee, C.K., et al.
(author)
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Prognostic nomogram to predict progression-free survival in patients with platinum-sensitive recurrent ovarian cancer
- 2011
-
In: British Journal of Cancer. - : Cancer Research UK. - 0007-0920 .- 1532-1827. ; 105:8, s. 1144-1150
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n = 955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n = 340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.
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| 49. |
- Lord, Edna, et al.
(author)
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Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Journal article (peer-reviewed)abstract
- Guinea pigs (Cavia spp.) have a long association with humans. From as early as 10,000 years ago they were a wild food source. Later, domesticated Cavia porcellus were dispersed well beyond their native range through pre-Columbian exchange networks and, more recently, widely across the globe. Here we present 46 complete mitogenomes of archaeological guinea pigs from sites in Peru, Bolivia, Colombia, the Caribbean, Belgium and the United States to elucidate their evolutionary history, origins and paths of dispersal. Our results indicate an independent centre of domestication of Cavia in the eastern Colombian Highlands. We identify a Peruvian origin for the initial introduction of domesticated guinea pigs (Cavia porcellus) beyond South America into the Caribbean. We also demonstrate that Peru was the probable source of the earliest known guinea pigs transported, as part of the exotic pet trade, to both Europe and the southeastern United States. Finally, we identify a modern reintroduction of guinea pigs to Puerto Rico, where local inhabitants use them for food. This research demonstrates that the natural and cultural history of guinea pigs is more complex than previously known and has implications for other studies regarding regional to global-scale studies of mammal domestication, translocation, and distribution.
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| 50. |
- Xu, Jin, et al.
(author)
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Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort
- 2021
-
In: Biomedicines. - : MDPI. - 2227-9059. ; 9:11
-
Journal article (peer-reviewed)abstract
- BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
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