| 1. |
- Blanton, Michael R., et al.
(författare)
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Sloan Digital Sky Survey IV : Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
- 2017
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Ingår i: Astronomical Journal. - : IOP Publishing Ltd. - 0004-6256 .- 1538-3881. ; 154:1
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Tidskriftsartikel (refereegranskat)abstract
- We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and. high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median z similar to 0.03). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between z similar to 0.6 and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs. and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the. Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.
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The Seventeenth Data Release of the Sloan Digital Sky Surveys : Complete Release of MaNGA, MaStar, and APOGEE-2 Data
- 2022
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Ingår i: Astrophysical Journal Supplement Series. - : Institute of Physics (IOP). - 0067-0049 .- 1538-4365. ; 259:2
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Tidskriftsartikel (refereegranskat)abstract
- This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 survey that publicly releases infrared spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the subsurvey Time Domain Spectroscopic Survey data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey subsurvey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated value-added catalogs. This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper, Local Volume Mapper, and Black Hole Mapper surveys.
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| 3. |
- Abolfathi, Bela, et al.
(författare)
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The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
- 2018
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Ingår i: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
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Tidskriftsartikel (refereegranskat)abstract
- The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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| 6. |
- Bombarda, F., et al.
(författare)
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Runaway electron beam control
- 2019
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 1361-6587 .- 0741-3335. ; 61:1
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Tidskriftsartikel (refereegranskat)
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| 17. |
- Krasilnikov, A., et al.
(författare)
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Evidence of 9 Be + p nuclear reactions during 2ω CH and hydrogen minority ICRH in JET-ILW hydrogen and deuterium plasmas
- 2018
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 58:2
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Tidskriftsartikel (refereegranskat)abstract
- The intensity of 9Be + p nuclear fusion reactions was experimentally studied during second harmonic (2ω CH) ion-cyclotron resonance heating (ICRH) and further analyzed during fundamental hydrogen minority ICRH of JET-ILW hydrogen and deuterium plasmas. In relatively low-density plasmas with a high ICRH power, a population of fast H+ ions was created and measured by neutral particle analyzers. Primary and secondary nuclear reaction products, due to 9Be + p interaction, were observed with fast ion loss detectors, γ-ray spectrometers and neutron flux monitors and spectrometers. The possibility of using 9Be(p, d)2α and 9Be(p, α)6Li nuclear reactions to create a population of fast alpha particles and study their behaviour in non-active stage of ITER operation is discussed in the paper.
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| 20. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 26. |
- Szatmari, Peter, et al.
(författare)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Tidskriftsartikel (refereegranskat)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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| 27. |
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| 28. |
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- 2018
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 58:1
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Forskningsöversikt (refereegranskat)
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| 29. |
- Abel, I, et al.
(författare)
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Overview of the JET results with the ITER-like wall
- 2013
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10, s. 104002-
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Tidskriftsartikel (refereegranskat)abstract
- Following the completion in May 2011 of the shutdown for the installation of the beryllium wall and the tungsten divertor, the first set of JET campaigns have addressed the investigation of the retention properties and the development of operational scenarios with the new plasma-facing materials. The large reduction in the carbon content (more than a factor ten) led to a much lower Z(eff) (1.2-1.4) during L- and H-mode plasmas, and radiation during the burn-through phase of the plasma initiation with the consequence that breakdown failures are almost absent. Gas balance experiments have shown that the fuel retention rate with the new wall is substantially reduced with respect to the C wall. The re-establishment of the baseline H-mode and hybrid scenarios compatible with the new wall has required an optimization of the control of metallic impurity sources and heat loads. Stable type-I ELMy H-mode regimes with H-98,H-y2 close to 1 and beta(N) similar to 1.6 have been achieved using gas injection. ELM frequency is a key factor for the control of the metallic impurity accumulation. Pedestal temperatures tend to be lower with the new wall, leading to reduced confinement, but nitrogen seeding restores high pedestal temperatures and confinement. Compared with the carbon wall, major disruptions with the new wall show a lower radiated power and a slower current quench. The higher heat loads on Be wall plasma-facing components due to lower radiation made the routine use of massive gas injection for disruption mitigation essential.
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| 30. |
- Badria, Adel, et al.
(författare)
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Acrylate-free tough 3D printable thiol-ene thermosets and composites for biomedical applications
- 2022
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Ingår i: Journal of Applied Polymer Science. - : Wiley. - 0021-8995 .- 1097-4628. ; 139:43
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Tidskriftsartikel (refereegranskat)abstract
- Polymer thermosets and composites based on rigid trizaine-trione (TATO) alkene and thiol monomers show great promise as bone fixation materials and dental composites due to their ability to efficiently crosslink via thiol-ene coupling chemistry into stiff and strong materials. In order to broaden the scope of these materials, a TATO thermoset was optimized for sterolithography (SLA) 3D printing through the addition of either a diluent (PETMP) and photo-absorber (Sudan I), or the addition of a free radical inhibitor (pyrogallol). A 3D printable hydroxyapatite (HA) composite was also formulated by adding a combination of nano-HA and micro-HA particles, which were found to increase the thermal stability and modulus of the material, respectively. The modulus of the printed thermosets containing Sudan I and pyrogallol exceeded any previously published acrylate-free thiol-ene SLA resins, at 1.6 (0.1) and 1.85 (0.06) GPa, respectively. The printed HA composite formulation had a modulus of 2.4 (0.2) GPa. All three formulations showed a comparable resolution to a commercially available SLA resin and were non-toxic toward Raw 264.7 and human dermal fibroblast cells. These results demonstrate the potential of TATO based SLA resins for the construction of strong, fully-customizable, printed implants for biomedical applications.
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| 31. |
- Chesnut, Randall, et al.
(författare)
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A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring : the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
- 2020
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Ingår i: Intensive Care Medicine. - : Springer. - 0342-4642 .- 1432-1238. ; 46:5, s. 919-929
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Tidskriftsartikel (refereegranskat)abstract
- Background: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place.Methods: Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting.Results: We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms.Conclusions: These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference.
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| 32. |
- Chesnut, Randall M., et al.
(författare)
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Perceived Utility of Intracranial Pressure Monitoring in Traumatic Brain Injury : A Seattle International Brain Injury Consensus Conference Consensus-Based Analysis and Recommendations
- 2023
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Ingår i: Neurosurgery. - : Oxford University Press. - 0148-396X .- 1524-4040. ; 93:2, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Intracranial pressure (ICP) monitoring is widely practiced, but the indications are incompletely developed, and guidelines are poorly followed. OBJECTIVE: To study the monitoring practices of an established expert panel (the clinical working group from the Seattle International Brain Injury Consensus Conference effort) to examine the match between monitoring guidelines and their clinical decision-making and offer guidance for clinicians considering monitor insertion.METHODS: We polled the 42 Seattle International Brain Injury Consensus Conference panel members' ICP monitoring decisions for virtual patients, using matrices of presenting signs (Glasgow Coma Scale [GCS] total or GCS motor, pupillary examination, and computed tomography diagnosis). Monitor insertion decisions were yes, no, or unsure (traffic light approach). We analyzed their responses for weighting of the presenting signs in decision-making using univariate regression.RESULTS: Heatmaps constructed from the choices of 41 panel members revealed wider ICP monitor use than predicted by guidelines. Clinical examination (GCS) was by far the most important characteristic and differed from guidelines in being nonlinear. The modified Marshall computed tomography classification was second and pupils third. We constructed a heatmap and listed the main clinical determinants representing 80% ICP monitor insertion consensus for our recommendations.CONCLUSION: Candidacy for ICP monitoring exceeds published indicators for monitor insertion, suggesting the clinical perception that the value of ICP data is greater than simply detecting and monitoring severe intracranial hypertension. Monitor insertion heatmaps are offered as potential guidance for ICP monitor insertion and to stimulate research into what actually drives monitor insertion in unconstrained, real-world conditions.
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| 33. |
- Colding-Rasmussen, Thomas, et al.
(författare)
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Biomechanical Variability and Usability of a Novel Customizable Fracture Fixation Technique
- 2023
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Ingår i: Bioengineering. - : MDPI AG. - 2306-5354. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- A novel in situ customizable osteosynthesis technique, Bonevolent™ AdhFix, demonstrates promising biomechanical properties under the expertise of a single trained operator. This study assesses inter- and intra-surgeon biomechanical variability and usability of the AdhFix osteosynthesis platform. Six surgeons conducted ten osteosyntheses on a synthetic bone fracture model after reviewing an instruction manual and completing one supervised osteosynthesis. Samples underwent 4-point bending tests at a quasi-static loading rate, and the maximum bending moment (BM), bending stiffness (BS), and AdhFix cross-sectional area (CSA: mm²) were evaluated. All constructs exhibited a consistent appearance and were suitable for biomechanical testing. The mean BM was 2.64 ± 0.57 Nm, and the mean BS was 4.35 ± 0.44 Nm/mm. Statistically significant differences were observed among the six surgeons in BM (p < 0.001) and BS (p = 0.004). Throughout ten trials, only one surgeon demonstrated a significant improvement in BM (p < 0.025), and another showed a significant improvement in BS (p < 0.01). A larger CSA corresponded to a statistically significantly higher value for BM (p < 0.001) but not for BS (p = 0.594). In conclusion, this study found consistent biomechanical stability both across and within the surgeons included, suggesting that the AdhFix osteosynthesis platform can be learned and applied with minimal training and, therefore, might be a clinically viable fracture fixation technique. The variability in BM and BS observed is not expected to have a clinical impact, but future clinical studies are warranted.
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| 34. |
- Cramwinckel, Margot J., et al.
(författare)
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Global and Zonal-Mean Hydrological Response to Early Eocene Warmth
- 2023
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Ingår i: Paleoceanography and Paleoclimatology. - 2572-4517 .- 2572-4525. ; 38:6
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Tidskriftsartikel (refereegranskat)abstract
- Earth's hydrological cycle is expected to intensify in response to global warming, with a wet-gets-wetter, dry-gets-drier response anticipated over the ocean. Subtropical regions (similar to 15 degrees-30 degrees N/S) are predicted to become drier, yet proxy evidence from past warm climates suggests these regions may be characterized by wetter conditions. Here we use an integrated data-modeling approach to reconstruct global and zonal-mean rainfall patterns during the early Eocene (similar to 56-48 million years ago). The Deep-Time Model Intercomparison Project (DeepMIP) model ensemble indicates that the mid-(30 degrees-60 degrees N/S) and high-latitudes (>60 degrees N/S) are characterized by a thermodynamically dominated hydrological response to warming and overall wetter conditions. The tropical band (0 degrees-15 degrees N/S) is also characterized by wetter conditions, with several DeepMIP models simulating narrowing of the Inter-Tropical Convergence Zone. However, the latter is not evident from the proxy data. The subtropics are characterized by negative precipitation-evaporation anomalies (i.e., drier conditions) in the DeepMIP models, but there is surprisingly large inter-model variability in mean annual precipitation (MAP). Intriguingly, we find that models with weaker meridional temperature gradients (e.g., CESM, GFDL) are characterized by a reduction in subtropical moisture divergence, leading to an increase in MAP. These model simulations agree more closely with our new proxy-derived precipitation reconstructions and other key climate metrics and imply that the early Eocene was characterized by reduced subtropical moisture divergence. If the meridional temperature gradient was even weaker than suggested by those DeepMIP models, circulation-induced changes may have outcompeted thermodynamic changes, leading to wetter subtropics. This highlights the importance of accurately reconstructing zonal temperature gradients when reconstructing past rainfall patterns. As the world warms, the atmosphere is able to hold more moisture however, this moisture will not fall evenly across the globe. Some regions are expected to become wetter, whereas other regions will become drier. This is the basis of the familiar paradigm wet-gets-wetter, dry-gets-drier and is largely supported by future model projections. However, evidence from the geological record contradicts this hypothesis and suggests that a warmer world could be characterized by wetter (rather than drier) subtropics. Here, we use an integrated data-modeling approach to investigate the hydrological response to warming during an ancient warm interval (the early Eocene, 56-48 million years ago). We show that models with weaker latitudinal temperature gradients are characterized by a reduction in subtropical moisture divergence. However, this was not sufficient to induce subtropical wetting. If the meridional temperature gradient was weaker than suggested by the models, circulation-induced changes may have lead to wetter subtropics. This work shows that the latitudinal temperature gradient is a key factor that influences hydroclimate in the subtropics, especially in past warm climates.
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| 35. |
- Fan, Yanmiao, et al.
(författare)
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Placenta Powder-Infused Thiol-Ene PEG Hydrogels as Potential Tissue Engineering Scaffolds
- 2023
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 24:4, s. 1617-1626
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Tidskriftsartikel (refereegranskat)abstract
- Human placenta is a source of extracellular matrix for tissue engineering. In this study, placenta powder (PP), made from decellularized human placenta, was physically incorporated into synthetic poly(ethylene glycol) (PEG)-based hydrogels via UV-initiated thiol-ene coupling (TEC). The PP-incorporated PEG hydrogels (MoDPEG+) showed tunable storage moduli ranging from 1080 ± 290 to 51,400 ± 200 Pa. The addition of PP (1, 4, or 8 wt %) within the PEG hydrogels increased the storage moduli, with the 8 wt % PP hydrogels showing the highest storage moduli. PP reduced the swelling ratios compared with the pristine hydrogels (MoDPEG). All hydrogels showed good biocompatibility in vitro toward human skin cells and murine macrophages, with cell viability above 91%. Importantly, cells could adhere and proliferate on MoDPEG+ hydrogels due to the bioactive PP, while MoDPEG hydrogels were bio-inert as cells moved away from the hydrogel or were distributed in a large cluster on the hydrogel surface. To showcase their potential use in application-driven research, the MoDPEG+ hydrogels were straightforwardly (i) 3D printed using the SLA technique and (ii) produced via high-energy visible light (HEV-TEC) to populate damaged soft-tissue or bone cavities. Taking advantage of the bioactivity of PP and the tunable physicochemical properties of the synthetic PEG hydrogels, the presented MoDPEG+ hydrogels show great promise for tissue regeneration.
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| 36. |
- Feurdean, Angelica, et al.
(författare)
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Origin of the forest steppe and exceptional grassland diversity in Transylvania (central-eastern Europe)
- 2015
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Ingår i: Journal of Biogeography. - : Wiley. - 1365-2699 .- 0305-0270. ; 42:5, s. 951-963
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Tidskriftsartikel (refereegranskat)abstract
- Aim The forest steppe of the Transylvanian Plain is a landscape of exceptionally diverse steppe-like and semi-natural grasslands. Is this vegetation a remnant of a once continuous temperate forest extensively cleared by humans, or has the area, since the last glacial, always been a forest steppe? Understanding the processes that drive temperate grassland formation is important because effective management of this biome is critical to the conservation of the European cultural landscape. Location Lake Stiucii, north-western Romania, central-eastern Europe. Methods We analysed multi-proxy variables (pollen, coprophilous fungi, plant macroremains, macrocharcoal) from a 55,000year discontinuous sequence (c. 55,000-35,000; 13,000-0cal. yr bp), integrating models of pollen-based vegetation cover, biome reconstruction, global atmospheric simulations and archaeological records. Results Needleleaf woodland occurred during glacial Marine Isotope Stage (MIS) 3, but contracted at the end of this period. Forest coverage of c. 55% (early Holocene) and 65% (mid-Holocene) prevailed through the Holocene, but Bronze Age humans extensively cleared forests after 3700cal. yr bp. Forest coverage was most widespread between 8600 and 3700cal. yr bp, whereas grasses, steppe and xerothermic forbs were most extensive between 11,700 and 8600cal. yr bp and during the last 3700cal. yr bp. Cerealia pollen indicate the presence of arable agriculture by c. 7000cal. yr bp. Main conclusions We have provided the first unequivocal evidence for needleleaf woodland during glacial MIS 3 in this region. Extensive forests prevailed prior to 3700cal. yr bp, challenging the hypothesis that the Transylvanian lowlands were never wooded following the last glaciation. However, these forests were never fully closed either, reflecting dry growing season conditions, recurrent fires and anthropogenic impacts, which have favoured grassland persistence throughout the Holocene. The longevity of natural and semi-natural grasslands in the region may explain their current exceptional biodiversity. This longer-term perspective implies that future climatic warming and associated fire will maintain these grasslands.
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| 37. |
- Figueroa, Jonine D., et al.
(författare)
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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
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Tidskriftsartikel (refereegranskat)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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| 38. |
- Hawryluk, Gregory W. J., et al.
(författare)
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A management algorithm for patients with intracranial pressure monitoring : the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
- 2019
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Ingår i: Intensive Care Medicine. - : Springer. - 0342-4642 .- 1432-1238. ; 45:12, s. 1783-1794
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Tidskriftsartikel (refereegranskat)abstract
- Background: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based.Methods: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations.Results: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.Conclusions: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.
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| 39. |
- Hutchinson, Daniel, et al.
(författare)
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Highly Customizable Bone Fracture Fixation through the Marriage of Composites and Screws
- 2021
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Ingår i: Advanced Functional Materials. - : John Wiley and Sons Inc. - 1616-301X .- 1616-3028. ; 31:41
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Tidskriftsartikel (refereegranskat)abstract
- Open reduction internal fixation (ORIF) metal plates provide exceptional support for unstable bone fractures; however, they often result in debilitating soft-tissue adhesions and their rigid shape cannot be easily customized by surgeons. In this work, a surgically feasible ORIF methodology, called AdhFix, is developed by combining screws with polymer/hydroxyapatite composites, which are applied and shaped in situ before being rapidly cured on demand via high-energy visible-light-induced thiol–ene coupling chemistry. The method is developed on porcine metacarpals with transverse and multifragmented fractures, resulting in strong and stable fixations with a bending rigidity of 0.28 (0.03) N m2 and a maximum load before break of 220 (15) N. Evaluations on human cadaver hands with proximal phalanx fractures show that AdhFix withstands the forces from finger flexing exercises, while short- and long-term in vivo rat femur fracture models show that AdhFix successfully supports bone healing without degradation, adverse effects, or soft-tissue adhesions. This procedure represents a radical new approach to fracture fixation, which grants surgeons unparalleled customizability and does not result in soft-tissue adhesions. © 2021 The Authors.
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| 40. |
- Hutchinson, Daniel J., et al.
(författare)
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2-Methyl-4,6-bis-(1-methyl-hydrazino)pyrimidine
- 2009
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Ingår i: Acta Crystallographica Section E. - 1600-5368. ; 65:Pt 7, s. o1546-
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Tidskriftsartikel (refereegranskat)abstract
- In the title compound, C(7)H(14)N(6), the amine groups of the two methyl-hydrazino substituents are orientated in the opposite direction to the methyl substituent at the 2-position of the pyrimidine ring. The mol-ecule is almost planar with only the two amine N atoms lying substanti-ally out of the mean plane of the pyrimidine ring [by 0.1430 (2) and 0.3092 (2) A]. The H atoms on these amine groups point inwards towards the aromatic ring, such that the lone pair of electrons points outwards from the mol-ecule. Each mol-ecule is linked to two others through N-Hcdots, three dots, centeredN hydrogen bonds between the two amino groups, forming a one-dimensional chain in the [010] direction. Offset face-to-face pi-pi stacking inter-actions between the pyrimidine rings organize these chains into a two-dimensional array [centroid-centroid distance = 3.789 (2) A].
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| 41. |
- Hutchinson, Daniel J., et al.
(författare)
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Control of self-assembly through the influence of terminal hydroxymethyl groups on the metal coordination of pyrimidine-hydrazone Cu(II) complexes
- 2010
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 49:13, s. 5923-34
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and characterization of 6-hydroxymethylpyridine-2-carboxaldehyde (2-methyl-pyrimidine-4,6-diyl)bis(1-methylhydrazone) (1) is reported. Ligand 1 was designed as a ditopic pyrimidine-hydrazone molecular strand with hydroxymethyl groups attached to the terminal pyridine rings. Coordination of 1 with Cu(ClO(4))(2) x 6 H(2)O or Cu(SO(3)CF(3))(2) x 4 H(2)O in a 1:2 molar ratio resulted in the dinuclear Cu(II) complexes [Cu(2)1(CH(3)CN)(4)](ClO(4))(4) x CH(3)CN (4) and [Cu(2)1(SO(3)CF(3))(2)(CH(3)CN)(2)](SO(3)CF(3))(2) x CH(3)CN (5). X-ray crystallography and (1)H NMR NOESY experiments showed that 1 adopted a horseshoe shape with both pyrimidine-hydrazone (pym-hyz) bonds in a transoid conformation, while 4 and 5 were linear in shape, with both pym-hyz bonds in a cisoid conformation. Coordination of 1 with Cu(ClO(4))(2) x 6 H(2)O or Cu(SO(3)CF(3))(2) x 4 H(2)O in a 1:1 molar ratio resulted in three different bent complexes, [Cu(1H)(ClO(4))(2)](ClO(4)) (6), [Cu(1H)(CH(3)CN)](ClO(4))(3) x 0.5 H(2)O (7), and [Cu1(SO(3)CF(3))](2)(SO(3)CF(3))(2) x CH(3)CN (8), where the pym-hyz bond of the occupied coordination site adopted a cisoid conformation, while the pym-hyz bond of the unoccupied site retained a transoid conformation. Both 6 and 7 showed protonation of the pyridine nitrogen donor in the empty coordination site; complex 8, however, was not protonated. A variety of Cu(II) coordination geometries were seen in structures 4 to 8, including distorted octahedral, trigonal bipyramidal, and square pyramidal geometries. Coordination of the hydroxymethyl arm in the mononuclear Cu(II) complexes 6, 7, and 8 appeared to inhibit the formation of a [2 x 2] grid by blocking further access to the Cu(II) coordination sphere. In addition, the terminal hydroxymethyl groups contributed to the supramolecular structures of the complexes through coordination to the Cu(II) ions and hydrogen bonding.
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| 42. |
- Hutchinson, Daniel J., et al.
(författare)
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Influence of terminal acryloyl arms on the coordination chemistry of a ditopic pyrimidine-hydrazone ligand : comparison of Pb(II), Zn(II), Cu(II), and Ag(I) complexes
- 2013
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 52:5, s. 2716-28
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Tidskriftsartikel (refereegranskat)abstract
- A new ditopic pyrimidine-hydrazone ligand, 6-hydroxymethylacryloyl-2-pyridinecarboxaldehyde, 2,2'-[2,2'-(2-methyl-4,6-pyrimidinediyl)bis(1-methylhydrazone)] (L2), was synthesized with terminal acryloyl functional groups to allow incorporation into copolymer gel actuators. NMR spectroscopy was used to show that L2 adopted a horseshoe shape with transoid-transoid pym-hyz-py linkages. Metal complexation studies were performed with L2 and salts of Pb(II), Zn(II), Cu(II), and Ag(I) ions in CH3CN in a variety of metal to ligand ratios. Reacting L2 with an excess amount of any of the metal ions resulted in linear complexes where the pym-hyz-py linkages were rotated to a cisoid-cisoid conformation. NMR spectroscopy showed that the acryloyl arms of L2 did not interact with the bound metal ions in solution. Seven of the linear complexes (1-7) were crystallized and analyzed by X-ray diffraction. Most of these complexes (4-7) also showed no coordination between the acryloyl arms and the metal ions; however, complexes 1-3 showed some interactions. Both of the acryloyl arms were coordinated to Pb(II) ions in [Pb2L2(SO3CF3)4] (1), one through the carbonyl oxygen donor and the other through the alkoxy oxygen donor. One of the acryloyl arms of [Cu2L2(CH3CN)3](SO3CF3)4 (2) was coordinated to one of the Cu(II) ions through the carbonyl oxygen donor. There appeared to be a weak association between the alkoxy donors of the acryloyl arms and the Pb(II) ions of [Pb2L2(ClO4)4].CH3CN (3). Reaction of excess AgSO3CF3 with L2 was repeated in CD3NO2, resulting in crystals of {[Ag7(L2)2(SO3CF3)6(H2O)2] SO3CF3}infinity (8), the polymeric structure of which resulted from coordination between the carbonyl donors of the acryloyl arms and the Ag(I) ions. In all cases the coordination and steric effects of the acryloyl arms did not inhibit isomerization of the pym-hyz bonds of L2 or the core shape of the linear complexes.
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| 43. |
- Hutchinson, Daniel J., et al.
(författare)
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Metal-induced isomerization of a molecular strand containing contradictory dynamic coordination sites
- 2014
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 53:4, s. 2122-32
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Tidskriftsartikel (refereegranskat)abstract
- A new hydroxymethyl terminated pyrimidine-hydrazone (pym-hyz) ligand (L1) was synthesized with a central hyz-pyridine-hyz (hyz-py-hyz) motif replacing the usual hyz-pym-hyz unit, to create a molecular strand that underwent metal-induced isomerization with a minimal net change in ligand length. NMR spectroscopy showed that L1 had a horseshoe shape due to the hyz-py-hyz and pym-hyz bonds adopting transoid conformations. The ligand was successfully reacted with Pb(II), Zn(II), and Ag(I) salts in either CH3CN or CH3NO2 resulting in horseshoe-shaped M(n+)3L1A3n (where A = ClO4(-) or SO3CF3(-)) complexes in the solution phase. Crystals were grown from these solutions, the structures of which were highly dependent on the metal ion and solvent used, and were distinctly different from those seen in solution. The crystals grown from mixtures of Pb(ClO4)2.3H2O and L1 in either CH3CN or CH3NO2 resulted in the horseshoe-shaped [Pb3L1(ClO4)4(H2O)2](ClO4)2.CH3CN (1) complex or the {[Pb3L1(ClO4)4(H2O)](ClO4)2}infinity.CH3NO2 (2) helical coordination polymer, respectively. The horseshoe-shaped [Pb3L1(SO3CF3)6].CH3CN (3) complex was crystallized from a solution of Pb(SO3CF3)2.H2O and L1 in CH3CN, while the crystals grown from the solution of Zn(SO3CF3)2 and L1 in CH3CN consisted of the zigzag-shaped [Zn3L1(H2O)7](SO3CF3)6 (4) complex. The [Ag3(L1)2](SO3CF3)3 (5) double-helicate and the macrocycle-like [Ag6(L1)2](SO3CF3)6 (6) complex were crystallized from solutions of AgSO3CF3 and L1 in either CH3CN or CH3NO2, respectively.
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| 44. |
- Hutchinson, Daniel J., et al.
(författare)
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Metal ion-controlled self-assembly using pyrimidine hydrazone molecular strands with terminal hydroxymethyl groups : a comparison of Pb(II) and Zn(II) complexes
- 2011
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 50:16, s. 7637-49
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Tidskriftsartikel (refereegranskat)abstract
- Metal complexation studies were performed with the ditopic pyrimidine-hydrazone (pym-hyz) strand 6-hydroxymethylpyridine-2-carboxaldehyde (2-methyl-pyrimidine-4,6-diyl)bis(1-methylhydrazone) (1) and Pb(ClO(4))(2).3H(2)O, Pb(SO(3)CF(3))(2).H(2)O, Zn(SO(3)CF(3))(2), and Zn(BF(4))(2) to examine the ability of 1 to form various supramolecular architectures. X-ray crystallographic and NMR studies showed that coordination of the Pb(II) salts with 1 on a 2:1 metal/ligand ratio in CH(3)CN and CH(3)NO(2) resulted in the linear complexes [Pb(2)1(ClO(4))(4)] (2), [Pb(2)1(ClO(4))(3)(H(2)O)]ClO(4) (3), and [Pb(2)1(SO(3)CF(3))(3)(H(2)O)]SO(3)CF(3) (4). Two unusually distorted [2 x 2] grid complexes, [Pb1(ClO(4))](4)(ClO(4))(4) (5) and [Pb1(ClO(4))](4)(ClO(4))(4).4CH(3)NO(2) (6), were formed by reacting Pb(ClO(4))(2).6H(2)O and 1 on a 1:1 metal/ligand ratio in CH(3)CN and CH(3)NO(2). These grids formed despite coordination of the hydroxymethyl arms due to the large, flexible coordination sphere of the Pb(II) ions. A [2 x 2] grid complex was formed in solution by reacting Pb(SO(3)CF(3))(2).H(2)O and 1 on a 1:1 metal/ligand ratio in CH(3)CN as shown by (1)H NMR, microanalysis, and ESMS. Reacting the Zn(II) salts with 1 on a 2:1 metal/ligand ratio gave the linear complexes [Zn(2)1(H(2)O)(4)](SO(3)CF(3))(4).C(2)H(5)O (7) and [Zn(2)1(BF(4))(H(2)O)(2)(CH(3)CN)](BF(4))(3).H(2)O (8). (1)H NMR studies showed the Zn(II) and Pb(II) ions in these linear complexes were labile undergoing metal ion exchange. All of the complexes exhibited pym-hyz linkages in their cisoid conformation and binding between the hydroxymethyl arms and the metal ions. No complexes were isolated from reacting either of the Zn(II) salts with 1 on a 1:1 metal/ligand ratio, due to the smaller size of the Zn(II) coordination sphere as compared to the much larger Pb(II) ions.
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| 45. |
- Hutchinson, Daniel J., et al.
(författare)
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Sensitivity of silver(I) complexes of a pyrimidine-hydrazone ligand to solvent, counteranion, and metal-to-ligand ratio changes
- 2012
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 51:9, s. 5070-81
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Tidskriftsartikel (refereegranskat)abstract
- Metal complexation studies were performed with AgSO(3)CF(3) and AgBF(4) and the ditopic pyrimidine-hydrazone ligand 6-(hydroxymethyl)pyridine-2-carboxaldehyde (2-methylpyrimidine-4,6-diyl)bis(1-methylhydrazone) (1) in both CH(3)CN and CH(3)NO(2) in a variety of metal-to-ligand ratios. The resulting complexes were studied in solution by NMR spectroscopy and in the solid state by X-ray crystallography. Reacting either AgSO(3)CF(3) or AgBF(4) with 1 in either CH(3)CN or CH(3)NO(2) in a 1:1 metal-to-ligand ratio produced a double helicate in solution. This double helicate could be converted into a linear complex by increasing the metal-to-ligand ratio; however, the degree of conversion depended on the solvent and counteranion used. Attempts to crystallize the linear AgSO(3)CF(3) complex resulted in crystals with the dimeric structure [Ag(2)1(CH(3)CN)(2)](2)(SO(3)CF(3))(4) (2), while attempts to crystallize the AgSO(3)CF(3) double helicate from CH(3)CN resulted in crystals of another dimeric complex, [Ag(2)1(SO(3)CF(3))(CH(3)CN)(2)](2)(SO(3)CF(3))(2).H(2)O (3). The AgSO(3)CF(3) double helicate was successfully crystallized from a mixture of CH(3)CN and CH(3)NO(2) and had the structure [Ag(2)1(2)](SO(3)CF(3))(2).3CH(3)NO(2) (4). The linear AgBF(4) complex could not be isolated from the double helicate in solution; however, crystals grown from a solution containing both the AgBF(4) double helicate and linear complexes in CH(3)CN had the structure [Ag(2)1(CH(3)CN)(2)](BF(4))(2) (5). The AgBF(4) double helicate could only be crystallized from CH(3)NO(2) and had the structure [Ag(2)1(2)](BF(4))(2).2CH(3)NO(2) (6).
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| 46. |
- Hutchinson, Daniel J., et al.
(författare)
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Supramolecular self-assembly of heterobimetallic complexes : a new N,P-based, selective heteroditopic ligand
- 2018
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9226 .- 1477-9234. ; 47:4, s. 1053-1061
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Tidskriftsartikel (refereegranskat)abstract
- Pyrimidine-hydrazone and phosphole architectures have been combined to create a new heteroditopic ligand capable of forming heterobimetallic Zn(II)/Pd(II), Pb(II)/Pd(II) and Cu(II)/Pd(II) complexes in high yielding stepwise or one pot reactions. The catalytic activity of these complexes in Heck coupling and Miyaura borylation reactions was investigated.
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| 47. |
- Hutchinson, Daniel J., et al.
(författare)
-
Tetratopic pyrimidine-hydrazone ligands modified with terminal hydroxymethyl and acryloyl arms and their Pb(II), Zn(II), Cu(II) and Ag(I) complexes
- 2014
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9226 .- 1477-9234. ; 43:22, s. 8205-18
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Tidskriftsartikel (refereegranskat)abstract
- The first tetratopic pyrimidine-hydrazone (pym-hyz) molecular strands containing terminal hydroxymethyl (L1) and acryloyl (L2) functional groups have been synthesised. L1 was produced by step-wise imine condensation reactions, starting with 6-hydroxymethyl-2-pyridinecarboxaldehyde. L2 was then synthesised through the treatment of L1 with acryloyl chloride. NMR spectroscopy and X-ray crystallography showed that the ligands adopted a helical shape, comprised of 1 and 1/3 helical turns. Both L1 and L2 uncoiled upon reaction with an excess amount of Pb(II), Zn(II) and Cu(II) ions, resulting in linear M4LA8 complexes (where M = Pb(II), Zn(II), or Cu(II); L = L1 or L2; and A = ClO4(-), SO3CF3(-) or BF4(-)). Horse-shoe shaped Pb2LA4 complexes were also formed by reacting Pb(II) ions with either L1 or L2 in a 2 : 1 metal to ligand ratio. The addition of Ag(I) ions to either L1 or L2 resulted in Ag2L2A2 double helicates, which were stable in the presence of excess Ag(I). The Pb(II), Zn(II) and Ag(I) complexes were characterised by NMR spectroscopy, while UV-Vis spectroscopy was used to probe the Cu(II) complexes. In addition, X-ray crystallography was used to analyse the linear Pb4L1A8, horse-shoe shaped Pb2L1(ClO4)4, twisted Cu3L2(SO3CF3)6, and double helicate Ag2L12(SO3CF3)2 complexes yielding the structures [Pb4L1(ClO4)7(H2O)]ClO4.4CH3NO2 (1), [Pb4L1(SO3CF3)8]2.6CH3CN.H2O (2), [Pb2L1(ClO4)2(CH3CN)(H2O)](ClO4)2.2CH3CN.C4H10O.H2O (3), [Cu3L2(SO3CF3)3(CH3CN)2(H2O)](SO3CF3)3.2CH3CN.H2O (4) and [Ag2L12](SO3CF3)2.CH3CN.H2O (5), respectively.
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| 48. |
- Hutchinson, Daniel J., et al.
(författare)
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The one pot synthesis of heterobimetallic complexes from a homoditopic pyrimidine–hydrazone ligand
- 2014
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 4:28, s. 14550-14556
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Tidskriftsartikel (refereegranskat)abstract
- The symmetrical, homoditopic, pyrimidine-hydrazone (pym-hyz) ligand L1 was used to synthesise three new heterobimetallic complexes, CuPbL1(ClO4)4, CuAgL1(SO3CF3)3, and CuZnL1(SO3CF3)4. Each of the complexes was produced in a one-pot reaction in CH3CN, and was isolated in high yield and purity simply by precipitation through the addition of diethyl ether. Analysis was carried out by IR, UV-Vis and ESMS spectroscopy, as well as microanalysis. Crystals were also grown for the purposes of X-ray diffraction studies, which yielded the structures [CuPbL1(ClO4)(CH3CN)2(H2O)](ClO4)3(1),[CuAgL1(SO3CF3)(CH3CN)2](SO3CF3)2$CH3CN (2), and CuZnL1(SO3CF3)2(CH3CN)(H2O)](SO3CF3)2$CH3CN (3), all of which were linear complexes containing a Cu(II) ion in one of the pym-hyz-py coordination sites, and either a Pb(II), Ag(I), or Zn(II) ion in the other.
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| 49. |
- Hutchinson, Daniel J., et al.
(författare)
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The Self-Assembly of AgI -Containing Heterobimetallic Complexes with a Discriminatory N,P-Based Heteroditopic Ligand
- 2018
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Ingår i: European Journal of Inorganic Chemistry. - : Wiley. - 1434-1948 .- 1099-1948 .- 1099-0682. ; 2018:44, s. 4790-4796
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Tidskriftsartikel (refereegranskat)abstract
- Pyrimidine-hydrazone and phosphole architectures have been combined to create a new heteroditopic ligand capable of forming heterobimetallic ZnII/PdII,PbII/PdII and CuII/PdII complexes in high yielding stepwise or one pot reactions. The catalytic activity of these complexes in Heck coupling and Miyaura borylation reactions was investigated.
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| 50. |
- Hutchinson, David K., et al.
(författare)
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The Eocene-Oligocene transition : a review of marine and terrestrial proxy data, models and model data comparisons
- 2021
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 17:1, s. 269-315
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Forskningsöversikt (refereegranskat)abstract
- The Eocene-Oligocene transition (EOT) was a climate shift from a largely ice-free greenhouse world to an icehouse climate, involving the first major glaciation of Antarctica and global cooling occurring similar to 34 million years ago (Ma) and lasting similar to 790 kyr. The change is marked by a global shift in deep-sea delta O-18 representing a combination of deep-ocean cooling and growth in land ice volume. At the same time, multiple independent proxies for ocean temperature indicate sea surface cooling, and major changes in global fauna and flora record a shift toward more cold-climateadapted species. The two principal suggested explanations of this transition are a decline in atmospheric CO2 and changes to ocean gateways, while orbital forcing likely influenced the precise timing of the glaciation. Here we review and synthesise proxy evidence of palaeogeography, temperature, ice sheets, ocean circulation and CO2 change from the marine and terrestrial realms. Furthermore, we quantitatively compare proxy records of change to an ensemble of climate model simulations of temperature change across the EOT. The simulations compare three forcing mechanisms across the EOT: CO2 decrease, palaeogeographic changes and ice sheet growth. Our model ensemble results demonstrate the need for a global cooling mechanism beyond the imposition of an ice sheet or palaeogeographic changes. We find that CO2 forcing involving a large decrease in CO2 of ca. 40 % (similar to 325 ppm drop) provides the best fit to the available proxy evidence, with ice sheet and palaeogeographic changes playing a secondary role. While this large decrease is consistent with some CO2 proxy records (the extreme endmember of decrease), the positive feedback mechanisms on ice growth are so strong that a modest CO2 decrease beyond a critical threshold for ice sheet initiation is well capable of triggering rapid ice sheet growth. Thus, the amplitude of CO2 decrease signalled by our data-model comparison should be considered an upper estimate and perhaps artificially large, not least because the current generation of climate models do not include dynamic ice sheets and in some cases may be undersensitive to CO2 forcing. The model ensemble also cannot exclude the possibility that palaeogeographic changes could have triggered a reduction in CO2.
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