| 1. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 2. |
- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
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| 4. |
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| 5. |
- Blokland, G. A. M., et al.
(author)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Journal article (peer-reviewed)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 7. |
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| 8. |
- Carter, J. A., et al.
(author)
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Ground-based and additional science support for SMILE
- 2024
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In: Earth and Planetary Physics. - : Science Press. - 2096-3955. ; 8:1, s. 275-298
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Journal article (peer-reviewed)abstract
- The joint European Space Agency and Chinese Academy of Sciences Solar wind Magnetosphere Ionosphere Link Explorer (SMILE) mission will explore global dynamics of the magnetosphere under varying solar wind and interplanetary magnetic field conditions, and simultaneously monitor the auroral response of the Northern Hemisphere ionosphere. Combining these large-scale responses with medium and fine-scale measurements at a variety of cadences by additional ground-based and space-based instruments will enable a much greater scientific impact beyond the original goals of the SMILE mission. Here, we describe current community efforts to prepare for SMILE, and the benefits and context various experiments that have explicitly expressed support for SMILE can offer. A dedicated group of international scientists representing many different experiment types and geographical locations, the Ground-based and Additional Science Working Group, is facilitating these efforts. Preparations include constructing an online SMILE Data Fusion Facility, the discussion of particular or special modes for experiments such as coherent and incoherent scatter radar, and the consideration of particular observing strategies and spacecraft conjunctions. We anticipate growing interest and community engagement with the SMILE mission, and we welcome novel ideas and insights from the solar-terrestrial community.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Jaffee, E. M., et al.
(author)
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Future cancer research priorities in the USA: a Lancet Oncology Commission
- 2017
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In: Lancet Oncology. - 1470-2045. ; 18:11
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Research review (peer-reviewed)abstract
- We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$ 2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.
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| 13. |
- Wright, Gillian, et al.
(author)
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The Mid-infrared Instrument for JWST and Its In-flight Performance
- 2023
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In: Publications of the Astronomical Society of the Pacific. - 0004-6280 .- 1538-3873. ; 135:1046
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Journal article (peer-reviewed)abstract
- The Mid-Infrared Instrument (MIRI) extends the reach of the James Webb Space Telescope (JWST) to 28.5 μm. It provides subarcsecond-resolution imaging, high sensitivity coronagraphy, and spectroscopy at resolutions of λ/Δλ ∼ 100-3500, with the high-resolution mode employing an integral field unit to provide spatial data cubes. The resulting broad suite of capabilities will enable huge advances in studies over this wavelength range. This overview describes the history of acquiring this capability for JWST. It discusses the basic attributes of the instrument optics, the detector arrays, and the cryocooler that keeps everything at approximately 7 K. It gives a short description of the data pipeline and of the instrument performance demonstrated during JWST commissioning. The bottom line is that the telescope and MIRI are both operating to the standards set by pre-launch predictions, and all of the MIRI capabilities are operating at, or even a bit better than, the level that had been expected. The paper is also designed to act as a roadmap to more detailed papers on different aspects of MIRI.
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| 14. |
- Akbarian, S, et al.
(author)
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The PsychENCODE project
- 2015
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In: Nature neuroscience. - : Springer Science and Business Media LLC. - 1546-1726 .- 1097-6256. ; 18:12, s. 1707-1712
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Journal article (peer-reviewed)
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| 15. |
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| 16. |
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| 17. |
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| 18. |
- Alvarez-Madrazo, S, et al.
(author)
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Discontinuation, persistence and adherence to subcutaneous biologics delivered via a homecare route to Scottish adults with rheumatic diseases: a retrospective study
- 2019
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In: BMJ open. - : BMJ. - 2044-6055. ; 9:9, s. e027059-
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Journal article (peer-reviewed)abstract
- To understand patterns of subcutaneous (SC) biologics use over time in adults with inflammatory rheumatic musculoskeletal diseases receiving a homecare delivery service.DesignRetrospective cohort.SettingPatients in secondary care receiving SC biologics in the largest Scottish Health Board.ParticipantsA new bespoke cohort was created from routine data gathered as part of a health board Homecare Service Database. Patients over 18 years who received a supply of SC biologic from January 2012 to May 2015 with a diagnosis for rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) were included.Outcomes measuredA standardised framework was applied by measuring discontinuation rates, persistence using Kaplan-Meier analysis and Cox regression and adherence using medication refill adherence (MRA) and compliance rate (CR).Results751 patients were identified (AS: 105, PsA: 227, RA: 419) of whom 89.3% had more than one biologic delivery (median days’ follow-up: AS: 494; PsA: 544; RA: 529) and 83.2% did not switch biologic. For all conditions, approximately half were persistent on their index biologic (52% AS, 54% PsA, 48%RA). Of patients who discontinued treatment, the majority reinitiated with the same biologic (19% AS, 18% PsA and 21% RA). Overall adherence during the period of treatment was over 80% when calculated using MRA (median %MRA: AS: 84.0%, PsA: 85.0%, RA: 82.4%) or CR (median %CR: AS: 96.6%, PsA: 97%, RA: 96.6%).ConclusionUse of linked routine data is a sustainable pathway to enable ongoing evaluation of biologics use. A more consistent approach to studying use (discontinuation, persistence and adherence metrics) should be adopted to enable comparability of studies.
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| 19. |
- Arun, K. G., et al.
(author)
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New horizons for fundamental physics with LISA
- 2022
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In: Living Reviews in Relativity. - : Springer Science and Business Media LLC. - 1433-8351 .- 2367-3613. ; 25:1
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Research review (peer-reviewed)abstract
- The Laser Interferometer Space Antenna (LISA) has the potential to reveal wonders about the fundamental theory of nature at play in the extreme gravity regime, where the gravitational interaction is both strong and dynamical. In this white paper, the Fundamental Physics Working Group of the LISA Consortium summarizes the current topics in fundamental physics where LISA observations of gravitational waves can be expected to provide key input. We provide the briefest of reviews to then delineate avenues for future research directions and to discuss connections between this working group, other working groups and the consortium work package teams. These connections must be developed for LISA to live up to its science potential in these areas.
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| 20. |
- Barack, Leor, et al.
(author)
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Black holes, gravitational waves and fundamental physics : a roadmap
- 2019
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In: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 36:14
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Research review (peer-reviewed)abstract
- The grand challenges of contemporary fundamental physics dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
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| 21. |
- Baum, Sebastian, et al.
(author)
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Paleodetectors for Galactic supernova neutrinos
- 2020
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In: Physical Review D. - : American Physical Society (APS). - 2470-0010 .- 2470-0029. ; 101:10
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Journal article (peer-reviewed)abstract
- Paleodetectors are a proposed experimental technique in which one would search for traces of recoiling nuclei in ancient minerals. Natural minerals on Earth are as old as O(1) Gyr and, in many minerals, the damage tracks left by recoiling nuclei are also preserved for timescales long compared to 1 Gyr once created. Thus, even reading out relatively small target samples of order 100 g, paleodetectors would allow one to search for very rare events thanks to the large exposure, epsilon similar to 100 g Gyr = 10(5) t yr. Here, we explore the potential of paleodetectors to measure nuclear recoils induced by neutrinos from Galactic core collapse supernovae. We find that they would not only allow for a direct measurement of the average core collapse supernova rate in the Milky Way, but would also contain information about the time dependence of the local supernova rate over the past similar to 1 Gyr. Since the supernova rate is thought to be directly proportional to the star formation rate, such a measurement would provide a determination of the local star formation history. We investigate the sensitivity of paleodetectors to both a smooth time evolution and an enhancement of the core collapse supernova rate on relatively short timescales, as would be expected for a starburst period in the local group.
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| 22. |
- Beuther, H., et al.
(author)
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JWST Observations of Young protoStars (JOYS): Outflows and accretion in the high-mass star-forming region IRAS 23385+6053
- 2023
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 673
-
Journal article (peer-reviewed)abstract
- Context. Understanding the earliest stages of star formation, and setting it in the context of the general cycle of matter in the interstellar medium, is a central aspect of research with the James Webb Space Telescope (JWST). Aims. The JWST program JOYS (JWST Observations of Young protoStars) aims to characterize the physical and chemical properties of young high- and low-mass star-forming regions, in particular the unique mid-infrared diagnostics of the warmer gas and solid-state components. We present early results from the high-mass star formation region IRAS 23385+6053. Methods. The JOYS program uses the Mid-Infrared Instrument (MIRI) Medium Resolution Spectrometer (MRS) with its integral field unit (IFU) to investigate a sample of high- and low-mass star-forming protostellar systems. Results. The full 5-? 28 μm MIRI MRS spectrum of IRAS 23385+6053 shows a plethora of interesting features. While the general spectrum is typical for an embedded protostar, we see many atomic and molecular gas lines boosted by the higher spectral resolution and sensitivity compared to previous space missions. Furthermore, ice and dust absorption features are also present. Here, we focus on the continuum emission, outflow tracers such as the H2(0-? 0)S(7), [FeII](4F9/2-6D9/2), and [NeII](2P1/2-2P3/2) lines, and the potential accretion tracer Humphreys α H I(7-6). The short-wavelength MIRI data resolve two continuum sources, A and B; mid-infrared source A is associated with the main millimeter continuum peak. The combination of mid-infrared and millimeter data reveals a young cluster in the making. Combining the mid-infrared outflow tracers H2, [FeII], and [NeII] with millimeter SiO data reveals a complex interplay of at least three molecular outflows driven by protostars in the forming cluster. Furthermore, the Humphreys α line is detected at a 3-?4σ? level toward the mid-infrared sources A and B. One can roughly estimate both accretion luminosities and corresponding accretion rates to be between ∼2.6 × 10-6 and ∼0.9 × 10-4 Mo yr-1. This is discussed in the context of the observed outflow rates. Conclusions. The analysis of the MIRI MRS observations for this young high-mass star-forming region reveals connected outflow and accretion signatures, as well as the enormous potential of JWST to boost our understanding of the physical and chemical processes at play during star formation.
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| 23. |
- Brem, Jürgen, et al.
(author)
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Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- 2022
-
In: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
-
Journal article (peer-reviewed)abstract
- Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
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| 24. |
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| 25. |
- Edwards, Thomas D. P., et al.
(author)
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Digging for dark matter : Spectral analysis and discovery potential of paleo-detectors
- 2019
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In: Physical Review D. Particles and fields. - : AMER PHYSICAL SOC. - 0556-2821 .- 1089-4918. ; 99:4
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Journal article (peer-reviewed)abstract
- Paleo-detectors are a recently proposed method for the direct detection of dark matter (DM). In such detectors, one would search for the persistent damage features left by DM–nucleus interactions in ancient minerals. Initial sensitivity projections have shown that paleo-detectors could probe much of the remaining weakly interacting massive particle (WIMP) parameter space. In this paper, we improve upon the cut-and-count approach previously used to estimate the sensitivity by performing a full spectral analysis of the background- and DM-induced signal spectra. We consider two scenarios for the systematic errors on the background spectra: (i) systematic errors on the normalization only, and (ii) systematic errors on the shape of the backgrounds. We find that the projected sensitivity is rather robust to imperfect knowledge of the backgrounds. Finally, we study how well the parameters of the true WIMP model could be reconstructed in the hypothetical case of a WIMP discovery.
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| 26. |
- Francis, L., et al.
(author)
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JOYS: MIRI/MRS spectroscopy of gas-phase molecules from the high-mass star-forming region IRAS 23385+6053
- 2024
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In: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 683
-
Journal article (peer-reviewed)abstract
- Context. Space-based mid-infrared (IR) spectroscopy is a powerful tool for the characterization of important star formation tracers of warm gas which are unobservable from the ground. The previous mid-IR spectra of bright high-mass protostars with the Infrared Space Observatory (ISO) in the hot-core phase typically show strong absorption features from molecules such as CO2, C2H2, and HCN. However, little is known about their fainter counterparts at earlier stages. Aims. We aim to characterize the gas-phase molecular features in James Webb Space Telescope Mid-Infrared Instrument Medium Resolution Spectrometer (MIRI/MRS) spectra of the young and clustered high-mass star-forming region IRAS 23385+6053. Methods. Spectra were extracted from several locations in the MIRI/MRS field of view, targeting two mid-IR sources tracing embedded massive protostars as well as three H2 bright outflow knots at distances of >8000 au from the multiple. Molecular features in the spectra were fit with local thermodynamic equilibrium (LTE) slab models, with their caveats discussed in detail. Results. Rich molecular spectra with emission from CO, H2, HD, H2O, C2H2, HCN, CO2, and OH are detected towards the two mid-IR sources. However, only CO and OH are seen towards the brightest H2 knot positions, suggesting that the majority of the observed species are associated with disks or hot core regions rather than outflows or shocks. The LTE model fits to 12CO2, C2H2, HCN emission suggest warm 120a-200 K emission arising from a disk surface around one or both protostars. The abundances of CO2 and C2H2 of ~10âà  à  7 are consistent with previous observations of high-mass protostars. Weak ~500 K H2O emission at ~6a-7 μm is detected towards one mid-IR source, whereas 250a-1050 K H2O absorption is found in the other. The H2O absorption may occur in the disk atmosphere due to strong accretion-heating of the midplane, or in a disk wind viewed at an ideal angle for absorption. CO emission may originate in the hot inner disk or outflow shocks, but NIRSpec data covering the 4.6 μm band head are required to determine the physical conditions of the CO gas, as the high temperatures seen in the MIRI data may be due to optical depth. OH emission is detected towards both mid-IR source positions and one of the shocks, and is likely excited by water photodissociation or chemical formation pumping in a highly non-LTE manner. Conclusions. The observed molecular spectra are consistent with disks having already formed around two protostars in the young IRAS 23385+6054 system. Molecular features mostly appear in emission from a variety of species, in contrast to the more evolved hot core phase protostars which typically show only absorption; however, further observations of young high-mass protostars are needed to disentangle geometry and viewing angle effects from evolution.
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| 27. |
- Gasman, Danny, et al.
(author)
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JWST MIRI/MRS in-flight absolute flux calibration and tailored fringe correction for unresolved sources
- 2023
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 673
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Journal article (peer-reviewed)abstract
- Context. The Medium Resolution Spectrometer (MRS) is one of the four observing modes of JWST/MIRI. Using JWST in-flight data of unresolved (point) sources, we can derive the MRS absolute spectral response function (ASRF) starting from raw data. Spectral fringing, caused by coherent reflections inside the detector arrays, plays a critical role in the derivation and interpretation of the MRS ASRF. The fringe corrections implemented in the current pipeline are not optimal for non-extended sources, and a high density of molecular features particularly inhibits an accurate correction. Aims. In this paper, we present an alternative way to calibrate the MIRI/MRS data. Firstly, we derive a fringe correction that accounts for the dependence of the fringe properties on the MIRI/MRS pupil illumination and detector pixel sampling of the point spread function. Secondly, we derive the MRS ASRF using an absolute flux calibrator observed across the full 5- 28 µm wavelength range of the MRS. Thirdly, we apply the new ASRF to the spectrum of a G dwarf and compare it with the output of the JWST/MIRI default data reduction pipeline. Finally, we examine the impact of the different fringe corrections on the detectability of molecular features in the G dwarf and K giant. Methods. The absolute flux calibrator HD 163466 (A-star) was used to derive tailored point source fringe flats at each of the default dither locations of the MRS. The fringe-corrected point source integrated spectrum of HD 163466 was used to derive the MRS ASRF using a theoretical model for the stellar continuum. A cross-correlation was run to quantify the uncertainty on the detection of CO, SiO, and OH in the K giant and CO in the G dwarf for different fringe corrections. Results. The point-source-tailored fringe correction and ASRF are found to perform at the same level as the current corrections, beating down the fringe contrast to the sub-percent level in the G dwarf in the longer wavelengths, whilst mitigating the alteration of real molecular features. The same tailored solutions can be applied to other MRS unresolved targets. Target acquisition is required to ensure the pointing is accurate enough to apply this method. A pointing repeatability issue in the MRS limits the effectiveness of the tailored fringe flats is at short wavelengths. Finally, resulting spectra require no scaling to make the sub-bands match, and a dichroic spectral leak at 12.2 µm is removed.
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| 28. |
- Gieser, C., et al.
(author)
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JOYS: Disentangling the warm and cold material in the high-mass IRAS 23385+6053 cluster
- 2023
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In: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 679
-
Journal article (peer-reviewed)abstract
- Context. High-mass star formation occurs in a clustered mode where fragmentation is observed from an early stage onward. Young protostars can now be studied in great detail with the recently launched James Webb Space Telescope (JWST). Aims. We study and compare the warm (>100 K) and cold (<100 K) material toward the high-mass star-forming region (HMSFR) IRAS 23385+6053 (IRAS 23385 hereafter) combining high-angular-resolution observations in the mid-infrared (MIR) with the JWST Observations of Young protoStars (JOYS) project and with the NOrthern Extended Millimeter Array (NOEMA) at millimeter (mm) wavelengths at angular resolutions of 0.a2 1.a0. Methods. We investigated the spatial morphology of atomic and molecular species using line-integrated intensity maps. We estimated the temperature and column density of different gas components using H2 transitions (warm and hot component) and a series of CH3CN transitions as well as 3 mm continuum emission (cold component). Results. Toward the central dense core of IRAS 23385, the material consists of relatively cold gas and dust ( 50 K), while multiple outflows create heated and/or shocked H2 and show enhanced temperatures ( 400 K) along the outflow structures. An energetic outflow with enhanced emission knots of [FeII] and [NiII] suggests J-type shocks, while two other outflows have enhanced emission of only H2 and [SI] caused by C-type shocks. The latter two outflows are also more prominent in molecular line emission at mm wavelengths (e.g., SiO, SO, H2CO, and CH3OH). Data of even higher angular resolution are needed to unambiguously identify the outflow-driving sources given the clustered nature of IRAS 23385. While most of the forbidden fine structure transitions are blueshifted, [NeII] and [NeIII] peak at the source velocity toward the MIR source A/mmA2 suggesting that the emission is originating from closer to the protostar. Conclusions. The warm and cold gas traced by MIR and mm observations, respectively, are strongly linked in IRAS 23385. The outflows traced by MIR H2 lines have molecular counterparts in the mm regime. Despite the presence of multiple powerful outflows that cause dense and hot shocks, a cold dense envelope still allows star formation to further proceed. To study and fully understand the spatially resolved MIR properties, a representative sample of low- and high-mass protostars has to be probed using JWST.
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| 29. |
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| 34. |
- Kavanagh, K L, et al.
(author)
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The SDR superfamily : functional and structural diversity within a family of metabolic and regulatory enzymes
- 2008
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 65:24, s. 3895-3906
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Journal article (peer-reviewed)abstract
- Short-chain dehydrogenases/reductases (SDRs) constitute a large family of NAD(P)(H)-dependent oxidoreductases, sharing sequence motifs and displaying similar mechanisms. SDR enzymes have critical roles in lipid, amino acid, carbohydrate, cofactor, hormone and xenobiotic metabolism as well as in redox sensor mechanisms. Sequence identities are low, and the most conserved feature is an alpha/beta folding pattern with a central beta sheet flanked by 2 - 3 alpha-helices from each side, thus a classical Rossmannfold motif for nucleotide binding. The conservation of this element and an active site, often with an Asn-Ser-Tyr-Lys tetrad, provides a platform for enzymatic activities encompassing several EC classes, including oxidoreductases, epimerases and lyases. The common mechanism is an underlying hydride and proton transfer involving the nicotinamide and typically an active site tyrosine residue, whereas substrate specificity is determined by a variable C-terminal segment. Relationships exist with bacterial haloalcohol dehalogenases, which lack cofactor binding but have the active site architecture, emphasizing the versatility of the basic fold in also generating hydride transfer-independent lyases. The conserved fold and nucleotide binding emphasize the role of SDRs as scaffolds for an NAD(P)(H) redox sensor system, of importance to control metabolic routes, transcription and signalling.
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| 35. |
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| 36. |
- Mesher, David, et al.
(author)
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Population-level effects of human papillomavirus vaccination programs on infections with nonvaccine genotypes
- 2016
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In: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 22:10, s. 1732-1740
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Journal article (peer-reviewed)abstract
- We analyzed human papillomavirus (HPV) prevalences during prevaccination and postvaccination periods to consider possible changes in nonvaccine HPV genotypes after introduction of vaccines that confer protection against 2 high-risk types, HPV16 and HPV18. Our meta-analysis included 9 studies with data for 13,886 girls and women ≤19 years of age and 23,340 women 20–24 years of age. We found evidence of cross-protection for HPV31 among the younger age group after vaccine introduction but little evidence for reductions of HPV33 and HPV45. For the group this same age group, we also found slight increases in 2 nonvaccine high-risk HPV types (HPV39 and HPV52) and in 2 possible high-risk types (HPV53 and HPV73). However, results between age groups and vaccines used were inconsistent, and the increases had possible alternative explanations; consequently, these data provided no clear evidence for type replacement. Continued monitoring of these HPV genotypes is important.
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| 37. |
- Pilipchuk, Sophia P, et al.
(author)
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Micropatterned Scaffolds with Immobilized Growth Factor Genes Regenerate Bone and Periodontal Ligament-Like Tissues.
- 2018
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In: Advanced healthcare materials. - : Wiley. - 2192-2659 .- 2192-2640. ; 7:22
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Journal article (peer-reviewed)abstract
- Periodontal disease destroys supporting structures of teeth. However, tissue engineering strategies offer potential to enhance regeneration. Here, the strategies of patterned topography, spatiotemporally controlled growth factor gene delivery, and cell-based therapy to repair bone-periodontal ligament (PDL) interfaces are combined. Micropatterned scaffolds are fabricated for the ligament regions using polycaprolactone (PCL)/polylactic-co-glycolic acid and combined with amorphous PCL scaffolds for the bone region. Scaffolds are modified using chemical vapor deposition, followed by spatially controlled immobilization of vectors encoding either platelet-derived growth factor-BB or bone morphogenetic protein-7, respectively. The scaffolds are seeded with human cells and delivered to large alveolar bone defects in athymic rats. The effects of dual and single gene delivery with and without micropatterning are assessed after 3, 6, and 9 weeks. Gene delivery results in greater bone formation at three weeks. Micropatterning results in regenerated ligamentous tissues similar to native PDL. The combination results in more mature expression of collagen III and periostin, and with elastic moduli of regenerated tissues that are statistically indistinguishable from those of native tissue, while controls are less stiff than native tissues. Thus, controlled scaffold microtopography combined with localized growth factor gene delivery improves the regeneration of periodontal bone-PDL interfaces.
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| 38. |
- Rocha, W. R.M., et al.
(author)
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JWST Observations of Young protoStars (JOYS+): Detecting icy complex organic molecules and ions: I. CH4, SO2, HCOO, OCN, H2CO, HCOOH, CH3CH2OH, CH3CHO, CH3OCHO, and CH3COOH
- 2024
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In: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 683
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Journal article (peer-reviewed)abstract
- Context. Complex organic molecules (COMs) are ubiquitously detected in the gas phase and thought to be mostly formed on icy grains. Nevertheless, there have not been any unambiguous detections of COMs larger than CH3OH in ices reported thus far. Exploring this matter in greater detail has now become possible with the unprecedented possibilities offered by the James Webb Space Telescope (JWST) within the infrared (IR) spectral range with its very high sensitivity and spectral resolution in the critical 5 10 μm range, the fingerprint region of oxygen-bearing COMs. Aims. In the JWST Observations of Young protoStars (JOYS+) program, more than 30 protostars are undergoing observation with the Medium Resolution Spectrograph (MRS) of the Mid-IR Instrument (MIRI). The goal of this study is to comprehensively explore the COMs ice signatures in one low- and one high-mass protostar: NGC 1333 IRAS 2A and IRAS 23385+6053, respectively. Methods. We performed global continuum and silicate subtractions of the MIRI-MRS spectra, followed by a local continuum subtraction in optical depth scale in the range around 6.8 and 8.6 μm, the ice COM fingerprint region. We explored different choices for the local continuum and silicate subtraction. Next, we fit the observational data with a large sample of available IR laboratory ice spectra. We used the ENIIGMA fitting tool, a genetic algorithm-based code that not only finds the best fit between the lab data and the observations, but also performs a statistical analysis of the solutions, such as deriving the confidence intervals and quantifying fit degeneracy. Results. We report the best fits for the spectral ranges between 6.8 and 8.6 μm in NGC 1333 IRAS 2A and IRAS 23385+6053, originating from simple molecules and COMs, as well as negative ions. Overall, we find that ten chemical species are needed to reproduce the astronomical data. The strongest feature in this range (7.7 μm) is dominated by CH4, with contributions from SO2 and OCN. Our results indicate that the 7.2 and 7.4 μm bands are mostly dominated by HCOO. We also find statistically robust detections of COMs based on multiple bands, most notably, CH3CHO, CH3CH2OH, and CH3OCHO. We also report a likely detection of CH3COOH. Based on the ice column density ratios between CH3CH2OH and CH3CHO of NGC 1333 IRAS 2A and IRAS 23385+6053, we find compelling evidence that these COMs are formed on icy grains. Finally, the derived ice abundances for NGC 1333 IRAS 2A correlate well with those in comet 67P/GC within a factor of 5. Conclusions. Based on the high-quality JWST (MIRI-MRS) spectra, we conclude that COMs are present in interstellar ices, thus providing additional proof for the solid-state origin of these species in star-forming regions. In addition, the good correlation between the ice abundances in comet 67P and NGC 1333 IRAS 2A is fully in line with the idea that cometary COMs may be inherited from the early protostellar phases to a significant extent.
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| 39. |
- Rodríguez-Gómez, José A, et al.
(author)
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Microglia : Agents of the CNS Pro-Inflammatory Response.
- 2020
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In: Cells. - : MDPI AG. - 2073-4409. ; 9:7
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Journal article (peer-reviewed)abstract
- The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.
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| 40. |
- Tychoniec, Łukasz, et al.
(author)
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JWST Observations of Young protoStars (JOYS) Linked accretion and ejection in a Class I protobinary system
- 2024
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In: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 687
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Journal article (peer-reviewed)abstract
- Context. Accretion and ejection dictate the outcomes of star and planet formation processes. The mid-infrared (MIR) wavelength range offers key tracers of processes that have been difficult to detect and spatially resolve in protostars until now. Aims. We aim to characterize the interplay between accretion and ejection in the low-mass Class I protobinary system TMC1, comprising two young stellar objects: TMC1-W and TMC1-E at a 85 au separation. Methods. Using the James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) observations in 5–28 µm range, we measured the intensities of emission lines of H2, atoms, and ions, for instance, the [Fe II] and [Ne II], and HI recombination lines. We analyzed the spatial distribution of the different species using the MIRI Medium Resolution Spectrometer (MRS) capabilities to spatially resolve emission at 0'.́2–0'.́7 scales. we compared these results with the corresponding Atacama Large Millimeter/submillimeter Array (ALMA) maps tracing cold gas and dust. Results. We detected H2 outflow coming from TMC1-E, with no significant H2 emission from TMC1-W. The H2 emission from TMC1-E outflow appears narrow and extends to wider opening angles with decreasing Eup from S(8) to S(1) rotational transitions, indicating the disk wind as its origin. The outflow from TMC1-E protostar shows spatially extended emission lines of [Ne II], [Ne III], [Ar II], and [Ar III], with their line ratios consistent with UV radiation as a source of ionization. With ALMA, we detected an accretion streamer infalling from >1000 au scales onto the TMC1-E component. The TMC1-W protostar powers a collimated jet, detected with [Fe II] and [Ni II], making it consistent with energetic flow. A much weaker ionized jet is observed from TMC1-E, and both jets appear strikingly parallel to each other, indicating that the disks are co-planar. TMC1-W is associated with strong emission from hydrogen recombination lines, tracing the accretion onto the young star. Conclusions. MIRI-MRS observations provide an unprecedented view of protostellar accretion and ejection processes on 20 au scales. Observations of a binary Class I protostellar system show that the two processes are clearly intertwined, with accretion from the envelope onto the disk influencing a wide-angle wind ejected on disk scales. Finally, the accretion from the protostellar disk onto the protostar is associated with the source launching a collimated high-velocity jet within the innermost regions of the disk.
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