| 1. |
- Bossart, Martin, et al.
(författare)
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Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
- 2022
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Ingår i: Cell Metabolism. - : CELL PRESS. - 1550-4131 .- 1932-7420. ; 34:1, s. 59-
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Tidskriftsartikel (refereegranskat)abstract
- Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
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| 2. |
- Schmidt, Keith T, et al.
(författare)
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Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors.
- 2020
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 86:4, s. 475-486
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model.METHODS: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling.RESULTS: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%).CONCLUSION: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.
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| 3. |
- Buder, Sven, et al.
(författare)
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The GALAH plus survey : Third data release
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 506:1, s. 150-201
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Tidskriftsartikel (refereegranskat)abstract
- The ensemble of chemical element abundance measurements for stars, along with precision distances and orbit properties, provides high-dimensional data to study the evolution of the Milky Way. With this third data release of the Galactic Archaeology with HERMES (GALAH) survey, we publish 678 423 spectra for 588 571 mostly nearby stars (81.2 per cent of stars are within <2 kpc), observed with the HERMES spectrograph at the Anglo-Australian Telescope. This release (hereafter GALAH+ DR3) includes all observations from GALAH Phase 1 (bright, main, and faint survey, 70 per cent), K2-HERMES (17 per cent), TESS-HERMES (5 per cent), and a subset of ancillary observations (8 per cent) including the bulge and >75 stellar clusters. We derive stellar parameters T-eff, logg, [Fe/H], v(mic), v(broad), and v(rad) using our modified version of the spectrum synthesis code Spectroscopy Made Easy (SME) and 1D MARCS model atmospheres. We break spectroscopic degeneracies in our spectrum analysis with astrometry from Gaia DR2 and photometry from 2MASS. We report abundance ratios [X/Fe] for 30 different elements (11 of which are based on non-LTE computations) covering five nucleosynthetic pathways. We describe validations for accuracy and precision, flagging of peculiar stars/measurements and recommendations for using our results. Our catalogue comprises 65 per cent dwarfs, 34 per cent giants, and 1 per cent other/unclassified stars. Based on unflagged chemical composition and age, we find 62 per cent young low-alpha, 9 per cent young high-alpha, 27 per cent old high-alpha, and 2 per cent stars with [Fe/H] <= -1. Based on kinematics, 4 per cent are halo stars. Several Value-Added-Catalogues, including stellar ages and dynamics, updated after Gaia eDR3, accompany this release and allow chrono-chemodynamic analyses, as we showcase.
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| 4. |
- Buder, Sven, et al.
(författare)
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The GALAH+ survey : Third data release
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 506:1, s. 150-201
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Tidskriftsartikel (refereegranskat)abstract
- The ensemble of chemical element abundance measurements for stars, along with precision distances and orbit properties, provides high-dimensional data to study the evolution of the Milky Way. With this third data release of the Galactic Archaeology with HERMES (GALAH) survey, we publish 678 423 spectra for 588 571 mostly nearby stars (81.2 per cent of stars are within <2 kpc), observed with the HERMES spectrograph at the Anglo-Australian Telescope. This release (hereafter GALAH+ DR3) includes all observations from GALAH Phase 1 (bright, main, and faint survey, 70 per cent), K2-HERMES (17 per cent), TESS-HERMES (5 per cent), and a subset of ancillary observations (8 per cent) including the bulge and >75 stellar clusters. We derive stellar parameters Teff, log g, [Fe/H], vmic, vbroad, and vrad using our modified version of the spectrum synthesis code Spectroscopy Made Easy (sme) and 1D marcs model atmospheres. We break spectroscopic degeneracies in our spectrum analysis with astrometry from Gaia DR2 and photometry from 2MASS. We report abundance ratios [X/Fe] for 30 different elements (11 of which are based on non-LTE computations) covering five nucleosynthetic pathways. We describe validations for accuracy and precision, flagging of peculiar stars/measurements and recommendations for using our results. Our catalogue comprises 65 per cent dwarfs, 34 per cent giants, and 1 per cent other/unclassified stars. Based on unflagged chemical composition and age, we find 62 per cent young low-α, 9 per cent young high-α, 27 per cent old high-α, and 2 per cent stars with [Fe/H] ≤ −1. Based on kinematics, 4 per cent are halo stars. Several Value-Added-Catalogues, including stellar ages and dynamics, updated after Gaia eDR3, accompany this release and allow chrono-chemodynamic analyses, as we showcase.
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| 5. |
- Gao, Xudong, et al.
(författare)
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The GALAH survey : a new constraint on cosmological lithium and Galactic lithium evolution from warm dwarf stars
- 2020
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966 .- 1745-3925 .- 1745-3933. ; 497:1, s. L30-L34
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Tidskriftsartikel (refereegranskat)abstract
- Lithium depletion and enrichment in the cosmos is not yet well understood. To help tighten constraints on stellar and Galactic evolution models, we present the largest high-resolution analysis of Li abundances A(Li) to date, with results for over 100000 GALAH (Galactic Archeology with HERMES) field stars spanning effective temperatures 5900K≲Teff≲7000K and metallicities −3 ≲ [Fe/H] ≲ +0.5. We separated these stars into two groups, on the warm and cool sides of the so-called Li dip, a localized region of the Kiel diagram wherein lithium is severely depleted. We discovered that stars in these two groups show similar trends in the A(Li)–[Fe/H] plane, but with a roughly constant offset in A(Li) of 0.4dex, the warm group having higher Li abundances. At [Fe/H]≳−0.5, a significant increase in Li abundance with increasing metallicity is evident in both groups, signalling the onset of significant Galactic production. At lower metallicity, stars in the cool group sit on the Spite plateau, showing a reduced lithium of around 0.4dex relative to the primordial value predicted from big bang nucleosynthesis (BBN). However, stars in the warm group between [Fe/H] = −1.0 and −0.5 form an elevated plateau that is largely consistent with the BBN prediction. This may indicate that these stars in fact preserve the primordial Li produced in the early Universe.
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| 6. |
- Peel, Jessica N., et al.
(författare)
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Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals
- 2024
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Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 134:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Weakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODS. This study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTS. We found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSION. These findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.
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| 7. |
- Sharda, Piyush, et al.
(författare)
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The impact of carbon and oxygen abundances on the metal-poor initial mass function
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 518:3, s. 3985-3998
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Tidskriftsartikel (refereegranskat)abstract
- Star formation models predict that the metal-poor initial mass function (IMF) can be substantially different from that observed in the metal-rich Milky Way. This changeover occurs because metal-poor gas clouds cool inefficiently due to their lower abundance of metals and dust. However, predictions for the metal-poor IMF to date rely on assuming solar-scaled abundances, i.e. [X/O] = 0 at all [O/H]. There is now growing evidence that elements such as C and O that dominate metal line cooling in the ISM do not follow solar scaling at low metallicities. In this work, we extend models that predict the variation in the characteristic (or the peak) IMF mass as a function of metallicity using [C/O] ratios derived from observations of metal-poor Galactic stars and of Hii regions in dwarf galaxies. These data show [C/O] < 0 at subsolar [O/H], which leads to a substantially different metal-poor IMF in the metallicity range where Ci and Cii cooling dominate ISM thermodynamics, resulting in an increase in the characteristic mass by a factor as large as 7. An important consequence of this difference is a shift in the location of the transition from a top- to a bottom-heavy IMF upwards by 0.5-1 dex in metallicity. Our findings indicate that the IMF is very sensitive to the assumptions around solar-scaled ISM compositions in metal-poor systems (e.g. dwarf galaxies, the Galactic halo, and metal-poor stars) that are a key focus of JWST.
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| 8. |
- Wang, Ella Xi, et al.
(författare)
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3D NLTE spectral line formation of lithium in late-type stars
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 500:2, s. 2159-2176
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Tidskriftsartikel (refereegranskat)abstract
- Accurately known stellar lithium abundances may be used to shed light on a variety of astrophysical phenomena such as big bang nucleosynthesis, radial migration, ages of stars and stellar clusters, and planet engulfment events. We present a grid of synthetic lithium spectra that are computed in non-local thermodynamic equilibrium (NLTE) across the STAGGER grid of three-dimensional (3D) hydrodynamic stellar atmosphere models. This grid covers three Li lines at 610.4, 670.8, and 812.6 nmfor stellar parameters representative of FGK-type dwarfs and giants, spanning T-eff = 4000-7000 K, log g = 1.5-5.0, [Fe/H] = -4.0-0.5, and A(Li) = -0.5-4.0. We find that our abundance corrections are up to 0.15 dex more negative than in previous work, due to a previously overlooked NLTE effect of blocking of UV lithium lines by background opacities, which has important implications for a wide range of science cases. We derive a new 3D NLTE solar abundance of A(Li) = 0.96 +/- 0.05, which is 0.09 dex lower than the commonly used value. We make our grids of synthetic spectra and abundance corrections publicly available through the BREIDABLIK package. This package includes methods for accurately interpolating our grid to arbitrary stellar parameters through methods based on Kriging (Gaussian process regression) for line profiles, and multilayer perceptrons (a class of fully connected feedforward neural networks) for NLTE corrections and 3D NLTE abundances from equivalent widths, achieving interpolation errors of the order of 0.01 dex.
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| 9. |
- Zhou, Yixiao, et al.
(författare)
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The relationship between photometric and spectroscopic oscillation amplitudes from 3D stellar atmosphere simulations
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 503:1, s. 13-27
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Tidskriftsartikel (refereegranskat)abstract
- We establish a quantitative relationship between photometric and spectroscopic detections of solar-like oscillations using ab initio, 3D, hydrodynamical numerical simulations of stellar atmospheres. We present a theoretical derivation as a proof of concept for our method. We perform realistic spectral line formation calculations to quantify the ratio between luminosity and radial velocity amplitude for two case studies: the Sun and the red giant ϵ Tau. Luminosity amplitudes are computed based on the bolometric flux predicted by 3D simulations with granulation background modelled the same way as asteroseismic observations. Radial velocity amplitudes are determined from the wavelength shift of synthesized spectral lines with methods closely resembling those used in Birmingham Solar Oscillations Network (BiSON) and Stellar Oscillations Network Group (SONG) observations. Consequently, the theoretical luminosity to radial velocity amplitude ratios are directly comparable with corresponding observations. For the Sun, we predict theoretical ratios of 21.0 and 23.7 ppm [m s−1]−1 from BiSON and SONG, respectively, in good agreement with observations 19.1 and 21.6 ppm [m s−1]−1. For ϵ Tau, we predict K2 and SONG ratios of 48.4 ppm [m s−1]−1, again in good agreement with observations 42.2 ppm [m s−1]−1, and much improved over the result from conventional empirical scaling relations that give 23.2 ppm [m s−1]−1. This study thus opens the path towards a quantitative understanding of solar-like oscillations, via detailed modelling of 3D stellar atmospheres.
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