| 1. |
- Bossart, Martin, et al.
(author)
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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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In: Cell Metabolism. - : CELL PRESS. - 1550-4131 .- 1932-7420. ; 34:1, s. 59-
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Journal article (peer-reviewed)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.
(author)
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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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In: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 86:4, s. 475-486
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Journal article (peer-reviewed)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.
(author)
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The GALAH plus survey : Third data release
- 2021
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 506:1, s. 150-201
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Journal article (peer-reviewed)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.
(author)
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The GALAH Survey : second data release
- 2018
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In: Monthly notices of the Royal Astronomical Society. - : OXFORD UNIV PRESS. - 0035-8711 .- 1365-2966. ; 478:4, s. 4513-4552
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Journal article (peer-reviewed)abstract
- The Galactic Archaeology with HERMES (GALAH) survey is a large-scale stellar spectroscopic survey of the Milky Way, designed to deliver complementary chemical information to a large number of stars covered by the Gaia mission. We present the GALAH second public data release (GALAH DR2) containing 342 682 stars. For these stars, the GALAH collaboration provides stellar parameters and abundances for up to 23 elements to the community. Here we present the target selection, observation, data reduction, and detailed explanation of how the spectra were analysed to estimate stellar parameters and element abundances. For the stellar analysis, we have used a multistep approach. We use the physics-driven spectrum synthesis of Spectroscopy Made Easy (SME) to derive stellar labels (T-eff, log g, [Fe/H], [X/Fe], v(mic), vsin i, AKS) for a representative training set of stars. This information is then propagated to the whole sample with the data-driven method of The Cannon. Special care has been exercised in the spectral synthesis to only consider spectral lines that have reliable atomic input data and are little affected by blending lines. Departures from local thermodynamic equilibrium (LTE) are considered for several key elements, including Li, O, Na, Mg, Al, Si, and Fe, using 1D MARCS stellar atmosphere models. Validation tests including repeat observations, Gaia benchmark stars, open and globular clusters, and K2 asteroseismic targets lend confidence to our methods and results. Combining the GALAH DR2 catalogue with the kinematic information from Gaia will enable a wide range of Galactic Archaeology studies, with unprecedented detail, dimensionality, and scope.
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| 5. |
- Buder, Sven, et al.
(author)
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The GALAH+ survey : Third data release
- 2021
-
In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 506:1, s. 150-201
-
Journal article (peer-reviewed)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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| 6. |
- Gao, Xudong, et al.
(author)
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The GALAH survey : verifying abundance trends in the open cluster M67 using non-LTE modelling
- 2018
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 481:2, s. 2666-2684
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Journal article (peer-reviewed)abstract
- Open cluster members are coeval and share the same initial bulk chemical composition. Consequently, differences in surface abundances between members of a cluster that are at different evolutionary stages can be used to study the effects of mixing and internal chemical processing. We carry out an abundance analysis of seven elements (Li, O, Na, Mg, Al, Si, and Fe) in 66 stars belonging to the open cluster m67, based on high resolution GALAH spectra, 1D MARCS model atmospheres, and non-local thermodynamic equilibrium (non-LTE) radiative transfer. From the non-LTE analysis, we find a typical star-to-star scatter in the abundance ratios of around O.05 dex. We find trends in the abundance ratios with effective temperature, indicating systematic differences in the surface abundances between turn-off and giant stars; these trends are more pronounced when LTE is assumed. However, trends with effective temperature remain significant for Al and Si also in non-LTE. Finally, we compare the derived abundances with prediction from stellar evolution models including effects of atomic diffusion. We find overall good agreement for the abundance patterns of dwarfs and sub-giant stars, but the abundances of cool giants are lower relative to less evolved stars than predicted by the diffusion models, in particular for Mg.
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| 7. |
- Gao, Xudong, et al.
(author)
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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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In: 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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Journal article (peer-reviewed)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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| 8. |
- Giorgio, Elisa, et al.
(author)
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Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression
- 2013
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In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:8, s. 1160-1171
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Journal article (peer-reviewed)abstract
- Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
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| 9. |
- Peel, Jessica N., et al.
(author)
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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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In: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 134:8
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Journal article (peer-reviewed)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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| 10. |
- Sharda, Piyush, et al.
(author)
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The impact of carbon and oxygen abundances on the metal-poor initial mass function
- 2022
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 518:3, s. 3985-3998
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Journal article (peer-reviewed)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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