11 research outputs found
A Quantitative Comparison of SMC, LMC, and Milky Way UV to NIR Extinction Curves
We present an exhaustive, quantitative comparison of all of the known
extinction curves in the Small and Large Magellanic Clouds (SMC and LMC) with
our understanding of the general behavior of Milky Way extinction curves. The
R_V dependent CCM relationship and the sample of extinction curves used to
derive this relationship is used to describe the general behavior of Milky Way
extinction curves. The ultraviolet portion of the SMC and LMC extinction curves
are derived from archival IUE data, except for one new SMC extinction curve
which was measured using HST/STIS observations. The optical extinction curves
are derived from new (for the SMC) and literature UBVRI photometry (for the
LMC). The near-infrared extinction curves are calculated mainly from 2MASS
photometry supplemented with DENIS and new JHK photometry. For each extinction
curve, we give R_V = A(V)/E(B-V) and N(HI) values which probe the same dust
column as the extinction curve. We compare the properties of the SMC and LMC
extinction curves with the CCM relationship three different ways: each curve by
itself, the behavior of extinction at different wavelengths with R_V, and
behavior of the extinction curve FM fit parameters with R_V. As has been found
previously, we find that a small number of LMC extinction curves are consistent
with the CCM relationship, but majority of the LMC and all of the SMC curves do
not follow the CCM relationship. For the first time, we find that the CCM
relationship seems to form a bound on the properties of all of the LMC and SMC
extinction curves. This result strengthens the picture of dust extinction
curves exhibit a continuum of properties between those found in the Milky Way
and the SMC Bar. (abridged)Comment: 18 pages, 10 figures, ApJ in pres
Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.
Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.We thank M. Jaeger (Radboudumc) for kindly providing flourescein
isothiocyanate-labelled Candida albicans. D. Williams (East
Tennessee State University) provided the β-glucan we used in our
initial experiments. H. Lemmers (Radboudumc) kindly prepared the
purified lipopolysaccharide used for stimulation of primary human
monocytes and macrophages. Part of the figures were prepared
using (among other software) Biorender.com. B.N. is supported
by a National Health and Medical Research Council (Australia)
Investigator Grant (APP1173314). This work was supported by
National Institutes of Health grants R01 HL144072, R01 CA220234
and P01 HL131478, as well as a Vici grant from the Dutch Research
Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N.
was supported by a Spinoza grant from Dutch Research Council
NWO and an ERC Advanced Grant (#833247).S
Nanoemulsion platform for diagnostic and therapeutic purposes
Les nanoémulsions huile dans eau (H/E) sont utilisées depuis plus de 50 ans en clinique humaine comme source de lipides en nutrition parentérale. Si cette dernière décennie a vu émerger la mise à profit de cette forme comme véhicule de substances actives lipophiles, l’utilisation des nanoémulsions comme vecteur d'agents thérapeutique ou diagnostique reste encore sous-exploitée. L’objectif de cette thèse a été le développement d'une plateforme de nanoémulsions comme vecteur alternatif aux nanosystèmes classiquement utilisés. Deux applications ont été visées : le diagnostic de la plaque vulnérable d'athérosclérose et le traitement de la maladie de Parkinson. Les nanoémulsions ont été fonctionnalisées avec des anticorps humanisés dirigés contre l’athérome et chargées avec des particules magnétiques pour servir d’agent de contraste moléculaire pour l’imagerie par résonance magnétique (IRM) et pour une nouvelle technique : l’imagerie par particules magnétique (IPM). L'efficacité du nanosystème pour le ciblage de la plaque a été démontré sur des souris athéromateuses. L’inclusion de chromophores lipophiles originaux et ultrabrillants ainsi que la possibilité d'incorporer des substances actives ont permis d’ouvrir la voie vers le développement de formulations multimodales et théranostiques. Les nanoémulsions thérapeutiques contre Parkinson ont été développées pour rétablir le pH lysosomal des neurones dopaminergiques par l'encapsulation d'un polymère (PLGA). Ce défaut d’acidification favorise la mort cellulaire par l’accumulation de déchets dans les neurones. La formulation a été optimisée pour le passage intracérébral par voie intraveineuse ou intranasale. Les résultats montrent un passage cérébral in vivo par voie intraveineuse avec une confirmation in vitro de la régénération du pH. Les perspectives de ce travail sont la poursuite de la plateforme et l'ouverture vers de nouvelles applications comme l'hyperthermie magnétique dans les cancers.Oil in water (O/W) nanoemulsions have been used for over 50 years in human clinics as a lipids source in parenteral nutrition. Even if nanoemulsions have recently emerged as vehicles for lipophilic active pharmaceutical ingredient (API) their use as a therapeutic or diagnostic agent is still under-exploited. The objective of this Ph.D thesis was to develop an nanoemulsions platform as an alternative to conventionally used nanosystems. In this work, 2 applications have been studied: the diagnosis of vulnerable plaque in atherosclerosis, and the treatment of Parkinson's disease. Nanoemulsions have been functionalized with humanized antibody targeting atheroma and loaded with magnetic particles as molecular contrast agents for magnetic resonance imaging (MRI) and an emerging technique: magnetic particle imaging (MPI). The successful plaque targeting has been demonstrated in atheromatous mice. The inclusion of original and ultra-bright lipophilic chromophores as well as the loading of API have paved the way to the development of multimodal and theranostic formulations. Therapeutic nanoemulsions against Parkinson’s disease have been developed to restore lysosomal pH of dopaminergic neurons with acidic polymer (PLGA). Acidification dysfunction leads to cell death due to the accumulation of waste inside neurons. The formulation has been optimized for brain delivery through intravenous or intranasal administration. The results show brain delivery in vivo trough intravenous injection associated with a pH rescue in vitro. The perspectives will focus on optimizing this platform and use it for new applications such as magnetic hyperthermia in cancers
Plateforme de nanoémulsions destinées au diagnostic et à la thérapeutique
Oil in water (O/W) nanoemulsions have been used for over 50 years in human clinics as a lipids source in parenteral nutrition. Even if nanoemulsions have recently emerged as vehicles for lipophilic active pharmaceutical ingredient (API) their use as a therapeutic or diagnostic agent is still under-exploited. The objective of this Ph.D thesis was to develop an nanoemulsions platform as an alternative to conventionally used nanosystems. In this work, 2 applications have been studied: the diagnosis of vulnerable plaque in atherosclerosis, and the treatment of Parkinson's disease. Nanoemulsions have been functionalized with humanized antibody targeting atheroma and loaded with magnetic particles as molecular contrast agents for magnetic resonance imaging (MRI) and an emerging technique: magnetic particle imaging (MPI). The successful plaque targeting has been demonstrated in atheromatous mice. The inclusion of original and ultra-bright lipophilic chromophores as well as the loading of API have paved the way to the development of multimodal and theranostic formulations. Therapeutic nanoemulsions against Parkinson’s disease have been developed to restore lysosomal pH of dopaminergic neurons with acidic polymer (PLGA). Acidification dysfunction leads to cell death due to the accumulation of waste inside neurons. The formulation has been optimized for brain delivery through intravenous or intranasal administration. The results show brain delivery in vivo trough intravenous injection associated with a pH rescue in vitro. The perspectives will focus on optimizing this platform and use it for new applications such as magnetic hyperthermia in cancers.Les nanoémulsions huile dans eau (H/E) sont utilisées depuis plus de 50 ans en clinique humaine comme source de lipides en nutrition parentérale. Si cette dernière décennie a vu émerger la mise à profit de cette forme comme véhicule de substances actives lipophiles, l’utilisation des nanoémulsions comme vecteur d'agents thérapeutique ou diagnostique reste encore sous-exploitée. L’objectif de cette thèse a été le développement d'une plateforme de nanoémulsions comme vecteur alternatif aux nanosystèmes classiquement utilisés. Deux applications ont été visées : le diagnostic de la plaque vulnérable d'athérosclérose et le traitement de la maladie de Parkinson. Les nanoémulsions ont été fonctionnalisées avec des anticorps humanisés dirigés contre l’athérome et chargées avec des particules magnétiques pour servir d’agent de contraste moléculaire pour l’imagerie par résonance magnétique (IRM) et pour une nouvelle technique : l’imagerie par particules magnétique (IPM). L'efficacité du nanosystème pour le ciblage de la plaque a été démontré sur des souris athéromateuses. L’inclusion de chromophores lipophiles originaux et ultrabrillants ainsi que la possibilité d'incorporer des substances actives ont permis d’ouvrir la voie vers le développement de formulations multimodales et théranostiques. Les nanoémulsions thérapeutiques contre Parkinson ont été développées pour rétablir le pH lysosomal des neurones dopaminergiques par l'encapsulation d'un polymère (PLGA). Ce défaut d’acidification favorise la mort cellulaire par l’accumulation de déchets dans les neurones. La formulation a été optimisée pour le passage intracérébral par voie intraveineuse ou intranasale. Les résultats montrent un passage cérébral in vivo par voie intraveineuse avec une confirmation in vitro de la régénération du pH. Les perspectives de ce travail sont la poursuite de la plateforme et l'ouverture vers de nouvelles applications comme l'hyperthermie magnétique dans les cancers
FSH-blocking therapeutic for osteoporosis
Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions, namely osteoporosis, obesity, and Alzheimer\u27s disease. Blocking FSH action prevents bone loss, fat gain and neurodegeneration in mice. We recently developed a first-in-class, humanized, epitope-specific FSH-blocking antibody, MS-Hu6, with a K of 7.52 nM. Using a GLP-compliant platform, we now report the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice and parameters of acute safety in monkeys. Biodistribution studies using Zr-labelled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. MS-Hu6 displayed a β phase t of 7.5 days (180 hours) in humanized Tg32 mice. We tested 217 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze-thaw and at different temperatures, with minimal aggregation, and without self-, cross-, or hydrophobic interactions or appreciable binding to relevant human antigens. MS-Hu6 showed the same level of \u27humanness\u27 as human IgG1 and was non-immunogenic in ELISPOT assays for IL-2 and IFNg in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable, and manufacturable, and is therefore poised for future human testing