Critical roles of dendritic cells and macrophages in cardiovascular disease

Cardiovascular disease is a major cause of mortality in the world, and is rapidly increasing. To understand the inflammatory response of various diseases, we have made tremendous advances in molecular and cellular research to show clear evidence that macrophages and dendritic cells play central roles in cardiovascular diseases, such as atherosclerosis and myocardial infarction. We have identified the two conventional DCs subsets (cDC1 and cDC2) in heart of healthy mouse. As expected, we found that the IRF8-expressing cDC1, but not the IRF4-expressing cDC2, was dependent on Flt3 for its development. Myocardial infarction significantly increased the infiltration of CD45+ leukocytes in the infarcted heart, including macrophages, neutrophils and DCs. Among cDC, the most significantly increased subset was the cDC2. The diphtheria toxin receptor (DTR) mediated depletion of Zbtb46-expressing DCs in myocardial infarcted mice led to a significant decrease of IL-1β expression together with an increased recruitment of leukocytes. This dramatically reduced the infarcted size and improved cardiac function, suggesting that cardiac DCs play an important role in immune cell infiltration following myocardial infarction. In another study, we developed, for the first time, a lipid probe-based flow cytometry method to analyze foam cells in atherosclerotic aorta. Our method enables to isolate foamy and non-foamy macrophages in order to perform the transcriptomic analysis of these cells. In addition, this technique allows to assess the severity of atherosclerosis and the characteristics of foam cells. RNA-seq analysis showed that lipid-laden foamy macrophages in atherosclerotic lesions clearly expressed different transcripts compared to non-foamy macrophages. Surprisingly, we found that non-foamy macrophages showed a pro-inflammatory signature reflected by the up-regulation of cytokines, such as Il1β, Tnf and Nlrp3. However, foamy macrophages up-regulated genes related to the transport and uptake of lipids (cholesterol and fatty acid). Collectively, we specifically identified the function of dendritic cells and macrophages in the pathogenesis of cardiovascular diseases. Understanding the precise role of these cells will help to develop appropriate immune-therapeutic strategy to attenuate cardiovascular disease.Les maladies cardiovasculaires représentent un risque majeur de mortalité dans le monde et la prévalence de ces pathologies ne cesse d’augmenter. Pour comprendre la réponse inflammatoire de ces maladies, nous avons fait d’énormes progrès dans la recherche moléculaire et cellulaire afin de démontrer clairement que les macrophages et les cellules dendritiques jouent un rôle central dans l’athérosclérose et l’infarctus du myocarde, deux maladies cardiovasculaires mortelles. Nous avons trouvé que, à l’état normal, le coeur de souris abrite les deux types de cellules dendritiques classiques (cDC1 et cDC2). Conformément à ce qui est connue sur ces les cDC, nous avons constaté que les cDC1, qui expriment IRF8, dépendent du Flt3, un facteur de croissance important pour leur développement alors que les cDC2, qui expriment IRF4, sont Flt3 indépendantes. Nous avons trouvé que le nombre total leucocytes CD45+ augment dans le coeur des souris ayant subi l'infarctus du myocarde. Ces leucocytes étaient majoritairement des macrophages, des neutrophiles et des cDCs. Parmi ces dernières, les cDC2 ont connu une plus forte augmentation. Dans un premier projet, nous avons vérifié le rôle de ces cDCs dans cette pathologie. Pour ce faire, nous avons procédé à la déplétion de ces cellules en utilisant un modèle de souris exprimant le récepteur de la toxine diphtérique (DTR) au même temps que Zbtb46. L’expression spécifique de ce dernier dans les cDCs induit l’expression de la DRT et l’injection ultérieure de la toxine diphtérique provoque la déplétion des cDCs chez ces souris transgéniques. Nos travaux ont montré que la déplétion des cDCs diminue le recrutement des leucocytes et l'expression de la cytokine inflammatoire l'IL-1β dans le coeur des souris ayant subi l’infarctus du myocarde. Cela réduit considérablement l’ampleur de l'infarctus et améliore la fonction cardiaque, suggérant que les cDCs jouent un rôle important dans l'infiltration de cellules immunitaires après infarctus du myocarde. Dans une autre étude, nous avons mis au point, pour la première fois, une méthode basée sur l’utilisation de sonde lipidique pour analyser les cellules spumeuses de l'aorte par cytométrie en flux. Cette méthode permet de cibler et isoler les macrophages spumeux et non-spumeux afin d’analyser leur profile transcriptomique. En plus de caractériser ces cellules, cette technique permet d’évaluer la taille des plaques d’athérosclérose. Le séquençage des ARN (ARN-seq) a montré que les macrophages spumeux chargés de lipides dans les lésions athérosclérotiques expriment clairement différents transcrits par rapport aux macrophages non-spumeux. De manière surprenante, nous avons constaté que les macrophages nonspumeux présentaient une signature pro-inflammatoire reflétée par une régulation à la hausse de l’Il1β, le Tnf et Nlrp3. Par contre, les macrophages spumeux présentait un profile non inflammatoire caractérisé une augmentation de l’expression des gènes liés au transport et à l'absorption de lipides (cholestérol et acides gras). Contrairement à ce qui est connue jusqu’à maintenant sur le rôle pathogénique des macrophages spumeux, nos résultats montrent que ces cellules jouent un rôle plutôt protecteur dans l’athérosclérose. Collectivement, nous avons spécifiquement identifié la fonction des cDC et des macrophages dans la pathogenèse des maladies cardiovasculaires. Comprendre le rôle précis de ces cellules aidera à développer une stratégie immunothérapeutique appropriée pour atténuer les maladies cardiovasculaires

μ-Oxido-bis­[bis­(penta­fluoro­phenolato)(η5-penta­methyl­cyclo­penta­dien­yl)titanium(IV)]

The dinuclear title complex, [Ti2(C10H15)2(C6F5O)4O], features two TiIV atoms bridged by an O atom, which lies on an inversion centre. The TiIV atom is bonded to a η5-penta­methyl­cyclo­penta­dienyl ring, two penta­fluoro­phenolate anions and to the bridging O atom. The environment around the TiIV atom can be considered as a distorted tetra­hedron. The cyclo­penta­dienyl ring is disordered over two sets of sites [site occupancy = 0.824 (8) for the major component]

Type I interferon is critical for the homeostasis and functional maturation of type 3 γδ T cells

Iridium­(III) cyclometalates (<b>1c</b> and <b>2c</b>) in which the two carborane units on the 4- or 5-positions of 2-phenylpyridine (ppy) ligands were tethered by an alkylene linker were prepared to investigate the effect of free rotation of <i>o</i>-carborane on phosphorescence efficiency. In comparison with the unlinked complex, tethering the <i>o</i>-carboranes to the 5-positions of ppy ligands (<b>2c</b>) enhanced phosphorescence efficiency by over 30-fold in polar medium (Φ_PL = 0.37 vs 0.011 in THF), while restricting the rotation of <i>o</i>-carborane at the 4-positions (<b>1c</b>) negatively affected the phosphorescence efficiency. The different effects of restricted rotation of <i>o</i>-carborane on phosphorescence efficiency were likely a result of the different variations of the carboranyl C–C bond distances in the excited state

DSTEA: Improving Dialogue State Tracking via Entity Adaptive Pre-training

Dialogue State Tracking (DST) is critical for comprehensively interpreting user and system utterances, thereby forming the cornerstone of efficient dialogue systems. Despite past research efforts focused on enhancing DST performance through alterations to the model structure or integrating additional features like graph relations, they often require additional pre-training with external dialogue corpora. In this study, we propose DSTEA, improving Dialogue State Tracking via Entity Adaptive pre-training, which can enhance the encoder through by intensively training key entities in dialogue utterances. DSTEA identifies these pivotal entities from input dialogues utilizing four different methods: ontology information, named-entity recognition, the spaCy, and the flair library. Subsequently, it employs selective knowledge masking to train the model effectively. Remarkably, DSTEA only requires pre-training without the direct infusion of extra knowledge into the DST model. This approach resulted in substantial performance improvements of four robust DST models on MultiWOZ 2.0, 2.1, and 2.2, with joint goal accuracy witnessing an increase of up to 2.69% (from 52.41% to 55.10%). Further validation of DSTEA's efficacy was provided through comparative experiments considering various entity types and different entity adaptive pre-training configurations such as masking strategy and masking rate

Dangling and hydrolyzed ligand arms in [Mn3] and [Mn6] coordination assemblies: synthesis, characterization, and functional activity

Two flexible, branched, and sterically constrained di- and tripodal side arms around a phenol backbone were utilized in ligands H3L1 and H5L2 to isolate {Mn6} and {Mn3} coordination aggregates. 2,6-Bis{(1-hydroxy-2-methylpropan-2-ylimino)methyl}-4-methylphenol (H3L1) gave trinuclear complex [Mn3(μ-H2L1)2(μ1,3-O2CCH3)4(CH3OH)2](ClO4)2·4CH3OH (1), whereas 2,6-bis[{1-hydroxy-2-(hydroxymethyl)butan-2-ylimino}methyl]-4-methylphenol (H5L2) provided hexanuclear complex [Mn6(μ4-H2L2)2(μ-HL3)2(μ3-OH)2(μ1,3-O2CC2H5)4](ClO4)2·2H2O (2). Binding of acetates and coordination of {H2L1}− provided a linear MnIIIMnIIMnIII arrangement in 1. A MnIII6 fused diadamantane-type assembly was obtained in 2 from propionate bridges, coordination of {H2L2}3–, and in situ generated {HL3}2–. The magnetic characterization of 1 and 2 revealed the properties dominated by intramolecular anti-ferromagnetic exchange interactions, and this was confirmed using density functional theory calculations. Complex 1 exhibited field-induced slow magnetic relaxation at 2 K due to the axial anisotropy of MnIII centers. Both the complexes show effective solvent-dependent catechol oxidation toward 3,5-di-tert-butylcatechol in air. The catechol oxidation abilities are comparable from two complexes of different nuclearity and structure

Bis(μ-trimethyl­silanolato-κ2 O:O)bis­{[2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentyl­phenolato-κ2 N,O]zinc}

The binuclear title complex, [Zn2(C22H28N3O)2(C3H9OSi)2], has a crystallographic imposed centre of symmetry. The ZnII atom is coordinated by three O and one N atom from one 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentyl­phenolate ligand and two bridging trimethyl­silanolate anions in a distorted tetra­hedral geometry. The dihedral angle between the benzotriazole ring system and the benzene ring is 19.83 (5)°. The tert-pentyl groups are disordered over two orientations with refined site-occupancy ratios of 0.858 (4):0.142 (4) and 0.665 (6):0.335 (6)

An Instantaneous Impact Point Guidance for Rocket with Aerodynamics Control

This paper aims to propose a new guidance algorithm for a rocket with aerodynamics control for launch operations, based on the concept of the instantaneous impact point (IIP). In this study, the rocket with aerodynamics control is considered with the purpose of reducing dispersion of the impact point after separation of the rocket for safety reasons. Since a very limited aerodynamic maneuverability is typically allowed for the rocket due to the structural limit, a guidance algorithm producing a huge acceleration demand is not desirable. Based on this aspect, the proposed guidance algorithm is derived directly from the underlying principle of the guidance process: forming the collision geometry towards a target point. To be more specific, the collision-ballistic-trajectory where the instantaneous impact point becomes the target point, and the corresponding heading error are first determined using a rapid ballistic trajectory prediction technique. Here, the trajectory prediction method is based on the partial closed-form solutions of the ballistic trajectory equations considering aerodynamic drag and gravity. And then, the proposed guidance algorithm works to nullify the heading error in a finite time, governed by the optimal error dynamics. The key feature of the proposed guidance algorithm lies in its simple implementation and exact collision geometry nature. Hence, the proposed method allows achieving the collision course with minimal guidance command, and it is a desirable property for the guidance algorithm of the rocket with the aerodynamics control. Finally, numerical simulations are conducted to demonstrate the effectiveness of the proposed guidance algorithm

Crystal structure of methyl 2-[5-(2-hydroxyphenyl)-2H-tetrazol-2-yl]acetate

The title compound, C10H10N4O3, was synthesized by the esterification of hydroxyphenyl tetrazole. There is an intramolecular O—H...N hydrogen bond present involving the hydroxy group and the tetrazole ring. The tetrazole ring is inclined to the phenol ring by 2.85 (13)°, while the methyl acetate group is almost normal to the tetrazole ring, making a dihedral angle of 82.61 (14)°. In the crystal, molecules are linked by pairs of C—H...O hydrogen bonds, forming inversion dimers. Within the dimers, the phenol rings are linked by offset π–π interactions [intercentroid distance = 3.759 (2) Å]. There are no further significant intermolecular interactions present in the crystal. The hydroxy group is disordered about positions 2 and 6 on the benzene ring, with a refined occupancy ratio of 0.531 (5):0.469 (5)