Elastin-derived peptides potentiate atherosclerosis through the immune Neu1-PI3Kγ pathway

Aims Elastin is degraded during vascular ageing and its products, elastin-derived peptides (EP), are present in the human blood circulation. EP binds to the elastin receptor complex (ERC) at the cell surface, composed of elastin-binding protein (EBP), a cathepsin A and a neuraminidase 1. Some in vitro functions have clearly been attributed to this binding, but the in vivo implications for arterial diseases have never been clearly investigated. Methods and results Here, we demonstrate that chronic doses of EP injected into mouse models of atherosclerosis increase atherosclerotic plaque size formation. Similar effects were observed following an injection of a VGVAPG peptide, suggesting that the ERC mediates these effects. The absence of phosphoinositide 3-kinase γ (PI3Kγ) in bone marrow-derived cells prevented EP-induced atherosclerosis development, demonstrating that PI3Kγ drive EP-induced arterial lesions. Accordingly, in vitro studies showed that PI3Kγ was required for EP-induced monocyte migration and ROS production and that this effect was dependent upon neuraminidase activity. Finally, we showed that degradation of elastic lamellae in LDLR−/− mice fed an atherogenic diet correlated with atherosclerotic plaque formation. At the same time, the absence of the cathepsin A-neuraminidase 1 complex in cells of the haematopoietic lineage abolished atheroma plaque size progression and decreased leucocytes infiltration, clearly demonstrating the role of this complex in atherogenesis and suggesting the involvement of endogenous EP. Conclusion Altogether, this work identifies EP as an enhancer of atherogenesis and defines the Neuraminidase 1/PI3Kγ signalling pathway as a key mediator of this function in vitro and in viv

Role of reactive oxygen species in atherosclerosis: Lessons from murine genetic models.

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Responses to Hypoxia and Endoplasmic Reticulum Stress Discriminate the Development of Vitreous and Floury Endosperms of Conventional Maize (Zea mays) Inbred Lines

Major nutritional and agronomical issues relating to maize (Zea mays) grains depend on the vitreousness/hardness of its endosperm. To identify the corresponding molecular and cellular mechanisms, most studies have been conducted on opaque/floury mutants, and recently on Quality Protein Maize, are version of an opaque2 mutation by modifier genes. These mutant lines are far from conventional maize crops. Therefore, a dent and a flint inbred line were chosen for analysis of the transcriptome, amino acid, and sugar metabolites of developing central and peripheral endosperm that is, the forth coming floury and vitreous regions of mature seeds, respectively. The results suggested that the formation of endosperm vitreousness is clearly associated with significant differences in the responses of the endosperm to hypoxia and endoplasmic reticulum stress. This occurs through a coordinated regulation of energy metabolism and storage protein (i.e., zein) biosynthesis during the grain-filling period. Indeed, genes involved in the glycolysis and tricarboxylic acid cycle are up-regulated in the periphery, while genes involved in alanine, sorbitol, and fermentative metabolisms are up-regulated in the endosperm center. This spatial metabolic regulation allows the production of ATP needed for the significant zein synthesis that occurs at the endosperm periphery; this finding agrees with the zein-decreasing gradient previously observed from the sub-aleurone layer to the endosperm center. The massive synthesis of proteins transiting through endoplasmic reticulum elicits the unfolded protein responses, as indicated by the splicing of bZip60 transcription factor. This splicing is relatively higher at the center of the endosperm than at its periphery. The biological responses associated with this developmental stress, which control the starch/protein balance, leading ultimately to the formation of the vitreous and floury regions of mature endosperm, are discussed

Nitride-on-Silicon microdisk lasers covering the blue to UV-C spectral range

International audienceUltra-violet semiconductor lasers have numerous applications for optical storage, biochemistry, sterilization or optical interconnects. However the usual design of deep UV-emitting ridge lasers relies on complex buffer layers or expensive substrates for the growth of the nitride heterostructures [1]. Moreover microlaser and nanophotonic devices with integrated sources require an alternative approach compatible with thin waveguides.In this work we demonstrate a series of nitride-on-silicon microdisk lasers covering a broad spectral range, from the blue (=470 nm) to the deep ultra-violet (=275nm), and operating at room temperature. They rely on the controlled growth of thin AlN buffer layers on silicon substrates, followed by the growth of GaN/AlN or InGaN/GaN multiple quantum wells (MQWs) with a high radiative efficiency up to T=300K. We exploit the possibility to under-etch selectively the silicon substrate in order to form nitride membranes for photonic resonators; this has allowed many demonstrations of microdisk and photonic crystal cavities with quality factors larger than 1000, ranging from the mid-IR [2] to the near-UV spectral range [3,4], now expanding to the UV-C [5].Following the demonstration of a UV-C microlaser operating atat 275 nm and at room temperature [5], the figure 1 presents the emission characteristics of a series of nitride-on-silicon microdisks with different active layers grown on a thin AlN buffer layer. Their whispering gallery modes are probed under continuous wave excitation at 266 nm with a 15 µm laser spot (Figure 1.b); the photoluminescence is collected from the edge of the microdisks. The chosen microdisk diameters in panel (b) are 5-6 µm in order to properly exhibit the modes, except for the 3 µm microdisk emitting at 275 nm. In all cases, the sharpest peaks are observed in the low energy tail of the PL spectrum where the absorption of the active layer is limited. The measured Q factors exceed 1000, and reach 4000 in the best resonators. The lasing operation is obtained under pulsed quasi-resonant optical pumping (266nm, 400ps pulses) with a threshold excitation density ranging from 2 to 40 nJ/pulse (Figure 1.a). The dependence of the lasing threshold will be discussed.In the UV-B and UV-C spectral ranges, these demonstrations underline the interest of simple binary GaN/AlN MQWs, grown on a thin AlN buffer on a silicon substrate, in order to obtain efficient active layers providing optical gain up to room temperature. The microdisk lasing in the visible spectral range, based on more mature InGaN/GaN MQWs, proves the versatility of the nitride-on-silicon photonic platform, that can embed a broad range of integrated sources

Demonstration of critical coupling in an active III-nitride microdisk photonic circuit on silicon

International audienceOn-chip microlaser sources in the blue constitute an important building block for complex integrated photonic circuits on silicon. We have developed photonic circuits operating in the blue spectral range based on microdisks and bus waveguides in III-nitride on silicon. We report on the interplay between microdisk-waveguide coupling and its optical properties. We observe critical coupling and phase matching, i.e. the most efficient energy transfer scheme, for very short gap sizes and thin waveguides (g = 45 nm and w = 170 nm) in the spontaneous emission regime. Whispering gallery mode lasing is demonstrated for a wide range of parameters with a strong dependence of the threshold on the loaded quality factor. We show the dependence and high sensitivity of the output signal on the coupling. Lastly, we observe the impact of processing on the tuning of mode resonances due to the very short coupling distances. Such small footprint on-chip integrated microlasers providing maximum energy transfer into a photonic circuit have important potential applications for visible-light communication and lab-on-chip bio-sensors

Q factor limitation at short wavelength (around 300 nm) in III-nitride-on-silicon photonic crystal cavities

International audienceIII-nitride-on-silicon L3 and H2 photonic crystal cavities with resonances down to 315 nm and quality factors up to 1085 at 337 nm have been demonstrated. The reduction of quality factor (Q) with decreasing wavelength is investigated. Besides the QW absorption below 340 nm a noteworthy contribution is attributed to the residual absorption present in thin AlN layers grown on silicon, as measured by spectroscopic ellipsometry. This residual absorption ultimately limits the Q factor to around 250 at 300 nm when no active layer is present

Blue Microlasers Integrated on a Photonic Platform on Silicon

International audienceThe main interest of group-III-nitride nanophotonic circuits is the integration of active structures and laser sources. A photonic platform of group-III-nitride microdisk lasers integrated on silicon and emitting in the blue spectral range is demonstrated. The active microdisks are side-coupled to suspended bus waveguides, and the coupled emission is guided and outcoupled to free space using grating couplers. A small gap size of less than 100 nm between the disk and the waveguide is required in the blue spectral range for optimal evanescent coupling. To avoid reabsorption of the microdisk emission in the waveguide, the quantum wells are etched away from the waveguide. Under continuous-wave excitation, loaded quality factors greater than 2000 are observed for the whispering gallery modes for devices with small gaps and large waveguide bending angles. Under pulsed excitation conditions, lasing is evidenced for 3 μm diameter microdisks integrated in a full photonic circuit. We thus present a first demonstration of a III-nitride microlaser coupled to a nanophotonic circuit

Elastin-derived peptides potentiate atherosclerosis through the immune Neu1-PI3Kγ pathway.

International audienceAIMS: Elastin is degraded during vascular ageing and its products, elastin-derived peptides (EP), are present in the human blood circulation. EP binds to the elastin receptor complex (ERC) at the cell surface, composed of elastin-binding protein (EBP), a cathepsin A and a neuraminidase 1. Some in vitro functions have clearly been attributed to this binding, but the in vivo implications for arterial diseases have never been clearly investigated. METHODS AND RESULTS: Here, we demonstrate that chronic doses of EP injected into mouse models of atherosclerosis increase atherosclerotic plaque size formation. Similar effects were observed following an injection of a VGVAPG peptide, suggesting that the ERC mediates these effects. The absence of phosphoinositide 3-kinase γ (PI3Kγ) in bone marrow-derived cells prevented EP-induced atherosclerosis development, demonstrating that PI3Kγ drive EP-induced arterial lesions. Accordingly, in vitro studies showed that PI3Kγ was required for EP-induced monocyte migration and ROS production and that this effect was dependent upon neuraminidase activity. Finally, we showed that degradation of elastic lamellae in LDLR(-/-) mice fed an atherogenic diet correlated with atherosclerotic plaque formation. At the same time, the absence of the cathepsin A-neuraminidase 1 complex in cells of the haematopoietic lineage abolished atheroma plaque size progression and decreased leucocytes infiltration, clearly demonstrating the role of this complex in atherogenesis and suggesting the involvement of endogenous EP. CONCLUSION: Altogether, this work identifies EP as an enhancer of atherogenesis and defines the Neuraminidase 1/PI3Kγ signalling pathway as a key mediator of this function in vitro and in vivo

Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies.

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function

Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events(1). Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly(2) and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5- phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5) P3 and PtdIns(4,5) P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function