1.55 µm wavelength band photonic crystal surface emitting laser with n-side photonic crystal and operation at up to 85 °C.

We describe the structure, fabrication, and measured performance of a 1543 nm wavelength photonic crystal surface emitting laser. An asymmetric double lattice design was used to achieve single mode lasing with side mode suppression ratios >40 dB. The photonic crystal was formed using encapsulated air holes in an n-doped InGaAsP layer with an InGaAlAs active layer then grown above it. In this way a laser with a low series resistance of 0.32 Ω capable of pulsed output powers of 171 mW at 25 °C and 40 mW at 85 °C was demonstrated.

Causal Role for Neutrophil Elastase in Thoracic Aortic Dissection in Mice.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved. METHODS: ß-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation. Multiple functional assays and biochemical analyses were conducted to unravel the underlying cellular and molecular mechanisms of NE in TAD. RESULTS: NE aortic gene expression and plasma activity was significantly increased during ß-aminopropionitrile monofumarate-induced TAD and in patients with acute TAD. NE deficiency prevents ß-aminopropionitrile monofumarate-induced TAD onset/development, and GW311616A administration ameliorated TAD formation/progression. Decreased levels of neutrophil extracellular traps, inflammatory cells, and MMP (matrix metalloproteinase)-2/9 were observed in NE-deficient mice. TBL1x (F-box-like/WD repeat-containing protein TBL1x) has been identified as a novel substrate and functional downstream target of NE in TAD. Loss-of-function studies revealed that NE mediated inflammatory cell transendothelial migration by modulating TBL1x-LTA4H (leukotriene A4 hydrolase) signaling and that NE regulated smooth muscle cell phenotype modulation under TAD pathological condition by regulating TBL1x-MECP2 (methyl CpG-binding protein 2) signal axis. Further mechanistic studies showed that TBL1x inhibition decreased the binding of TBL1x and HDAC3 (histone deacetylase 3) to MECP2 and LTA4H gene promoters, respectively. Finally, adeno-associated virus-2-mediated Tbl1x gene knockdown in aortic smooth muscle cells confirmed a regulatory role for TBL1x in NE-mediated TAD formation. CONCLUSIONS: We unravel a critical role of NE and its target TBL1x in regulating inflammatory cell migration and smooth muscle cell phenotype modulation in the context of TAD. Our findings suggest that the NE-TBL1x signal axis represents a valuable therapeutic for treating high-risk TAD patients.

Matrix Metalloproteinase in Abdominal Aortic Aneurysm and Aortic Dissection.

Abdominal Aortic Aneurysm (AAA) affects 4-5% of men over 65, and Aortic Dissection (AD) is a life-threatening aortic pathology associated with high morbidity and mortality. Initiators of AAA and AD include smoking and arterial hypertension, whilst key pathophysiological features of AAA and AD include chronic inflammation, hypoxia, and large modifications to the extra cellular matrix (ECM). As it stands, only surgical methods are available for preventing aortic rupture in patients, which often presents difficulties for recovery. No pharmacological treatment is available, as such researchers are attempting to understand the cellular and molecular pathophysiology of AAA and AD. Upregulation of matrix metalloproteinase (MMPs), particularly MMP-2 and MMP-9, has been identified as a key event occurring during aneurysmal growth. As such, several animal models of AAA and AD have been used to investigate the therapeutic potential of suppressing MMP-2 and MMP-9 activity as well as modulating the activity of other MMPs, and TIMPs involved in the pathology. Whilst several studies have offered promising results, targeted delivery of MMP inhibition still needs to be developed in order to avoid surgery in high risk patients.

Foam cell formation: A new target for fighting atherosclerosis and cardiovascular disease.

During atherosclerosis, the gradual accumulation of lipids into the subendothelial space of damaged arteries results in several lipid modification processes followed by macrophage uptake in the arterial wall. The way in which these modified lipoproteins are dealt with determines the likelihood of cholesterol accumulation within the monocyte-derived macrophage and thus its transformation into the foam cell that makes up the characteristic fatty streak observed in the early stages of atherosclerosis. The unique expression of chemokine receptors and cellular adhesion molecules expressed on the cell surface of monocytes points to a particular extravasation route that they can take to gain entry into atherosclerotic site, in order to undergo differentiation into the phagocytic macrophage. Indeed several GWAS and animal studies have identified key genes and proteins required for monocyte recruitment as well cholesterol handling involving lipid uptake, cholesterol esterification and cholesterol efflux. A re-examination of the previously accepted paradigm of macrophage foam cell origin has been called into question by recent studies demonstrating shared expression of scavenger receptors, cholesterol transporters and pro-inflammatory cytokine release by alternative cell types present in the neointima, namely; endothelial cells, vascular smooth muscle cells and stem/progenitor cells. Thus, therapeutic targets aimed at a more heterogeneous foam cell population with shared functions, such as enhanced protease activity, and signalling pathways, mediated by non-coding RNA molecules, may provide greater therapeutic outcome in patients. Finally, studies targeting each aspect of foam cell formation and death using both genetic knock down and pharmacological inhibition have provided researchers with a clearer understanding of the cellular processes at play, as well as helped researchers to identify key molecular targets, which may hold significant therapeutic potential in the future.

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis.

BACKGROUND: To investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved. METHODS AND RESULTS: NE genetic-deficient mice (Apolipoprotein E-/-/NE-/- mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high-fat diet (HFD)-fed wild-type (WT) (Apolipoprotein E-/-) mice but, as expected, not in NE-deficient mice. Selective NE knockout markedly reduced HFD-induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE-deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE-/- bone marrow cells significantly reduced HFD-induced atherosclerosis, while bone marrow reconstitution of NE-/- mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE-deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP-binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux. CONCLUSIONS: We outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease.

Power Budget Analysis for Waveguide-Enhanced Raman Spectroscopy.

Waveguide-enhanced Raman spectroscopy (WERS) is emerging as an attractive alternative to plasmonic surface-enhanced Raman spectroscopy approaches as it can provide more reproducible quantitative spectra on a robust chip without the need for nanostructured plasmonic materials. Realizing portable WERS systems with high sensitivity using low-cost laser diodes and compact spectrometers requires a detailed analysis of the power budget from laser to spectrometer chip. In this paper, we describe theoretical optimization of planar waveguides for maximum Raman excitation efficiency, demonstrate WERS for toluene on a silicon process compatible high index contrast tantalum pentoxide waveguide, measure the absolute conversion efficiency from pump power to received power in an individual Raman line, and compare this with a power budget analysis of the complete system including collection with an optical fiber and interfacing to a compact spectrometer. Optimized 110 nm thick Ta2O5 waveguides on silica substrates excited at a wavelength of 637 nm are shown experimentally to yield overall system power conversion efficiency of ∼0.5 × 10(-12) from the pump power in the waveguide to the collected Raman power in the 1002 cm(-1) Raman line of toluene, in comparison with a calculated efficiency of 3.9 × 10(-12) Collection efficiency is dictated by the numerical and physical apertures of the spectral detection system but may be improved by further engineering the spatial and angular Raman scattering distributions.

A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development.

OBJECTIVES: The toll-like receptors (TLRs), including TLR4, have been shown to play a crucial role in vascular inflammatory diseases, such as atherosclerosis and aneurysm. The main goal of this study was to determine the potential of IAXO-102 (Innaxon, Tewkesbury), a novel small molecule TLR4 antagonist, to modulate non-hematopoietic TLR4 proinflammatory signalling and inhibit experimental abdominal aortic aneurysm (AAA) development. METHODS: Human umbilical vein endothelial cells (HUVEC) and Angiotensin II-induced experimental AAA development were our in vitro and in vivo models respectively. Western blotting, antibody array and ELISA approaches were used to explore the effect of IAXO-102 on TLR4 functional activity on two levels: modulation of TLR4-induced mitogen activated protein kinases (MAPK) and p65 NF-kB phosphorylation and expression of TLR4 dependent proinflammatory proteins. RESULTS: Following activation of TLR4, in vitro/in vivo data revealed that IAXO-102 inhibited MAPK and p65 NF-kB phosphorylation associated with down regulation of the expression of TLR4 and TLR4 dependent proinflammatory proteins. Furthermore, IAXO-102 decreased Angiotensin II-induced aortic expansion, rupture and incidence of AAA. CONCLUSIONS: These results demonstrate the ability of IAXO-102 to negatively regulate TLR4 signalling and to inhibit experimental AAA development, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of AAA.

Pioglitazone Identifies a New Target for Aneurysm Treatment: Role of Egr1 in an Experimental Murine Model of Aortic Aneurysm.

Peroxisome proliferator-activated receptor x03B3; agonists have been shown to inhibit angiotensin II (AngII)-induced experimental abdominal aortic aneurysms. Macrophage infiltration to the vascular wall is an early event in this pathology, and therefore we explored the effects of the peroxisome proliferator-activated receptor x03B3; agonist pioglitazone on AngII-treated macrophages. Using microarray-based expression profiling of phorbol ester-stimulated THP-1 cells, we found that a number of aneurysm-related gene changes effected by AngII were modulated following the addition of pioglitazone. Among those genes, polycystic kidney disease 1 (PKD1) was significantly up-regulated (multiple testing corrected p < 0.05). The analysis of the PKD1 proximal promoter revealed a putative early growth response 1 (EGR1) binding site, which was confirmed by chromatin immunoprecipitation (ChIP) and quantitative PCR. Further analysis of publicly available ChIP-sequencing data revealed that this putative binding site overlapped with a conserved EGR1 binding peak present in 5 other cell lines. Quantitative real-time PCR showed that EGR1 suppressed PKD1, while AngII significantly up-regulated PKD1, an effect counteracted by pioglitazone. Conversely, in EGR1 short hairpin RNA lentivirally transduced THP-1 cells, reduced EGR1 led to a significant up-regulation of PKD1, especially after treatment with pioglitazone. In vivo, deficiency of Egr1 in the haematopoietic compartment of mice completely abolished the incidence of CaCl2-induced aneurysm formation.

Area Selective Growth of Titanium Diselenide Thin Films into Micropatterned Substrates by Low-Pressure Chemical Vapor Deposition.

The neutral, distorted octahedral complex [TiCl4(Se n Bu2)2] (1), prepared from the reaction of TiCl4 with the neutral Se n Bu2 in a 1:2 ratio and characterized by IR and multinuclear (1H, 13C{1H}, 77Se{1H}) NMR spectroscopy and microanalysis, serves as an efficient single-source precursor for low-pressure chemical vapor deposition (LPCVD) of titanium diselenide, TiSe2, films onto SiO2 and TiN substrates. X-ray diffraction patterns on the deposited films are consistent with single-phase, hexagonal 1T-TiSe2 (P3̅m1), with evidence of some preferred orientation of the crystallites in thicker films. The composition and structural morphology was confirmed by scanning electron microscopy (SEM), energy dispersive X-ray, and Raman spectroscopy. SEM imaging shows hexagonal plate crystallites growing perpendicular to the substrate, but these tend to align parallel to the surface when the quantity of reagent is reduced. The resistivity of the crystalline TiSe2 films is 3.36 ± 0.05 × 10-3 Ω·cm with a carrier density of 1 × 1022 cm-3. Very highly selective film growth from the reagent was observed onto photolithographically patterned substrates, with film growth strongly preferred onto the conducting TiN surfaces of SiO2/TiN patterned substrates. TiSe2 is selectively deposited within the smallest 2 µm diameter TiN holes of the patterned TiN/SiO2 substrates. The variation in crystallite size with different diameter holes is determined by microfocus X-ray diffraction and SEM, revealing that the dimensions increase with the hole size, but that the thickness of the crystals stops increasing above ∼20 µm hole size, whereas their lengths/widths continue to increase.

Highly sensitive biosensor based on UV-imprinted layered polymeric-inorganic composite waveguides.

An evanescent field sensor utilizing layered polymeric-inorganic composite waveguide configuration was developed in this work. The composite waveguide structure consists of a UV-imprint patterned polymer inverted rib waveguide with a Ta2O5 thin film sputter-deposited on top of the low refractive index polymer layers. The results suggest that the polymer based sensor can achieve a detection limit of 3 × 10(-7) RIU for refractive index sensing and corresponding limit of about 100 fg/mm2 for molecular adsorption detection. Besides enhancing the sensitivity significantly, the inorganic coating on the polymer layer was found to block water absorption effectively into the waveguide resulting in a stabilized sensor operation. The ability to use the developed sensor in specific molecular detection was confirmed by investigating antibody - antigen binding reactions. The results of this work demonstrate that high performance sensing capability can be obtained with the developed composite waveguide sensor.