Origins of clustered frequency combs in Kerr microresonators.

Recent experiments have demonstrated the generation of widely spaced parametric sidebands that can evolve into "clustered" optical frequency combs in Kerr microresonators. Here we describe the physics that underpins the formation of such clustered comb states. In particular, we show that the phase matching required for the initial sideband generation is such that (at least) one of the sidebands experiences anomalous dispersion, enabling the sideband to drive frequency comb formation via degenerate and non-degenerate four-wave mixing. We validate our proposal through a combination of experimental observations made in a magnesium-fluoride microresonator and corresponding numerical simulations. We also investigate the coherence properties of the resulting clustered frequency combs. Our findings provide valuable insights on the generation and dynamics of widely spaced parametric sidebands and clustered frequency combs in Kerr microresonators.

Widely tunable optical parametric oscillation in a Kerr microresonator.

We report on the first experimental demonstration of widely tunable parametric sideband generation in a Kerr microresonator. Specifically, by pumping a silica microsphere in the normal dispersion regime, we achieve the generation of phase-matched four-wave mixing sidebands at large frequency detunings from the pump. Thanks to the role of higher-order dispersion in enabling phase matching, small variations of the pump wavelength translate into very large and controllable changes in the wavelengths of the generated sidebands: we experimentally demonstrate over 720 nm of tunability using a low-power continuous-wave pump laser in the C-band. We also derive simple theoretical predictions for the phase-matched sideband frequencies and discuss the predictions in light of the discrete cavity resonance frequencies. Our experimentally measured sideband wavelengths are in very good agreement with theoretical predictions obtained from our simple phase-matching analysis.

Experimental observation of coherent cavity soliton frequency combs in silica microspheres.

We report on the experimental observation of coherent cavity soliton frequency combs in silica microspheres. Specifically, we demonstrate that careful alignment of the microsphere relative to the coupling fiber taper allows for the suppression of higher-order spatial modes, reducing mode interactions and enabling soliton formation. Our measurements show that the temporal cavity solitons have sub-100-fs durations, exhibit considerable Raman self-frequency shift, and generally come in groups of three or four, occasionally with equidistant spacing in the time domain. RF amplitude noise measurements and spectral interferometry confirm the high coherence of the observed soliton frequency combs, and numerical simulations show good agreement with experiments.

Nonlinear optics of fibre event horizons.

The nonlinear interaction of light in an optical fibre can mimic the physics at an event horizon. This analogue arises when a weak probe wave is unable to pass through an intense soliton, despite propagating at a different velocity. To date, these dynamics have been described in the time domain in terms of a soliton-induced refractive index barrier that modifies the velocity of the probe. Here we complete the physical description of fibre-optic event horizons by presenting a full frequency-domain description in terms of cascaded four-wave mixing between discrete single-frequency fields, and experimentally demonstrate signature frequency shifts using continuous wave lasers. Our description is confirmed by the remarkable agreement with experiments performed in the continuum limit, reached using ultrafast lasers. We anticipate that clarifying the description of fibre event horizons will significantly impact on the description of horizon dynamics and soliton interactions in photonics and other systems.

The factor VII activating protease G511E (Marburg) variant and cardiovascular risk.

A previous study had shown a strong relationship between a variant in factor VII activating protease (FSAP G511E) and advanced carotid atheroma. In-vitro, the variant has reduced fibrinolytic but normal pro-coagulant activity, which may constitute a prothrombotic state. The current study has addressed risk for coronary heart disease in a prospective study of cardiovascular disorders (Northwick Park Heart Study II). An interactive effect upon risk was found between the 511E allele and elevated levels of cholesterol and triglyceride. Fibrinogen could substitute for triglyceride levels in this risk-interaction analysis. The findings support the proposal that the FSAP 511E allele exacerbates atherosclerosis or its clinical sequelae.

R643G polymorphism in PECAM-1 influences transendothelial migration of monocytes and is associated with progression of CHD and CHD events.

The 643R allele of R643G polymorphism (also known as R670G in the premature protein) in PECAM-1 has been associated with risk of myocardial infarction (MI), while the 643G allele has been associated with risk of coronary artery stenosis (CAS). The aim of this study was to investigate this apparently conflicting association. The association of R643G with risk of MI was determined in the second Northwick Park Heart study (2037 men with 138 CHD events; mean age: 56 years). Smokers homozygous for the 643R allele showed increased risk of MI with a hazard ratio of 2.47 (95% CI: 1.23-4.97; P=0.01) compared to smokers homozygous for the 643G allele. Progression of disease was determined in the Lopid Coronary Angiography Trial (279 men; mean age: 58.9 years). The 643G homozygotes showed greater focal (-0.08 +/- 0.02 mm) and diffuse (-0.01 +/- 0.01 mm) progression of CAS compared to 643R homozygotes (-0.02 +/- 0.02 mm and 0.001 +/- 0.01 mm, respectively; P=0.04). While there was no genotype effect on platelet aggregation, PECAM-1 tyrosine phosphorylation in HUVECs of GG genotype was 2.4-fold greater (P <0.01) than cells of RR genotype, and the level of transendothelial migration of monocytes of GG genotype was greater than that of monocytes of RR genotype following stimulation with either IL-1beta (12% higher, P <0.01) or TNF-alpha (10% higher, P=0.05). These data confirm the association of the R643G polymorphism with MI and CAS and suggest that greater influx of monocytes in individuals homozygous for the 643G may explain the association with CAS.

The 4830C>A polymorphism within intron 5 affects the pattern of alternative splicing occurring within exon 6 of the thrombopoietin gene.

OBJECTIVE: A common variant in intron 5 of the thrombopoietin (TPO) gene (4830C>A) has been associated with risk of myocardial infarction (MI). To explore the molecular mechanism of this association, the ability of the intron to act as a transcription enhancer and to influence mRNA splicing was tested. METHOD AND RESULTS: In HepG2 cells the presence of intron 5 upstream of the TPO promoter decreased promoter activity to between 60% and 30%. This effect was orientation dependent; in the reverse orientation, intron 5 caused a twofold greater decrease in promoter activity compared to the forward orientation. However, the effects were similar with either the C or the 4830A allele. An in vitro exon trapping system was used to study the effect of the polymorphism on splicing events in exon 6. The full-length (TPO-1) and three previously reported splice variants (TPO-2, TPO-3, and TPO-5) were identified. The 4830A allele resulted in a small but statistically significant increase in production of the TPO-3 splice variant relative to the full-length transcript (10.6%+/-0.6%) compared to the 4830C allele (8.3%+/-0.6%) (p=0.02). Generation of TPO-5 was also slightly increased, but this did not reach significance. CONCLUSION: The identification of a potential "silencer" sequence in intron 5 of the TPO gene demonstrates the complexity of control of expression of the gene. Although the precise role of the different splice variants is not known, the finding that the 4830C>A sequence change alters their relative amounts, suggests a possible molecular mechanism whereby TPO genotype may influence the risk of MI.

A novel functional polymorphism in the PECAM-1 gene (53G>A) is associated with progression of atherosclerosis in the LOCAT and REGRESS studies.

A 53G>A polymorphism identified in the 5' untranslated region (5'UTR) of the platelet endothelial cell adhesion molecule-1 (PECAM-1) gene alters a putative shear stress responsive element (SSRE). PECAM-1 was shown to be responsive to shear stress and transient transfection of human umbilical vein endothelial cell (HUVECs) with two luciferase reporter constructs driven by the PECAM-1 promoter and 5'UTR showed a response of the 53G allele, not the 53A allele, to shear stress. Association between the 53G>A, and the previously published L125V polymorphism, and coronary atherosclerosis was examined in two angiographic studies. The frequencies of the rare alleles of the 53G>A and L125V polymorphisms were 0.01 and 0.49, respectively, in the Lopid Coronary Angiography Trial (LOCAT) study and 0.02 and 0.49, respectively, in the Regression Growth Evaluation Statin Study (REGRESS) study. Compared with 53G homozygotes, carriers of the 53A allele showed less focal progression of disease in the LOCAT study and a similar trend in the diffuse progression of disease in the REGRESS study, whereas no association between L125V and coronary atherosclerosis was observed in either study. These data demonstrate that the PECAM-1 gene is responsive to shear stress in vitro and that decreased PECAM-1 gene expression in 53A carriers may influence reduced progression of vessel stenosis in patients with coronary artery disease.