A switchable single-mode fibre coupler

Imperial Users onl

A monoclonal antibody recognizing very late activation antigen-4 inhibits eosinophil accumulation in vivo.

Using an in vivo test system, the role of the β1 integrin very late activation antigen-4 (VLA-4) in eosinophil accumulation in allergic and nonallergic inflammatory reactions was investigated. Eosinophil infiltration and edema formation were measured as the local accumulation of intravenously injected 111In-labeled eosinophils and 125I-human serum albumin. The inflammatory reactions investigated were a passive cutaneous anaphylaxis (PCA) reaction and responses elicited by intradermal soluble inflammatory mediators (platelet-activating factor, leukotriene B4, C5a des Arg), arachidonic acid, and zymosan particles. The in vitro pretreatment of 111In-eosinophils with the anti-VLA-4 monoclonal antibody (mAb) HP1/2, which crossreacts with guinea pig eosinophils, suppressed eosinophil accumulation in all the inflammatory reactions investigated. Eosinophil accumulation was inhibited to the same extent when mAb HP1/2 was administered intravenously. It is interesting that HP1/2 had no effect on stimulated edema formation. These results suggest a role for VLA-4 in eosinophil accumulation in vivo and indicate a dissociation between the inflammatory events of eosinophil accumulation and edema formation

Cavity enhanced atom interferometry

Atom Interferometry is a technique offering unparalleled sensitivity to a wide range of applications. Their sensitivity is currently limited by the available laser power and flatness of the optical wavefronts. We explore two solutions to these problems, high power high bandwidth operation and optical cavity enhancement. We have demonstrated a laboratory based, high bandwidth atom interferometer instrument and have performed an incipient gravity measurement with a fractional statistical uncertainty of $\sigma_g / g = 4.4\times 10^{-6}$ where g is the acceleration due to gravity. We have designed, constructed, and optimised a powerful Raman laser (12 W at 780nm) which will allow large momentum transfer beamsplitters to be implemented at high bandwidth for the first time. Cavity enhancement offers the ability to dramatically increase the laser power available for experiments, as well as filtering the spatial modes, thus improving the wavefront flatness. Difficulties in simultaneously realising large modes and spatial mode filtering, and accommodating Doppler shifts have limited the use of cavity enhancement thus far. We have designed and demonstrated a Doppler compensated optical cavity for atom interferometer enhancement. This cavity circumvents the Doppler shift limit whilst enabling mode filtering, power enhancement, and a large beam diameter simultaneously. Our novel design combines a magnified linear cavity with an intracavity Pockels cell. The Pockels cell introduces a voltage tunable birefringence, which is used to match the cavity resonances to the laser frequencies as they chirp to track Doppler shifts in the interferometer. The magnified linear geometry produces a large, 5.04mm 1/e$^2$, diameter beam waist in a 0.69m long cavity and allows the Gouy phase to be tuned, suppressing higher order spatial modes and avoiding regions of instability. These improvements address central limitations of current cavity enhanced systems. We propose refinements to this design, further improving performance, and allowing cavity enhancement of high bandwidth systems. The remaining limitation on cavity systems is the lifetime limit. Long, high finesse cavities have long photon lifetimes, causing severe distortion of short pulses. In proposed large scale atom interferometer based gravitational wave detectors, this appears to preclude the use of cavity enhancement. We propose a scheme for optical cavity enhanced atom interferometry, using circulating, spatially resolved pulses, and intracavity frequency modulation to overcome the cavity lifetime limit. We present parameters for the experimental realisation of the target $10^4 \hbar k$ momentum separation in a 1km interferometer using the 698nm clock transition in $^{87}$Sr, and describe potential performance enhancements in 10m scale devices operating on the 689nm intercombination line in $^{87}$Sr. Our scheme satisfies the most challenging requirements of these sensors and paves the way for the next generation of high sensitivity, large momentum transfer atom interferometers

The peritoneal tumour microenvironment of high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSC) disseminates early and extensively throughout the peritoneal space, causing multiple lesions that are a major clinical problem. The aim of this study was to investigate the cellular composition of peritoneal tumour deposits in patient biopsies and their evolution in mouse models using immunohistochemistry, intravital microscopy, confocal microscopy, and 3D modelling. Tumour deposits from the omentum of HGSC patients contained a prominent leukocyte infiltrate of CD3(+) T cells and CD68(+) macrophages, with occasional neutrophils. Alpha-smooth muscle actin(+) (α-SMA(+) ) pericytes and/or fibroblasts surrounded these well-vascularized tumour deposits. Using the murine bowel mesentery as an accessible mouse peritoneal tissue that could be easily imaged, and two different transplantable models, we found multiple microscopic tumour deposits after i.p. injection of malignant cells. Attachment to the peritoneal surface was rapid (6-48 h) with an extensive CD45(+) leukocyte infiltrate visible by 48 h. This infiltrate persisted until end point and in the syngeneic murine ID8 model, it primarily consisted of CD3(+) T lymphocytes and CD68(+) macrophages with α-SMA(+) cells also involved from the earliest stages. A majority of tumour deposits developed above existing mesenteric blood vessels, but in avascular spaces new blood vessels tracked towards the tumour deposits by 2-3 weeks in the IGROV-1 xenografts and 6 weeks in the ID8 syngeneic model; a vigorous convoluted blood supply was established by end point. Inhibition of tumour cell cytokine production by stable expression of shRNA to CXCR4 in IGROV-1 cells did not influence the attachment of cells to the mesentery but delayed neovascularization and reduced tumour deposit size. We conclude that the multiple peritoneal tumour deposits found in HGSC patients can be modelled in the mouse. The techniques described here may be useful for assessing treatments that target the disseminated stage of this disease

The spatiotemporal localization of JAM-C following sciatic nerve crush in adult rats

Peer reviewedPublisher PD

Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils.

Published versio

A targeting microbubble for ultrasound molecular imaging

Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld.To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging.Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab')2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification.Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)-(iii) desired for clinical applications

Design of an Activity-Based Probe for Human Neutrophil Elastase: Implementation of the Lossen Rearrangement To Induce Förster Resonance Energy Transfers.

Human neutrophil elastase is an important regulator of the immune response and plays a role in host defense mechanisms and further physiological processes. The uncontrolled activity of this serine protease may cause severe tissue alterations and impair inflammatory states. The design of an activity-based probe for human neutrophil elastase reported herein relies on a sulfonyloxyphthalimide moiety as a new type of warhead that is linker-connected to a coumarin fluorophore. The inhibitory potency of the activity-based probe was assessed against several serine and cysteine proteases, and the selectivity for human neutrophil elastase (Ki = 6.85 nM) was determined. The adequate fluorescent tag of the probe allowed for the in-gel fluorescence detection of human neutrophil elastase in the low nanomolar range. The coumarin moiety and the anthranilic acid function of the probe, produced in the course of a Lossen rearrangement, were part of two different Förster resonance energy transfers