The Role of Immune Correlates and Surrogate Markers in the Development of Vaccines and Immunotherapies for Plague

One of the difficulties in developing countermeasures to biothreat agents is the challenge inherent in demonstrating their efficacy in man. Since the first publication of the Animal Rule by the FDA, there has been increased discussion of potential correlates of protection in animal models and their use to establish surrogate markers of efficacy in man. The latter need to be relatively easy to measure in assays that are at least qualified, if not validated, in order to derive a quantitative assessment of the clinical benefit conferred. The demonstration of safety and clinical benefit is essential to achieve regulatory approval for countermeasures for which clinical efficacy cannot be tested directly, as is the case for example, for biodefence vaccines. Plague is an ancient, serious infectious disease which is still endemic in regions of the modern world and is a potential biothreat agent. This paper discusses potential immune correlates of protection for plague, from which it may be possible to derive surrogate markers of efficacy, in order to predict the clinical efficacy of candidate prophylaxes and therapies

Observed tidal braking in the earth/moon/sun system

The low degree and order terms in the spherical harmonic model of the tidal potential were observed through the perturbations which are induced on near-earth satellite orbital motions. Evaluations of tracking observations from 17 satellites and a GEM-T1 geopotential model were used in the tidal recovery which was made in the presence of over 600 long-wavelength coefficients from 32 major and minor tides. Wahr's earth tidal model was used as a basis for the recovery of the ocean tidal terms. Using this tidal model, the secular change in the moon's mean motion due to tidal dissipation was found to be -25.27 + or - 0.61 arcsec/century squared. The estimation of lunar acceleration agreed with that observed from lunar laser ranging techniques (-24.9 + or - 1.0 arcsec/century squared), with the corresponding tidal braking of earth's rotation being -5.98 + or - 0.22 x 10 to the minus 22 rad/second squared. If the nontidal braking of the earth due to the observed secular change in the earth's second zonal harmonic is considered, satellite techniques yield a total value of the secular change of the earth's rotation rate of -4.69 + or - 0.36 x 10 to the minus 22 rad/second squared

Towards a killer app for the Semantic Web

Killer apps are highly transformative technologies that create new markets and widespread patterns of behaviour. IT generally, and the Web in particular, has benefited from killer apps to create new networks of users and increase its value. The Semantic Web community on the other hand is still awaiting a killer app that proves the superiority of its technologies. There are certain features that distinguish killer apps from other ordinary applications. This paper examines those features in the context of the Semantic Web, in the hope that a better understanding of the characteristics of killer apps might encourage their consideration when developing Semantic Web applications

Optical spectroscopy of single quantum dots at tunable positive, neutral and negative charge states

We report on the observation of photoluminescence from positive, neutral and negative charge states of single semiconductor quantum dots. For this purpose we designed a structure enabling optical injection of a controlled unequal number of negative electrons and positive holes into an isolated InGaAs quantum dot embedded in a GaAs matrix. Thereby, we optically produced the charge states -3, -2, -1, 0, +1 and +2. The injected carriers form confined collective 'artificial atoms and molecules' states in the quantum dot. We resolve spectrally and temporally the photoluminescence from an optically excited quantum dot and use it to identify collective states, which contain charge of one type, coupled to few charges of the other type. These states can be viewed as the artificial analog of charged atoms such as H$^{-}$, H$^{-2}$, H$^{-3}$, and charged molecules such as H$_{2}^{+}$ and H$_{3}^{+2}$. Unlike higher dimensionality systems, where negative or positive charging always results in reduction of the emission energy due to electron-hole pair recombination, in our dots, negative charging reduces the emission energy, relative to the charge-neutral case, while positive charging increases it. Pseudopotential model calculations reveal that the enhanced spatial localization of the hole-wavefunction, relative to that of the electron in these dots, is the reason for this effect.Comment: 5 figure

Diurnal variation in harbour porpoise detection – potential implications for management

Peer reviewedPublisher PD

Finite Density QCD in the Chiral Limit

We present the first results of an exact simulation of full QCD at finite density in the chiral limit. We have used a MFA (Microcanonical Fermionic Average) inspired approach for the reconstruction of the Grand Canonical Partition Function of the theory; using the fugacity expansion of the fermionic determinant we are able to move continuously in the ($\beta -\mu$) plane with $m=0$.Comment: 3 pages, LaTeX, 3 figures, uses espcrc2.sty, psfig. Talk presented by A. Galante at Lattice 97. Correction of some reference

Application of a multibeam echosounder to document changes in animal movement and behaviour around a tidal turbine structure

Acknowledgements We acknowledge the support of Shaun Fraser, Vladimir Nikora, James Waggitt, Paul Bell, Ian Davies, Eric Armstrong, and staff at Marine Scotland Science and the European Marine Energy Centre. Hydrodynamic model data were provided by Pierre Cazenave and Ricardo Torres (Plymouth Marine Laboratory). The constructive and extensive comments from three reviewers of an earlier version of this manuscript are gratefully acknowledged. Funding This work was funded by NERC and Defra (NE/J004308/1, NE/J004200/1, NE/J004332/1, NE/N01765X/1), a NERC MREKEP Internship, Innovate UK KTP (KTP009812), and the UK Department for Business, Energy and Industrial Strategy’s offshore energy Strategic Environmental Assessment programme.Peer reviewedPublisher PD

Real-time assembly of ribonucleoprotein complexes on nascent RNA transcripts.

Cellular protein-RNA complexes assemble on nascent transcripts, but methods to observe transcription and protein binding in real time and at physiological concentrations are not available. Here, we report a single-molecule approach based on zero-mode waveguides that simultaneously tracks transcription progress and the binding of ribosomal protein S15 to nascent RNA transcripts during early ribosome biogenesis. We observe stable binding of S15 to single RNAs immediately after transcription for the majority of the transcripts at 35 °C but for less than half at 20 °C. The remaining transcripts exhibit either rapid and transient binding or are unable to bind S15, likely due to RNA misfolding. Our work establishes the foundation for studying transcription and its coupled co-transcriptional processes, including RNA folding, ligand binding, and enzymatic activity such as in coupling of transcription to splicing, ribosome assembly or translation

Improved methods for detecting gravitational waves associated with short gamma-ray bursts

In the era of second generation ground-based gravitational wave detectors, short gamma-ray bursts (GRBs) will be among the most promising astrophysical events for joint electromagnetic and gravitational wave observation. A targeted search for gravitational wave compact binary merger signals in coincidence with short GRBs was developed and used to analyze data from the first generation LIGO and Virgo instruments. In this paper, we present improvements to this search that enhance our ability to detect gravitational wave counterparts to short GRBs. Specifically, we introduce an improved method for estimating the gravitational wave background to obtain the event significance required to make detections; implement a method of tiling extended sky regions, as required when searching for signals associated to poorly localized GRBs from Fermi Gamma-ray Burst Monitor or the InterPlanetary Network; and incorporate astrophysical knowledge about the beaming of GRB emission to restrict the search parameter space. We describe the implementation of these enhancements and demonstrate how they improve the ability to observe binary merger gravitational wave signals associated with short GRBs.Comment: 13 pages, 6 figure

Non-Gaussian Radio-Wave Scattering in the Interstellar Medium

It was recently suggested by Boldyrev & Gwinn that the characteristics of radio scintillations from distant pulsars are best understood if the interstellar electron-density fluctuations that cause the time broadening of the radio pulses obey non-Gaussian statistics. In this picture the density fluctuations are inferred to be strong on very small scales ($\sim 10^8-10^{10} {cm}$). We argue that such density structures could correspond to the ionized boundaries of molecular regions (clouds) and demonstrate that the power-law distribution of scattering angles that is required to match the observations arises naturally from the expected intersections of our line of sight with randomly distributed, thin, approximately spherical ionized shells of this type. We show that the observed change in the time-broadening behavior for pulsar dispersion measures $\lesssim 30 {\rm pc} {\rm cm}^{-3}$ is consistent with the expected effect of the general ISM turbulence, which should dominate the scattering for nearby pulsars. We also point out that if the clouds are ionized by nearby stars, then their boundaries may become turbulent on account of an ionization front instability. This turbulence could be an alternative cause of the inferred density structures. An additional effect that might contribute to the strength of the small-scale fluctuations in this case is the expected flattening of the turbulent density spectrum when the eddy sizes approach the proton gyroscale.Comment: 15 pages, 3 figures, accepted to Ap