The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES.

Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective and specific, could be used to protect people from initial infection. One of the most promising of these for clinical use is 5P12-RANTES, a variant of the chemokine RANTES/CCL5. The N-terminal amino acid of 5P12-RANTES is glutamine (Gln; called Q0), a residue that is prone to spontaneous cyclization when at the N-terminus of a protein. It is not known how this cyclization affects the potency of the inhibitor or whether cyclization is necessary for the function of the protein, although the N-terminal region of RANTES has been shown to be critical for receptor interactions, with even small changes having a large effect. We have studied the kinetics of cyclization of 5P12-RANTES as well as N-terminal variations of the protein that either produce an identical cyclized terminus (Glu0) or that cannot similarly cyclize (Asn0, Phe0, Ile0, and Leu0). We find that the half life for N-terminal cyclization of Gln is roughly 20 h at pH 7.3 at 37 °C. However, our results show that cyclization is not necessary for the potency of this protein and that several replacement terminal amino acids produce nearly-equally potent HIV inhibitors while remaining CC chemokine receptor 5 (CCR5) antagonists. This work has ramifications for the production of active 5P12-RANTES for use in the clinic, while also opening the possibility of developing other inhibitors by varying the N-terminus of the protein

Correcting the influence of an asymmetric line spread function in 2-degree Field spectrograph data

We investigate the role of asymmetries in the line spread function of the 2-degree field spectrograph and the variations in these asymmetries with the CCD, the plate, the time of observation and the fibre. A data-reduction pipeline is developed that takes these deformations into account for the calibration and cross-correlation of the spectra. We show that, using the emission lines of calibration lamp observations, we can fit the line spread function with the sum of two Gaussian functions representing the theoretical signal and a perturbation of the system. This model is then used to calibrate the spectra and generate templates by downgrading high resolution spectra. Thus, we can cross-correlate the observed spectra with templates degraded in the same way. Our reduction pipeline is tested on real observations and provides a significant improvement in the accuracy of the radial velocities obtained. In particular, the systematic errors that were as high as ~20 km/s when applying the AAO reduction package 2dfDR are now reduced to ~5 km/s. Even though the 2-degree Field spectrograph is to be decommissioned at the end of 2005, the analysis of archival data and previous studies could be improved by the reduction procedure we propose here.Comment: 9 pages, 9 figures, accepted to PASA, minor change

Cell patterning on photolithographically defined parylene-C:SiO2 substrates

Cell patterning platforms support broad research goals, such as construction of predefined in vitro neuronal networks and the exploration of certain central aspects of cellular physiology. To easily combine cell patterning with Multi-Electrode Arrays (MEAs) and silicon-based ‘lab on a chip’ technologies, a microfabrication-compatible protocol is required. We describe a method that utilizes deposition of the polymer parylene-C on SiO(2 )wafers. Photolithography enables accurate and reliable patterning of parylene-C at micron-level resolution. Subsequent activation by immersion in fetal bovine serum (or another specific activation solution) results in a substrate in which cultured cells adhere to, or are repulsed by, parylene or SiO(2) regions respectively. This technique has allowed patterning of a broad range of cell types (including primary murine hippocampal cells, HEK 293 cell line, human neuron-like teratocarcinoma cell line, primary murine cerebellar granule cells, and primary human glioma-derived stem-like cells). Interestingly, however, the platform is not universal; reflecting the importance of cell-specific adhesion molecules. This cell patterning process is cost effective, reliable, and importantly can be incorporated into standard microfabrication (chip manufacturing) protocols, paving the way for integration of microelectronic technology

A theory for long-memory in supply and demand

Recent empirical studies have demonstrated long-memory in the signs of orders to buy or sell in financial markets [2, 19]. We show how this can be caused by delays in market clearing. Under the common practice of order splitting, large orders are broken up into pieces and executed incrementally. If the size of such large orders is power law distributed, this gives rise to power law decaying autocorrelations in the signs of executed orders. More specifically, we show that if the cumulative distribution of large orders of volume v is proportional to v to the power -alpha and the size of executed orders is constant, the autocorrelation of order signs as a function of the lag tau is asymptotically proportional to tau to the power -(alpha - 1). This is a long-memory process when alpha < 2. With a few caveats, this gives a good match to the data. A version of the model also shows long-memory fluctuations in order execution rates, which may be relevant for explaining the long-memory of price diffusion rates.Comment: 12 pages, 7 figure

A Minor Axis Surface Brightness Profile for M31

We use data from the Isaac Newton Telescope Wide Field Camera survey of M31 to determine the surface brightness profile of M31 along the south-east minor axis. We combine surface photometry and faint red giant branch star counts to trace the profile from the innermost regions out to a projected radius of 4 degrees (~55 kpc) where the V-band surface brightness is 32 mag per square arcsec; this is the first time the M31 minor axis profile has been mapped over such a large radial distance using a single dataset. We confirm the finding by Pritchet & van den Bergh (1994) that the minor axis profile can be described by a single de Vaucouleurs law out to a projected radius of 1.4 degrees or ~20 kpc. Beyond this, the surface brightness profile flattens considerably and is consistent with either a power-law of index -2.3 or an exponential of scalelength 14 kpc. The fraction of the total M31 luminosity contained in this component is ~2.5%. While it is tempting to associate this outer component with a true Population II halo in M31, we find that the mean colour of the stellar population remains approximately constant at V-i~1.6 from 0.5-3.5 degrees along the minor axis. This result suggests that the same metal-rich stellar population dominates both structural components.Comment: 11 pages, 3 figures, ApJ Letters in press, extremely minor modification

Fitting the Phenomenological MSSM

We perform a global Bayesian fit of the phenomenological minimal supersymmetric standard model (pMSSM) to current indirect collider and dark matter data. The pMSSM contains the most relevant 25 weak-scale MSSM parameters, which are simultaneously fit using `nested sampling' Monte Carlo techniques in more than 15 years of CPU time. We calculate the Bayesian evidence for the pMSSM and constrain its parameters and observables in the context of two widely different, but reasonable, priors to determine which inferences are robust. We make inferences about sparticle masses, the sign of the $\mu$ parameter, the amount of fine tuning, dark matter properties and the prospects for direct dark matter detection without assuming a restrictive high-scale supersymmetry breaking model. We find the inferred lightest CP-even Higgs boson mass as an example of an approximately prior independent observable. This analysis constitutes the first statistically convergent pMSSM global fit to all current data.Comment: Added references, paragraph on fine-tunin

KECK HIRES Spectroscopy of APM 08279+5255

With an optical R-band magnitude of 15.2, the recently discovered z=3.911 BAL quasar APM 08279+5255 is an exceptionally bright high redshift source. Its brightness has allowed us to acquire a high signal-to-noise ratio (~100), high resolution (~6 km/s) spectrum using the HIRES echelle spectrograph on the 10-m Keck I telescope. Given the quality of the data, these observations provide an unprecedented view of associated and intervening absorption systems. Here we announce the availability of this spectrum to the general astronomical community and present a brief analysis of some of its main features.Comment: 21 pages including 5 figures. Accepted for publication by PAS

Neuronal and psychological underpinnings of pathological gambling

Like in the case of drugs, gambling hijacks reward circuits in a brain which is not prepared to receive such intense stimulation. Dopamine is normally released in response to reward and uncertainty in order to allow animals to stay alive in their environment – where rewards are relatively unpredictable. In this case, behavior is regulated by environmental feedbacks, leading animals to persevere or to give up. In contrast, drugs provide a direct, intense pharmacological stimulation of the dopamine system that operates independently of environmental feedbacks, and hence causes “motivational runaways”. With respect to gambling, the confined environment experienced by gamblers favors the emergence of excitatory conditioned cues, so that positive feedbacks take over negative feedbacks. Although drugs and gambling may act differently, their abnormal activation of reward circuitry generates an underestimation of negative consequences and promotes the development of addictive/compulsive behavior. In Parkinson’s and Huntington’s disease, dopamine-related therapies may disrupt these feedbacks on dopamine signalling, potentially leading to various addictions, including pathological gambling. The goal of this Research Topic is to further our understanding of the neurobiological mechanisms underlying the development of pathological gambling. This eBook contains a cross-disciplinary collection of research and review articles, ranging in scope from animal behavioral models to human imaging studies