Effect of agitation on protein aggregation in vials made from glass or plastics

The increasing use of proteins as therapeutics including monoclonal antibodies has focused attention on the need to maintain the stability of these labile molecules during both storage and shipment. The degradation of therapeutic proteins can arise from aggregation and adsorption in primary containers, as well as from exposure to leachables, and chemical damage due to exposure to oxygen or light. Since vials continue to be used as primary containers for multiple-use applications, including vaccines and lyophilized drug products, we have compared the effect of mechanical stress on protein aggregation in vials made of glass versus vials made of the plastic cyclic olefin polymer (COP). The goal of the study was to first develop and characterize a simple stress model consisting of rotating vials placed horizontally on an orbital shaker. The second goal was to use this method to compare aggregation in vials made from COP or glass. It was shown that proteins have a reduced tendency to aggregate in COP, and that the level of aggregation was protein-dependent

Neutrinos From Individual Gamma-Ray Bursts in the BATSE Catalog

We calculate the neutrino emission from individual gamma-ray bursts observed by the BATSE detector on the Compton Gamma-Ray Observatory. Neutrinos are produced by photoproduction of pions when protons interact with photons in the region where the kinetic energy of the relativistic fireball is dissipated allowing the acceleration of electrons and protons. We also consider models where neutrinos are predominantly produced on the radiation surrounding the newly formed black hole. From the observed redshift and photon flux of each individual burst, we compute the neutrino flux in a variety of models based on the assumption that equal kinetic energy is dissipated into electrons and protons. Where not measured, the redshift is estimated by other methods. Unlike previous calculations of the universal diffuse neutrino flux produced by all gamma-ray bursts, the individual fluxes (compiled at http://www.arcetri.astro.it/~dafne/grb/) can be directly compared with coincident observations by the AMANDA telescope at the South Pole. Because of its large statistics, our predictions are likely to be representative for future observations with larger neutrino telescopes.Comment: 49 pages, 7 figures. Accepted for publication in Astroparticle Physic

Prompt TeV neutrinos from dissipative photospheres of gamma-ray bursts

Recently, it was suggested that a photospheric component that results from the internal dissipation occurring in the optically thick inner parts of relativistic outflows may be present in the prompt $\gamma$/X-ray emission of gamma-ray bursts or X-ray flashes. We explore high-energy neutrino emission in this dissipative photosphere model, assuming that the composition of the outflow is baryon-dominated. We find that neutrino emission from proton-proton collision process forms an interesting signature in the neutrino spectra. Under favorable conditions for the shock dissipation site, these low-energy neutrinos could be detected by ${\rm km^3}$ detectors, such as Icecube. Higher energies (\ga10 TeV) neutrino emission from proton-proton collision and photo-pion production processes could be significantly suppressed for dissipation at relatively small radii, due to efficient Bethe-Heitler cooling of protons and/or radiative cooling of the secondary mesons in the photosphere radiation. As the dissipation shocks continue further out, high energy neutrinos from photo-pion production process becomes dominant.Comment: Accepted by ApJ Letters, some changes made following the referees' comments, conclusions unchanged. The paper was originally submitted to PRL on June 6 (2008); resubmitted to ApJL on Oct.1 (2008); accepted by ApJL on Dec. 9 (2008

Using the Active Collimator and Shield Assembly of an EXIST-Type Mission as a Gamma-Ray Burst Spectrometer

The Energetic X-ray Imaging Survey Telescope (EXIST) is a mission design concept that uses coded masks seen by Cadmium Zinc Telluride (CZT) detectors to register hard X-rays in the energy region from 10 keV to 600 keV. A partially active or fully active anti-coincidence shield/collimator with a total area of between 15 and 35 square meters will be used to define the field of view of the CZT detectors and to suppress the background of cosmic-ray-induced events. In this paper, we describe the use of a sodium activated cesium iodide shield/collimator to detect gamma-ray bursts (GRBs) and to measure their energy spectra in the energy range from 100 keV up to 10 MeV. We use the code GEANT4 to simulate the interactions of photons and cosmic rays with the spacecraft and instrument and the code DETECT2000 to simulate the optical properties of the scintillation detectors. The shield collimator achieves a nu-F-nu sensitivity of 3 x 10^(-9) erg cm^(-2) s^(-1) and 2 x 10^(-8) erg cm^(-2) s^(-1) at 100 keV and 600 keV, respectively. The sensitivity is well matched to that of the coded mask telescope. The broad energy coverage of an EXIST-type mission with active shields will constrain the peak of the spectral energy distribution (SED) for a large number of GRBs. The measurement of the SED peak may be key for determining photometric GRB redshifts and for using GRBs as cosmological probes.Comment: 20 pages, 10 Figures, Accepted May 19, 2006 A&

Open Questions in GRB Physics

Open questions in GRB physics are summarized as of 2011, including classification, progenitor, central engine, ejecta composition, energy dissipation and particle acceleration mechanism, radiation mechanism, long term engine activity, external shock afterglow physics, origin of high energy emission, and cosmological setting. Prospects of addressing some of these problems with the upcoming Chinese-French GRB mission, SVOM, are outlined.Comment: 27 pages. To appear in a special issue of Comptes Rendus Physique "GRB studies in the SVOM era", Eds. F. Daigne, G. Dubu

Gamma--Ray Bursts associated with Supernovae: A systematic analysis of BATSE GRB candidates

We examined the properties of a sample of BATSE Gamma--Ray Bursts (GRBs) comprising events which have indications of association with a supernova (SN), some on the basis of indications of re--brightening in the optical afterglow light curve, but in most cases based only on the `loose' temporal and directional coincidence inferred from the cross correlation of catalogs. Despite of the large uncertainties in the latter selection method, the temporal and spectral analysis reveal three interesting statistical results when the sample is compared with that of all the BATSE GRBs: the GRBs tentatively associated with SNe are found to predominantly (in $\sim$ 80% of the cases) have single-peaked light curves, a softer spectrum (i.e. low energy power law index $\alpha \sim$ --1.5) and tend not to follow the Lag-Luminosity and Isotropic Energy--Peak Energy correlations. These three independent statistical properties point toward the existence of a significant number of under-luminous,GRB 980425-like events constituting -- at least from an observational point of view -- a tail or a separate class with respect to the whole of the BATSE GRB events. The unusually high percentage of SN Ibc among those identified by the catalog cross--correlation (factor $\sim 4$ higher than expected from SN catalog statistics) reinforces the non-randomness of (some of) the selected events.Comment: 12 pages, 8 figures, 1 table - accepted for publication in A&

Modelling of Usual Nutrient Intakes: Potential Impact of the Choices Programme on Nutrient Intakes in Young Dutch Adults

Introduction The Choices Programme is an internationally applicable nutrient profiling system with nutrition criteria for trans fatty acids (TFA), saturated fatty acids, sodium, added sugar and for some product groups energy and fibre. These criteria determine whether foods are eligible to carry a “healthier option” stamp. In this paper a nutrient intake modelling method is described to evaluate these nutritional criteria by investigating the potential effect on nutrient intakes. Methods Data were combined from the 2003 Dutch food consumption survey in young adults (aged 19–30) and the Dutch food composition table into the Monte Carlo Risk Assessment model. Three scenarios were calculated: the “actual intakes” (scenario 1) were compared to scenario 2, where all foods that did not comply were replaced by similar foods that did comply with the Choices criteria. Scenario 3 was the same as scenario 2 adjusted for the difference in energy density between the original and replacement food. Additional scenarios were calculated where snacks were not or partially replaced and stratified analyses for gender, age, Body Mass Index (BMI) and education. Results Calculated intake distributions showed that median energy intake was reduced by 16% by replacing normally consumed foods with Choices compliant foods. Intakes of nutrients with a maximal intake limit were also reduced (ranging from -23% for sodium and -62% for TFA). Effects on intakes of beneficial nutrients varied from an unintentional reduction in fat soluble vitamin intakes (-15 to -28%) to an increase of 28% for fibre and 17% calcium. Stratified analyses in this homogeneous study population showed only small differences across gender, age, BMI and education. Conclusions This intake modelling method showed that with consumption of Choices compliant foods, nutrient intakes shift towards population intake goals for the nutrients for which nutrition criteria were defined, while effects on beneficial nutrients were diverse

Survivability Is More Fundamental Than Evolvability

For a lineage to survive over long time periods, it must sometimes change. This has given rise to the term evolvability, meaning the tendency to produce adaptive variation. One lineage may be superior to another in terms of its current standing variation, or it may tend to produce more adaptive variation. However, evolutionary outcomes depend on more than standing variation and produced adaptive variation: deleterious variation also matters. Evolvability, as most commonly interpreted, is not predictive of evolutionary outcomes. Here, we define a predictive measure of the evolutionary success of a lineage that we call the k-survivability, defined as the probability that the lineage avoids extinction for k generations. We estimate the k-survivability using multiple experimental replicates. Because we measure evolutionary outcomes, the initial standing variation, the full spectrum of generated variation, and the heritability of that variation are all incorporated. Survivability also accounts for the decreased joint likelihood of extinction of sub-lineages when they 1) disperse in space, or 2) diversify in lifestyle. We illustrate measurement of survivability with in silico models, and suggest that it may also be measured in vivo using multiple longitudinal replicates. The k-survivability is a metric that enables the quantitative study of, for example, the evolution of 1) mutation rates, 2) dispersal mechanisms, 3) the genotype-phenotype map, and 4) sexual reproduction, in temporally and spatially fluctuating environments. Although these disparate phenomena evolve by well-understood microevolutionary rules, they are also subject to the macroevolutionary constraint of long-term survivability

Future paradigms for precision oncology.

Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used

Regeneration of myelin sheaths of normal length and thickness in the zebrafish CNS correlates with growth of axons in caliber

Demyelination is observed in numerous diseases of the central nervous system, including multiple sclerosis (MS). However, the endogenous regenerative process of remyelination can replace myelin lost in disease, and in various animal models. Unfortunately, the process of remyelination often fails, particularly with ageing. Even when remyelination occurs, it is characterised by the regeneration of myelin sheaths that are abnormally thin and short. This imperfect remyelination is likely to have implications for the restoration of normal circuit function and possibly the optimal metabolic support of axons. Here we describe a larval zebrafish model of demyelination and remyelination. We employ a drug-inducible cell ablation system with which we can consistently ablate 2/3rds of oligodendrocytes in the larval zebrafish spinal cord. This leads to a concomitant demyelination of 2/3rds of axons in the spinal cord, and an innate immune response over the same time period. We find restoration of the normal number of oligodendrocytes and robust remyelination approximately two weeks after induction of cell ablation, whereby myelinated axon number is restored to control levels. Remarkably, we find that myelin sheaths of normal length and thickness are regenerated during this time. Interestingly, we find that axons grow significantly in caliber during this period of remyelination. This suggests the possibility that the active growth of axons may stimulate the regeneration of myelin sheaths of normal dimensions