Improving gene annotation using peptide mass spectrometry

Annotation of protein-coding genes is a key goal of genome sequencing projects. In spite of tremendous recent advances in computational gene finding, comprehensive annotation remains a challenge. Peptide mass spectrometry is a powerful tool for researching the dynamic proteome and suggests an attractive approach to discover and validate protein-coding genes. We present algorithms to construct and efficiently search spectra against a genomic database, with no prior knowledge of encoded proteins. By searching a corpus of 18.5 million tandem mass spectra (MS/MS) from human proteomic samples, we validate 39,000 exons and 11,000 introns at the level of translation. We present translation-level evidence for novel or extended exons in 16 genes, confirm translation of 224 hypothetical proteins, and discover or confirm over 40 alternative splicing events. Polymorphisms are efficiently encoded in our database, allowing us to observe variant alleles for 308 coding SNPs. Finally, we demonstrate the use of mass spectrometry to improve automated gene prediction, adding 800 correct exons to our predictions using a simple rescoring strategy. Our results demonstrate that proteomic profiling should play a role in any genome sequencing project.

Selección de péptidos sintéticos del Virus de la Hepatitis G (GBV-C/HGV) inhibidores del Péptido de Fusión HIV-I

El GB virus C (GBV-C) o virus de l'hepatitis G (HGV) es un virus format per una única cadena de RNA que pertany a la familia Flaviviridae. En els últims anys, s'han publicat nombrosos treballs en els quals s'associa la coinfecció del GBV-C i del virus de la immunodeficiència humana (VIH) amb una menor progressió de l'esmentada malaltia així com amb una major supervivència dels pacients una vegada que la SIDA s'ha desenvolupat. El mecanisme pel qual el virus GBV-C/HGV exerceix un “efecte protector” en els pacients amb VIH encara no està descrit. L’estudi de la interacció entre els virus GBVC/HGV i VIH podria donar lloc al desenvolupament de nous agents terapèutics per al tractament de la SIDA.Treballs recents mostren com la capacitat inhibitòria del virus del GBV-C/HGV és deguda a la seva glicoproteina estructural E2. S’ha vist que aquesta proteina seria capaç d’inhibir la primera fase de replicació de VIH, així com la unió i la fusió amb les membranes cel•lulars. Sobre la base d’aquests estudis, l’objectiu d’aquest treball ha estat seleccionar inhibidors del pèptid de fusió del VIH utilitzant pèptids sintètics de la proteina E2 del GBV-C/HGV. El treball realitzat ha consistit en estudiar, utilitzant assajos biofísics de leakage i de lipid mixing, la capacitat dels pèptids de la proteina estructural del virus del GBV-C/HGV per inhibir la interacció i el procés de desestabilització de membranes induïdes pel pèptid de fusió de la glicoproteina de l’embolcall, GP41, del VIH. Aquests assajos, com es descriu en treballs anteriors, han resultat útils per a la selecció i la identificació de compostos amb activitat específica anti-GP41. Es pot afirmar que efectivament els pèptids seleccionats de la proteina E2 del virus del GBV-C/HGV inhibeixen l’activitat del pèptid de fusió del VIH probablement com a consequència d’un canvi conformacional en aquest darrer.

Extended truncated Tweedie-Poisson model

It has been argued that by truncating the sample space of the negative binomial and of the inverse Gaussian-Poisson mixture models at zero, one is allowed to extend the parameter space of the model. Here that is proved to be the case for the more general three parameter Tweedie-Poisson mixture model. It is also proved that the distributions in the extended part of the parameter space are not the zero truncation of mixed poisson distributions and that, other than for the negative binomial, they are not mixtures of zero truncated Poisson distributions either. By extending the parameter space one can improve the fit when the frequency of one is larger and the right tail is heavier than is allowed by the unextended model. Considering the extended model also allows one to use the basic maximum likelihood based inference tools when parameter estimates fall in the extended part of the parameter space, and hence when the m.l.e. does not exist under the unextended model. This extended truncated Tweedie-Poisson model is proved to be useful in the analysis of words and species frequency count data.

Antimicrobial peptide genes in Bacillus strains from plant environments

The presence of the antimicrobial peptide (AMP) biosynthetic genes srfAA (surfactin), bacA (bacylisin), fenD (fengycin), bmyB (bacyllomicin), spaS (subtilin), and ituC (iturin) was examined in 184 isolates of Bacillus spp. obtained from plant environments (aerial, rhizosphere, soil) in the Mediterranean land area of Spain. Most strains had between two and four AMP genes whereas strains with five genes were seldom detected and none of the strains had six genes. The most frequent AMP gene markers were srfAA, bacA, bmyB, and fenD, and the most frequent genotypes srfAA-bacA-bmyB and srfAAbacA-bmyB-fenD. The dominance of these particular genes in Bacillus strains associated with plants reinforces the competitive role of surfactin, bacyllomicin, fengycin, and bacilysin in the fitness of strains in natural environments. The use of these AMP gene markers may assist in the selection of putative biological control agents of plant pathogens

Information-theoretical derivation of an extended thermodynamical description of radiative systems

A radiative equation of the Cattaneo–Vernotte type is derived from information theory and the radiative transfer equation. The equation thus derived is a radiative analog of the equation that is used for the description of hyperbolic heat conduction. It is shown, without recourse to any phenomenological assumption, that radiative transfer may be included in a natural way in the framework of extendedirreversible thermodynamics

Simulation methods with extended stability for stiff biochemical kinetics

Background: With increasing computer power, simulating the dynamics of complex systems in chemistry and biology is becoming increasingly routine. The modelling of individual reactions in (bio)chemical systems involves a large number of random events that can be simulated by the stochastic simulation algorithm (SSA). The key quantity is the step size, or waiting time, τ, whose value inversely depends on the size of the propensities of the different channel reactions and which needs to be re-evaluated after every firing event. Such a discrete event simulation may be extremely expensive, in particular for stiff systems where τ can be very short due to the fast kinetics of some of the channel reactions. Several alternative methods have been put forward to increase the integration step size. The so-called τ-leap approach takes a larger step size by allowing all the reactions to fire, from a Poisson or Binomial distribution, within that step. Although the expected value for the different species in the reactive system is maintained with respect to more precise methods, the variance at steady state can suffer from large errors as τ grows. Results: In this paper we extend Poisson τ-leap methods to a general class of Runge-Kutta (RK) τ-leap methods. We show that with the proper selection of the coefficients, the variance of the extended τ-leap can be well-behaved, leading to significantly larger step sizes.Conclusions: The benefit of adapting the extended method to the use of RK frameworks is clear in terms of speed of calculation, as the number of evaluations of the Poisson distribution is still one set per time step, as in the original τ-leap method. The approach paves the way to explore new multiscale methods to simulate (bio)chemical systems.

Stable complexes involving acetylcholinesterase and amyloid-ß-peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer's fibrils

Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-beta peptide (Abeta) during its assembly into filaments, in agreement with its colocalization with the Abeta deposits of Alzheimer's brain. The association of the enzyme with nascent Abeta aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE-amyloid complexes is higher than that of the Abeta aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of Abeta fibrils and thus may determine the selective neuronal loss observed in Alzheimer's brain.

On Certain Greedoid Polyhedra, Partially Indexable Scheduling Problems, and Extended Restless Bandit Allocation Indices

We present a polyhedral framework for establishing general structural properties on optimal solutions of stochastic scheduling problems, where multiple job classes vie for service resources: the existence of an optimal priority policy in a given family, characterized by a greedoid (whose feasible class subsets may receive higher priority), where optimal priorities are determined by class-ranking indices, under restricted linear performance objectives (partial indexability). This framework extends that of Bertsimas and Niño-Mora (1996), which explained the optimality of priority-index policies under all linear objectives (general indexability). We show that, if performance measures satisfy partial conservation laws (with respect to the greedoid), which extend previous generalized conservation laws, then the problem admits a strong LP relaxation over a so-called extended greedoid polytope, which has strong structural and algorithmic properties. We present an adaptive-greedy algorithm (which extends Klimov's) taking as input the linear objective coefficients, which (1) determines whether the optimal LP solution is achievable by a policy in the given family; and (2) if so, computes a set of class-ranking indices that characterize optimal priority policies in the family. In the special case of project scheduling, we show that, under additional conditions, the optimal indices can be computed separately for each project (index decomposition). We further apply the framework to the important restless bandit model (two-action Markov decision chains), obtaining new index policies, that extend Whittle's (1988), and simple sufficient conditions for their validity. These results highlight the power of polyhedral methods (the so-called achievable region approach) in dynamic and stochastic optimization.

Health care provider choice in the case of patient-initiated contacts. An extended version of discrete choice of model demand

This paper analyzes the nature of health care provider choice inthe case of patient-initiated contacts, with special reference toa National Health Service setting, where monetary prices are zeroand general practitioners act as gatekeepers to publicly financedspecialized care. We focus our attention on the factors that mayexplain the continuously increasing use of hospital emergencyvisits as opposed to other provider alternatives. An extendedversion of a discrete choice model of demand for patient-initiatedcontacts is presented, allowing for individual and town residencesize differences in perceived quality (preferences) betweenalternative providers and including travel and waiting time asnon-monetary costs. Results of a nested multinomial logit model ofprovider choice are presented. Individual choice betweenalternatives considers, in a repeated nested structure, self-care,primary care, hospital and clinic emergency services. Welfareimplications and income effects are analyzed by computingcompensating variations, and by simulating the effects of userfees by levels of income. Results indicate that compensatingvariation per visit is higher than the direct marginal cost ofemergency visits, and consequently, emergency visits do not appearas an inefficient alternative even for non-urgent conditions.

On certain greedoid polyhedra, partially indexable scheduling problems and extended restless bandit allocation indices

We present a polyhedral framework for establishing general structural properties on optimal solutions of stochastic scheduling problems, where multiple job classes vie for service resources: the existence of an optimal priority policy in a given family, characterized by a greedoid(whose feasible class subsets may receive higher priority), where optimal priorities are determined by class-ranking indices, under restricted linear performance objectives (partial indexability). This framework extends that of Bertsimas and Niño-Mora (1996), which explained the optimality of priority-index policies under all linear objectives (general indexability). We show that, if performance measures satisfy partial conservation laws (with respect to the greedoid), which extend previous generalized conservation laws, then theproblem admits a strong LP relaxation over a so-called extended greedoid polytope, which has strong structural and algorithmic properties. We present an adaptive-greedy algorithm (which extends Klimov's) taking as input the linear objective coefficients, which (1) determines whether the optimal LP solution is achievable by a policy in the given family; and (2) if so, computes a set of class-ranking indices that characterize optimal priority policies in the family. In the special case of project scheduling, we show that, under additional conditions, the optimal indices can be computed separately for each project (index decomposition). We further apply the framework to the important restless bandit model (two-action Markov decision chains), obtaining new index policies, that extend Whittle's (1988), and simple sufficient conditions for their validity. These results highlight the power of polyhedral methods (the so-called achievable region approach) in dynamic and stochastic optimization.

Faint arc-minute extended radio emission around Cygnus X-3

Aims.We revisit the vicinity of the microquasar Cygnus X-3 at radio wavelengths. We aim to improve our previous search for possible associated extended radio features/hot spots in the position angle of the Cygnus X-3 relativistic jets focusing on shorter angular scales than previously explored. Methods.Our work is mostly based on analyzing modern survey and archive radio data, mainly including observations carried out with the Very Large Array and the Ryle Telescopes. We also used deep near-infrared images that we obtained in 2005. Results.We present new radio maps of the Cygnus X-3 field computed after combining multi-configuration Very Large Array archive data at 6 cm and different observing runs at 2 cm with the Ryle Telescope. These are probably among the deepest radio images of Cygnus X-3 reported to date at cm wavelengths. Both interferometers reveal an extended radio feature within a few arc-minutes of the microquasar position, thus making our detection more credible. Moreover, this extended emission is possibly non-thermal, although this point still needs confirmation. Its physical connection with the microquasar is tentatively considered under different physical scenarios. We also report on the serendipitous discovery of a likely Fanaroff-Riley type II radio galaxy only away from Cygnus X-3.

Quasilocal density functional theory and its application within the extended Thomas-Fermi approximation

In this paper we propose a generalization of the density functional theory. The theory leads to single-particle equations of motion with a quasilocal mean-field operator, which contains a quasiparticle position-dependent effective mass and a spin-orbit potential. The energy density functional is constructed using the extended Thomas-Fermi approximation and the ground-state properties of doubly magic nuclei are considered within the framework of this approach. Calculations were performed using the finite-range Gogny D1S forces and the results are compared with the exact Hartree-Fock calculations

Mean field model for spatially extended systems in the presence of multiplicative noise

We present a mean field model that describes the effect of multiplicative noise in spatially extended systems. The model can be solved analytically. For the case of the phi4 potential it predicts that the phase transition is shifted. This conclusion is supported by numerical simulations of this model in two dimensions.