5,578 research outputs found
β2 integrin LFA1 mediates airway damage following neutrophil trans-epithelial migration during RSV infection
RSV bronchiolitis is the most common cause of infant hospital admissions, but there is limited understanding of the mechanisms of disease and no specific anti-viral treatment. Using a novel in vitro primary trans-epithelial neutrophil migration model and innovative imaging methods, we show that RSV infection of nasal airway epithelium increased neutrophil trans-epithelial migration and adhesion to infected epithelial cells, which is associated with epithelial cell damage, reduced ciliary beat frequency, but also a reduction in infectious viral load.
Following migration, RSV infection results in greater neutrophil activation, degranulation and release of neutrophil elastase into the airway surface media compared to neutrophils that migrated across mock-infected nasal epithelial cells. Blocking of the interaction between the ligand on neutrophils (the β2 integrin LFA-1) for intracellular adhesion molecule-1 (ICAM-1) on epithelial cells reduced neutrophil adherence to RSV infected cells and epithelial cell damage to pre-infection levels, but did not reduce the numbers of neutrophils which migrated or prevent the reduction in infectious viral load.
These findings have provided important insights into the contribution of neutrophils to airway damage and viral clearance, which are relevant to pathophysiology of RSV bronchiolitis. This model is a convenient, quantitative pre-clinical model that will further elucidate mechanisms that drive disease severity and has utility in anti-viral drug discovery
mRNA Display Design of Fibronectin-based Intrabodies That Detect and Inhibit Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Protein
The nucleocapsid (N) protein of severe acute respiratory syndrome (SARS) coronavirus plays important roles in both viral replication and modulation of host cell processes. New ligands that target the N protein may thus provide tools to track the protein inside cells, detect interaction hot spots on the protein surface, and discover sites that could be used to develop new anti-SARS therapies. Using mRNA display selection and directed evolution, we designed novel antibody-like protein affinity reagents that target SARS N protein with high affinity and selectivity. Our libraries were based on an 88-residue variant of the 10th fibronectin type III domain from human fibronectin (10Fn3). This selection resulted in eight independent 10Fn3 intrabodies, two that require the N-terminal domain for binding and six that recognize the C terminus, one with K_d = 1.7 nM. 10Fn3 intrabodies are well expressed in mammalian cells and are relocalized by N in SARS-infected cells. Seven of the selected intrabodies tested do not perturb cellular function when expressed singly in vivo and inhibit virus replication from 11- to 5900-fold when expressed in cells prior to infection. Targeting two sites on SARS-N simultaneously using two distinct 10Fn3s results in synergistic inhibition of virus replication
Practical implementation, characterization and applications of a multi-colour time-gated luminescence microscope
Time-gated luminescence microscopy using long-lifetime molecular probes can effectively eliminate autofluorescence to enable high contrast imaging. Here we investigate a new strategy of time-gated imaging for simultaneous visualisation of multiple species of microorganisms stained with long-lived complexes under low-background conditions. This is realized by imaging two pathogenic organisms (Giardia lamblia stained with a red europium probe and Cryptosporidium parvum with a green terbium probe) at UV wavelengths (320-400 nm) through synchronization of a flash lamp with high repetition rate (1 kHz) to a robust time-gating detection unit. This approach provides four times enhancement in signal-to-background ratio over non-time-gated imaging, while the average signal intensity also increases six-fold compared with that under UV LED excitation. The high sensitivity is further confirmed by imaging the single europium-doped Y2O2S nanocrystals (150 nm). We report technical details regarding the time-gating detection unit and demonstrate its compatibility with commercial epi-fluorescence microscopes, providing a valuable and convenient addition to standard laboratory equipment
Gene Function Classification Using Bayesian Models with Hierarchy-Based Priors
We investigate the application of hierarchical classification schemes to the
annotation of gene function based on several characteristics of protein
sequences including phylogenic descriptors, sequence based attributes, and
predicted secondary structure. We discuss three Bayesian models and compare
their performance in terms of predictive accuracy. These models are the
ordinary multinomial logit (MNL) model, a hierarchical model based on a set of
nested MNL models, and a MNL model with a prior that introduces correlations
between the parameters for classes that are nearby in the hierarchy. We also
provide a new scheme for combining different sources of information. We use
these models to predict the functional class of Open Reading Frames (ORFs) from
the E. coli genome. The results from all three models show substantial
improvement over previous methods, which were based on the C5 algorithm. The
MNL model using a prior based on the hierarchy outperforms both the
non-hierarchical MNL model and the nested MNL model. In contrast to previous
attempts at combining these sources of information, our approach results in a
higher accuracy rate when compared to models that use each data source alone.
Together, these results show that gene function can be predicted with higher
accuracy than previously achieved, using Bayesian models that incorporate
suitable prior information
Towards Real-Time Crowd Simulation Under Uncertainty Using an Agent-Based Model and an Unscented Kalman Filter
Agent-based modelling (ABM) is ideally suited to simulating crowds of people as it captures the complex behaviours and interactions between individuals that lead to the emergence of crowding. Currently, it is not possible to use ABM for real-time simulation due to the absence of established mechanisms for dynamically incorporating real-time data. This means that, although models are able to perform useful offline crowd simulations, they are unable to simulate the behaviours of crowds in real time. This paper begins to address this drawback by demonstrating how a data assimilation algorithm, the Unscented Kalman Filter (UKF), can be used to incorporate pseudo-real data into an agent-based model at run time. Experiments are conducted to test how well the algorithm works when a proportion of agents are tracked directly under varying levels of uncertainty. Notably, the experiments show that the behaviour of unobserved agents can be inferred from the behaviours of those that are observed. This has implications for modelling real crowds where full knowledge of all individuals will never be known. In presenting a new approach for creating real-time simulations of crowds, this paper has important implications for the management of various environments in global cities, from single buildings to larger structures such as transportation hubs, sports stadiums, through to entire city regions
Connection Between Type A and E Factorizations and Construction of Satellite Algebras
Recently, we introduced a new class of symmetry algebras, called satellite
algebras, which connect with one another wavefunctions belonging to different
potentials of a given family, and corresponding to different energy
eigenvalues. Here the role of the factorization method in the construction of
such algebras is investigated. A general procedure for determining an so(2,2)
or so(2,1) satellite algebra for all the Hamiltonians that admit a type E
factorization is proposed. Such a procedure is based on the known relationship
between type A and E factorizations, combined with an algebraization similar to
that used in the construction of potential algebras. It is illustrated with the
examples of the generalized Morse potential, the Rosen-Morse potential, the
Kepler problem in a space of constant negative curvature, and, in each case,
the conserved quantity is identified. It should be stressed that the method
proposed is fairly general since the other factorization types may be
considered as limiting cases of type A or E factorizations.Comment: 20 pages, LaTeX, no figure, to be published in J. Phys.
Analysis of parallel process in HVAC systems using deep autoencoders
P. 15-26Heating, Ventilation, and Air Conditioning (HVAC) systems are generally built in a modular manner, comprising several identical subsystems in order to achieve their nominal capacity. These parallel subsystems and elements should have the same behavior and, therefore, differences between them can reveal failures and inefficiency in the system. The complexity in HVAC systems comes from the number of variables involved in these processes. For that reason, dimensionality reduction techniques can be a useful approach to reduce the complexity of the HVAC data and study their operation. However, for most of these techniques, it is not possible to project new data without retraining the projection and, as a result, it is not possible to easily compare several projections. In this paper, a method based on deep autoencoders is used to create a reference model with a HVAC system and new data is projected using this model to be able to compare them. The proposed approach is applied to real data from a chiller with 3 identical compressors at the Hospital of LeónS
Intraspecific Combinations of Flower and Leaf Volatiles Act Together in Attracting Hawkmoth Pollinators
Insects pinpoint mates, food and oviposition sites by olfactory cues. Recognizing and localizing a suitable target by olfaction is demanding. Odor sources emit characteristic blends of compounds that have to be identified against an environmentally derived olfactory background. This background, however, does not necessarily disturb the localization of a source. Rather, the contrary. Sex pheromones become more attractive to male moths when being presented against a relevant plant background. Here we asked whether such olfactory coaction also characterizes foraging cues. The tobacco hornworm Manduca sexta feeds on nectar from wild tobacco Nicotiana attenuata and sacred datura Datura wrightii flowers. We tested how leaf-derived volatile blends as a background affect the moths' approach to flower blends. We found coaction when a flower blend was presented against a conspecific leaf volatile background but not when the blend was presented against volatiles emitted by the other host plant or by a non-host plant. Hence, our results reveal a species-specific coaction between flower blend and leaf volatile background. The ability to integrate information from different odor sources on one plant might provide the moth with a fine-grained analysis of food site quality
An optical supernova associated with the X-ray flash XRF 060218
Long-duration gamma-ray bursts (GRBs) are associated with type Ic supernovae
that are more luminous than average and that eject material at very high
velocities. Less-luminous supernovae were not hitherto known to be associated
with GRBs, and therefore GRB-supernovae were thought to be rare events. Whether
X-ray flashes - analogues of GRBs, but with lower luminosities and fewer
gamma-rays - can also be associated with supernovae, and whether they are
intrinsically 'weak' events or typical GRBs viewed off the axis of the burst,
is unclear. Here we report the optical discovery and follow-up observations of
the type Ic supernova SN 2006aj associated with X-ray flash XRF 060218.
Supernova 2006aj is intrinsically less luminous than the GRB-supernovae, but
more luminous than many supernovae not accompanied by a GRB. The ejecta
velocities derived from our spectra are intermediate between these two groups,
which is consistent with the weakness of both the GRB output and the supernova
radio flux. Our data, combined with radio and X-ray observations, suggest that
XRF 060218 is an intrinsically weak and soft event, rather than a classical GRB
observed off-axis. This extends the GRB-supernova connection to X-ray flashes
and fainter supernovae, implying a common origin. Events such as XRF 060218 are
probably more numerous than GRB-supernovae.Comment: Final published versio
Phylogeny of Prokaryotes and Chloroplasts Revealed by a Simple Composition Approach on All Protein Sequences from Complete Genomes Without Sequence Alignment
The complete genomes of living organisms have provided much information on their phylogenetic relationships. Similarly, the complete genomes of chloroplasts have helped to resolve the evolution of this organelle in photosynthetic eukaryotes. In this paper we propose an alternative method of phylogenetic analysis using compositional statistics for all protein sequences from complete genomes. This new method is conceptually simpler than and computationally as fast as the one proposed by Qi et al. (2004b) and Chu et al. (2004). The same data sets used in Qi et al. (2004b) and Chu et al. (2004) are analyzed using the new method. Our distance-based phylogenic tree of the 109 prokaryotes and eukaryotes agrees with the biologists tree of life based on 16S rRNA comparison in a predominant majority of basic branching and most lower taxa. Our phylogenetic analysis also shows that the chloroplast genomes are separated to two major clades corresponding to chlorophytes s.l. and rhodophytes s.l. The interrelationships among the chloroplasts are largely in agreement with the current understanding on chloroplast evolution
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