Potential therapeutic implications of new insights into respiratory syncytial virus disease

Viral bronchiolitis is the most common cause of hospitalization in infants under 6 months of age, and 70% of all cases of bronchiolitis are caused by respiratory syncytial virus (RSV). Early RSV infection is associated with respiratory problems such as asthma and wheezing later in life. RSV infection is usually spread by contaminated secretions and infects the upper then lower respiratory tracts. Infected cells release proinflammatory cytokines and chemokines, including IL-1, tumor necrosis factor-α, IL-6, and IL-8. These activate other cells and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues. The pattern of cytokine production by T lymphocytes can be biased toward 'T-helper-1' or 'T-helper-2' cytokines, depending on the local immunologic environment, infection history, and host genetics. T-helper-1 responses are generally efficient in antiviral defense, but young infants have an inherent bias toward T-helper-2 responses. The ideal intervention for RSV infection would be preventive, but the options are currently limited. Vaccines based on protein subunits, live attenuated strains of RSV, DNA vaccines, and synthetic peptides are being developed; passive antibody therapy is at present impractical in otherwise healthy children. Effective vaccines for use in neonates continue to be elusive but simply delaying infection beyond the first 6 months of life might reduce the delayed morbidity associated with infantile disease.     

Structural characterization of genomes by large scale sequence-structure threading

Background  

Using sequence-structure threading we have conducted structural characterization of complete proteomes of 37 archaeal, bacterial and eukaryotic organisms (including worm, fly, mouse and human) totaling 167,888 genes.     

Butyrylcholinesterase-catalyzed hydrolysis of N-methylindoxyl acetate: analysis of volume changes upon reaction and hysteretic behavior

Hydrolysis of the neutral substrate N-methylindoxyl acetate (NMIA) by wild-type human butyrylcholinesterase (BuChE) and peripheral site mutants (D70G, Y332A, D70G/Y332A) was found to follow the Michaelis-Menten kinetics. K(m) was 0.14 mM for wild-type, and 0.07-0.16 mM for D70G, Y332A and D70G/Y332A, indicating that the peripheral site is not involved in NMIA binding. The values of k(cat) were of the same order for all enzymes: 12,000-18,000 min(-1). Volume changes upon substrate binding (-DeltaV(K(m))) and the activation volumes (DeltaV++(k(cat)) associated with hydrolysis of NMIA were calculated from the pressure dependence of the catalytic constants. Values of -DeltaV(K(m)) indicate that NMIA binds to an aromatic residue, presumed to be W82, the active site binding locus. Binding is accompanied by a release of water molecules from the gorge. Residue 70 controls the number of water molecules that are released upon substrate binding. The values of DeltaV++(k(cat)), which are positive for wild-type and faintly positive for D70G, clearly indicate that the catalytic steps are accompanied by re-entry of water into the gorge. Results support the premise that residue D70 is involved in the conformational stabilization of the active site gorge and in control of its hydration. A slow transient, preceding the steady state, was seen on a time scale of several minutes. The induction time rapidly increased with NMIA concentration to reach a limit at substrate saturation. Much shorter induction times (<1 min) were seen for hydrolysis of benzoylcholine (BzCh) by wild-type BuChE and for hydrolysis of butyrylthiocholine (BuSCh) by the active site mutants E197Q and E197Q/G117H. This slow transient was interpreted in terms of hysteresis without kinetic cooperativity. The hysteretic behavior of BuChE results from a slow conformational equilibrium between two enzyme states E and E'. NMIA binds only to the primed form E'. Kosmotropic salts and hydrostatic pressure were found to shift the equilibrium toward E'. The E-->E' transition is accompanied by a negative activation volume (DeltaV++(0)= -45+/-10 ml/mol), and the E' form is more compact than E. Hydration water in the gorge of E' appears to be more structured than in the unprimed form.     

Evolution of octopod sperm I: comparison of nuclear morphogenesis in Eledone and Octopus

Morphogenesis of the Eledone cirrhosa sperm nucleus, as studied by electron microscopic techniques, is compared with that of Octopus vulgaris. Both species of cephalopods belong to the family Octopodidae. The results indicate that extensive nuclear helicoidization during E. cirrhosa spermiogenesis is brought about by modifications of the function of structural components already present in the late steps of O. vulgaris spermiogenesis. In particular, changes in the regulation of perinuclear microtubule contraction in E. cirrhosa spermatids, as well as a decrease in basicity of protamines, promote nuclear helicoidization. Disulphide bond formation between protamine molecules fixes the completely helicoidal shape of the nucleus in mature sperm of E. cirrhosa.     

Seasonality in coastal benthic ecosystems

For historical reasons, knowledge about seasonality in the dynamics of marine benthic suspension feeders from temperate areas comes mainly from studies of cold temperate seas. Recent surveys of Mediterranean taxa show different patterns from those observed in cold temperate seas, which are characterized by winter dormancy. In the Mediterranean, summer dormancy predominates among taxa and appears to be related to energetic constraints. Temperature and food availability are crucial to the dynamics of benthic suspension feeders. However, because these factors tend to be positively correlated in cold temperate seas, it is difficult to distinguish between their effects. Such correlation does not occur in Mediterranean ecosystems. The contrast between recent studies in the Mediterranean and in other areas can help to disentangle confounded environmental controls.     

Dietary galacto-oligosaccharides prevent airway eosinophilia and hyperresponsiveness in a murine house dust mite-induced asthma model

Background

Allergic asthma is strongly associated with the exposure to house dust mite (HDM) and is characterized by eosinophilic pulmonary inflammation and airway hyperresponsiveness (AHR). Recently, there is an increased interest in using dietary oligosaccharides, also known as prebiotics, as a novel strategy to prevent the development of, or reduce, symptoms of allergy.

Aim

We investigated the preventive capacity of dietary galacto-oligosaccharides (GOS) compared to an intra-airway therapeutic treatment with budesonide on the development of HDM-induced allergic asthma in mice.

Methods

BALB/c mice were intranasally sensitized with 1 μg HDM on day 0 followed by daily intranasal challenge with PBS or 10 μg HDM on days 7 to 11. Two weeks prior to the first sensitization and throughout the experiment mice were fed a control diet or a diet containing 1% GOS. Reference mice were oropharyngeally instilled with budesonide (500 μg/kg) on days 7, 9, 11, and 13, while being fed the control diet. On day 14, AHR was measured by nebulizing increasing doses of methacholine into the airways. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lungs were collected.

Results

Sensitization and challenge with HDM resulted in AHR. In contrast to budesonide, dietary intervention with 1% GOS prevented the development of AHR. HDM sensitization and challenge resulted in a significant increase in BALF leukocytes numbers, which was suppressed by budesonide treatment and dietary intervention with 1% GOS. Moreover, HDM sensitization and challenge resulted in significantly enhanced concentrations of IL-6, CCL17, IL-33, CCL5 and IL-13 in lung tissue. Both dietary intervention with 1% GOS or budesonide treatment significantly decreased the HDM-induced increased concentrations of CCL5 and IL-13 in lung tissue, while budesonide also reduced the HDM-enhanced concentrations of IL-6 and CCL17 in lung tissue.

Conclusion

Not only did dietary intervention with 1% GOS during sensitization and challenge prevent the induction of airway eosinophilia and Th2-related cytokine and chemokine concentrations in the lung equally effective as budesonide treatment, it also prevented AHR development in HDM-allergic mice. GOS might be useful for the prevention and/or treatment of symptoms in asthmatic disease.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0171-0) contains supplementary material, which is available to authorized users.     

Effects of water velocity on picoplankton uptake by coral reef communities

In previous experiments, rates of picoplankton uptake into coral communities were controlled by sponge and ascidian biomass. Those experimental communities, however, had relatively few sponges and ascidians. In contrast, turbulent transport of particles into the momentum boundary layers can limit particle removal by layered, dense bivalve populations. In this study, the role of water velocity in controlling particulate nutrient-uptake by rubble communities was evaluated, in which the rubble was more completely covered by sponges and ascidians. Picoplankton uptake was proportional to concentration over a range of cell concentrations from 3.0 × 10⁵ to 9.5 × 10⁵ heterotrophic bacteria ml⁻¹, 4.1 × 10⁴ to 1.2 × 10⁵ Synechococcus sp. ml⁻¹ and 6.3 × 10³ to 1.8 × 10⁴ picoeukaryotes ml⁻¹. The first-order uptake rate constants, normalized to sponge and ascidian biomass, were similar to previous experimental communities. Picoplankton uptake increased 1.6-fold over a 7-fold change in water velocity, 0.05–0.35 m s⁻¹. This increase has been interpreted as a result of higher turbulent transport within the rough coral community (canopy), as indicated by a 1.6-fold increase in the bottom friction with increasing water velocity.     

Text-derived concept profiles support assessment of DNA microarray data for acute myeloid leukemia and for androgen receptor stimulation

Background  

High-throughput experiments, such as with DNA microarrays, typically result in hundreds of genes potentially relevant to the process under study, rendering the interpretation of these experiments problematic. Here, we propose and evaluate an approach to find functional associations between large numbers of genes and other biomedical concepts from free-text literature. For each gene, a profile of related concepts is constructed that summarizes the context in which the gene is mentioned in literature. We assign a weight to each concept in the profile based on a likelihood ratio measure. Gene concept profiles can then be clustered to find related genes and other concepts.