S1P lyase inhibition prevents lung injury following high pressure-controlled mechanical ventilation in aging mice.

Ventilator-induced Lung Injury (VILI) is characterized by hypoxia, inflammatory cytokine influx, loss of alveolar barrier integrity, and decreased lung compliance. Aging influences lung structure and function and is a predictive factor in the severity of VILI; however, the mechanisms of aging that influence the progression or increased susceptibility remain unknown. Aging impacts immune system function and may increase inflammation in healthy individuals. Recent studies suggest that the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) and the enzyme that degrades it S1P lyase (SPL) may be involved in lung pathologies including acute lung injury. It is unknown whether aging influences S1P and SPL expression that have been implicated in lung inflammation, injury, and cell apoptosis. We hypothesized that aging and injurious mechanical ventilation synergistically impair S1P levels and enhance S1P lyase (SPL) expression that amplifies alveolar barrier damage and diminishes pulmonary function. Young (2-3 mo) and old (20-25 mo) C57BL/6 mice were mechanically ventilated for 2 h using pressure-controlled mechanical ventilation (PCMV) at 45 cmH2O and 35 cmH2O, respectively. We assessed the impact of aging and PCMV on several indications of acute lung injury, immune cell recruitment, S1P levels and SPL activity. Furthermore, we evaluated the protective effects of inhibiting SPL by tetrahydroxybutylimidazol (THI) administration on the negative outcomes associated with aging and mechanical injury. PCMV exacerbated lung injury in old mice and increased neutrophil influx that was further exacerbated due to aging. SPL expression increased in the young and old ventilated mice and the old nonventilated group. THI treatment reduced several of the indicators of lung injury and resulted in elevated S1P levels in lung tissue and plasma from mice that were injured from mechanical ventilation. CD80 and CD206 activation markers of alveolar and interstitial macrophages were also influenced by THI. SPL inhibition may be a viable therapeutic approach for patients requiring mechanical ventilation by preventing or regulating the exaggerated inflammatory response and reducing lung injury.

Insect swarms can be bound together by repulsive forces.

The cohesion of insect swarms has been attributed to the fact that the resultant internal interactions of the swarming insects produce, on the average, a centrally attractive force that acts on each individual. Here it is shown how insect swarms can also be bound together by centrally forces that on the average are repulsive (outwardly directed from the swarm centres). This is predicted to arise when velocity statistics are heterogeneous (position-dependent). Evidence for repulsive forces is found in laboratory swarms of Chironomus riparius midges. In homogeneous swarms, the net inward acceleration balances the tendency of diffusion (stochastic noise) to transport individuals away from the centre of the swarm. In heterogenous swarms, turbophoresis --the tendency for individuals to migrate in the direction of decreasing kinetic energy-- is operating. The new finding adds to the growing realization that insect swarms are analogous to self-gravitating systems. By acting in opposition to central attraction (gravity), the effects of heterogeneous velocities (energies) are analogous to the effects of dark energy. The emergence of resultant forces from collective behaviours would not be possible if individual flight patterns were themselves unstable. It is shown how individuals reduce the potential for the loose of flight control by minimizing the influence of jerks to which they are subjected.

Inflammation and Monocyte Recruitment due to Aging and Mechanical Stretch in Alveolar Epithelium are Inhibited by the Molecular Chaperone 4-phenylbutyrate.

INTRODUCTION: Ventilator-Induced lung injury (VILI) is a form of acute lung injury that is initiated or exacerbated by mechanical ventilation. The aging lung is also more susceptible to injury. Harmful mechanical stretch of the alveolar epithelium is a recognized mechanism of VILI, yet little is known about how mechanical stretch affects aged epithelial cells. Disruption to Endoplasmic Reticulum (ER) homeostasis results in a condition known as ER stress that leads to disruption of cellular homeostasis, apoptosis, and inflammation. ER stress is increased with aging and other pathological stimuli. We hypothesized that age and mechanical stretch increase alveolar epithelial cells' proinflammatory responses that are mediated by ER stress. Furthermore, we believed that inhibition of this upstream mechanism with 4PBA, an ER stress reducer, alleviates subsequent inflammation and monocyte recruitment. METHODS: Type II alveolar epithelial cells (ATII) were harvested from C57Bl6/J mice 2 months (young) and 20 months (old) of age. The cells were cyclically stretched at 15% change in surface area for up to 24 hours. Prior to stretch, groups were administered 4PBA or vehicle as a control. RESULTS: Mechanical stretch and age upregulated ER stress and proinflammatory MCP-1/CCL2 and MIP-1ß/CCL4 chemokine expression in ATIIs. Age-matched and mismatched monocyte recruitment by ATII conditioned media was also quantified. CONCLUSIONS: Age increases susceptibility to stretch-induced ER stress and downstream inflammatory gene expression in a primary ATII epithelial cell model. Administration of 4PBA attenuated the increased ER stress and proinflammatory responses from stretch and/or age and significantly reduced monocyte migration to ATII conditioned media.

Langevin dynamics encapsulate the microscopic and emergent macroscopic properties of midge swarms.

In contrast to bird flocks, fish schools and animal herds, midge swarms maintain cohesion but do not possess global order. High-speed imaging techniques are now revealing that these swarms have surprising properties. Here, I show that simple models found on the Langevin equation are consistent with this wealth of recent observations. The models predict correctly that large accelerations, exceeding 10 g, will be common and they predict correctly the coexistence of core condensed phases surrounded by dilute vapour phases. The models also provide new insights into the influence of environmental conditions on swarm dynamics. They predict that correlations between midges increase the strength of the effective force binding the swarm together. This may explain why such correlations are absent in laboratory swarms but present in natural swarms which contend with the wind and other disturbances. Finally, the models predict that swarms have fluid-like macroscopic mechanical properties and will slosh rather than slide back and forth after being abruptly displaced. This prediction offers a promising avenue for future experimentation that goes beyond current quasi-static testing which has revealed solid-like responses.

Apnea, bradycardia and desaturation spells in premature infants: impact of a protocol for the duration of 'spell-free' observation on interprovider variability and readmission rates.

OBJECTIVE: To study the impact of implementing a protocol to standardize the duration of observation in preterm infants with apnea/bradycardia/desaturation spells before hospital discharge on length of stay (LOS) and readmission rates. STUDY DESIGN: A protocol to standardize the duration of in-hospital observation for preterm infants with apnea, bradycardia and desaturation spells who were otherwise ready for discharge was implemented in December 2013. We evaluated the impact of this protocol on the LOS and readmission rates of very low birth weight infants (VLBW). Data on readmission for apnea and an apparent life-threatening event (ALTE) within 30 days of discharge were collected. The pre-implementation epoch (2011 to 2013) was compared to the post-implementation period (2014 to 2016). RESULTS: There were 426 and 368 VLBW discharges before and after initiation of the protocol during 2011 to 2013 and 2014 to 2016, respectively. The LOS did not change with protocol implementation (66±42 vs 64±42 days before and after implementation of the protocol, respectively). Interprovider variability on the duration of observation for apneic spells (F-8.8, P=0.04) and bradycardia spells (F-17.4, P<0.001) decreased after implementation of the protocol. The readmission rate for apnea/ALTE after the protocol decreased from 12.1 to 3.4% (P=0.01). CONCLUSION: Implementing an institutional protocol for VLBW infants to determine the duration of apnea/bradycardia/ desaturation spell-free observation period as recommended by the American Academy of Pediatrics clinical report did not prolong the LOS but effectively reduced interprovider variability and readmission rates.

Extending Lévy search theory from one to higher dimensions: Lévy walking favours the blind.

A diverse range of organisms, including T cells, E. coli, honeybees, sharks, turtles, bony fish, jellyfish, wandering albatrosses and even human hunter-gatherers have movement patterns that can be approximated by Lévy walks (LW; sometimes called Lévy flights in the biological and ecological literature). These observations lend support to the 'Lévy flight foraging hypothesis' which asserts that natural selection should have led to adaptations for Lévy flight foraging, because Lévy flights can optimize search efficiencies. The hypothesis stems from a rigorous theory of one-dimensional searching and from simulation data for two-dimensional searching. The potential effectiveness of three-dimensional Lévy searches has not been examined but is central to a proper understanding of marine predators and T cells which have provided the most compelling empirical evidence for LW. Here I extend Lévy search theory from one to three dimensions. The new theory predicts that three-dimensional Lévy searching can be advantageous but only when targets are large compared with the perceptual range of the searchers, i.e. only when foragers are effectively blind and need to come into contact with a target to establish its presence. This may explain why effective blindness is a common factor among three-dimensional Lévy walkers.

Lévy flight movement patterns in marine predators may derive from turbulence cues.

The Lévy-flight foraging hypothesis states that because Lévy flights can optimize search efficiencies, natural selection should have led to adaptations for Lévy flight foraging. Some of the strongest evidence for this hypothesis has come from telemetry data for sharks, bony fish, sea turtles and penguins. Here, I show that the programming for these Lévy movement patterns does not need to be very sophisticated or clever on the predator's part, as these movement patterns would arise naturally if the predators change their direction of travel only after encountering patches of relatively strong turbulence (a seemingly natural response to buffeting). This is established with the aid of kinematic simulations of three-dimensional turbulence. Lévy flights movement patterns are predicted to arise in all but the most quiescent of oceanic waters.

Selection pressures give composite correlated random walks Lévy walk characteristics.

Composite correlated random walks have been posited as a strong alternative to Lévy walks as models of multi-scale forager movement patterns. Here it is shown that if plastic then intrinsic composite correlated random walks will, under selection pressures, evolve to resemble optimal Lévy walks when foraging is non-destructive. The fittest composite correlated random walkers are found to be those that come closest to being optimal Lévy walkers. This may explain why such a diverse range of foragers have movement patterns that can be approximated by optimal Lévy walks and shows that the 'Lévy-flight foraging' hypothesis has a broad hinterland. The new findings are consistent with recent observations of mussels Mytilus edulis and the Australian desert ant Melophorus bagoti which suggest that animals approximate a Lévy walk by adopting an intrinsic composite movement strategy with different modes.

Incorporating sweeps and ejections into Lagrangian stochastic models of spore trajectories within plant canopy turbulence: modeled contact distributions are heavy-tailed.

ABSTRACT The turbulent dispersal of fungal spores within plant canopies is very different from that within atmospheric boundary-layers and closely analogous to dispersal within turbulent mixing-layers. The process is dominated by the presence of large coherent flow structures, high-velocity downdrafts (sweeps) and updrafts (ejections), that punctuate otherwise quiescent flow. Turbulent dispersion within plant canopies is best predicted by Lagrangian stochastic (particle-tracking) models because other approaches (e.g., diffusion models and similarity theory) are either inappropriate or invalid. Nonetheless, attempts to construct such models have not been wholly successful. Accounting for sweeps and ejections has substantially worsened rather than improved model agreement with experimental dispersion data. Here we show how this long-standing difficulty with the formulation of Lagrangian stochastic models can be overcome. The new model is shown to be in good agreement with data from a carefully controlled, well-documented wind-tunnel study of scalar dispersion within plant canopy turbulence. Equally good agreement with this data is obtained using Thomson's (1987) Gaussian model. This bolsters confidence in the application of this simple model to the prediction of spore dispersal within plant canopy turbulence. Contact distributions-the probability distribution function for the distance of viable fungal spore movement until deposition-are predicted to have "heavy" inverse power-law tails. It is known that heavy-tailed contact distributions also characterize the dispersal of spores which pass through the canopy turbulence and enter into the overlying atmospheric boundary-layer. Plant disease epidemics due to the airborne dispersal of fungal spores are therefore predicted to develop as accelerating waves over a vast range of scales-from the within field scale to intercontinental scales. This prediction is consistent with recent analyses of field and historical data for rusts in wheat. Such plant disease epidemics are shown to be governed by space-fractional diffusion equations and by Lévy flights.

Distinguishing between Lévy walks and strong alternative models.

Lévy walks are a widely used but contentious model of animal movement patterns. They are contentious because they have been wrongly ascribed to some animal species through use of incorrect statistical methods and because they have not been adequately compared against strong alternative models, such as composite correlated random walks. This lack of comparison has been partly because the strong alternative models do not have simple likelihood functions. Here I show that power-spectra and the distribution of the first significant digits (the leading non-zero digits) of the step lengths can distinguish between Lévy walks and composite correlated random walks. Using these diagnostic tools, I bolster previous claims that honey bees use a movement strategy that can be approximated by Lévy walks when searching for their hive or for a food source.

Fitness-maximizing foragers can use information about patch quality to decide how to search for and within patches: optimal Levy walk searching patterns from optimal foraging theory.

Optimal foraging theory shows how fitness-maximizing foragers can use information about patch quality to decide how to search within patches. It is amply supported by empirical studies. Nonetheless, the theory largely ignores the fact that foragers may need to search for patches as well as for the targets within them. Here, using an exact but simple mathematical argument, it is shown how foragers can use information about patch quality to facilitate the execution of Lévy walk movement patterns with µ = 2 at inter-patch scales. These movement patterns are advantageous when searching for patches that are not depleted or rejected once visited but instead remain profitable. The analytical results are verified by the results of numerical simulations. The findings bring forth an innovative theoretical synthesis of searching for and within patches and, suggest that foragers' memories may be adaptive under spatially heterogeneous reward schedules.

Targeted gene delivery of BMPR2 attenuates pulmonary hypertension.

Pulmonary arterial hypertension (PAH) remains a fatal disease despite modern pharmacotherapy. Mutations in the gene for bone morphogenetic protein receptor type II (BMPR2) lead to reduced BMPR2 expression, which is causally linked to PAH. BMPR2 is predominantly expressed on pulmonary endothelium and has complex interactions with transforming growth factor (TGF)-ß signalling mechanisms. Our objectives were to assess the effect on PAH of upregulating BMPR2 by targeted adenoviral BMPR2 gene delivery to the pulmonary vascular endothelium. We used two established rat models of PAH: chronic hypoxia and monocrotaline (MCT). In both hypertensive models, those receiving BMPR2 had less right ventricular hypertrophy, less pulmonary vascular resistance, improved cardiac function and reduced vascular remodelling. In the MCT model, there was an increase in TGF-ß, which was prevented by BMPR2 treatment. In vitro, TGF-ß1-induced endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells, which was associated with reduced BMPR2 expression. EndMT was partially ameliorated by stimulating BMPR2 signalling with appropriate ligands even in the ongoing presence of TGF-ß1. Collectively, these results indicate therapeutic potential for upregulation of the BMPR2 axis in PAH, which may be, in part, mediated by countering the remodelling effects of TGF-ß.

Truncated Lévy walks are expected beyond the scale of data collection when correlated random walks embody observed movement patterns.

Translating observations taken at small spatio-temporal scales into expected patterns at greater scales is a major challenge in spatial ecology because there is typically insufficient relevant information. Here, it is shown that truncated Lévy walks are the most conservative, maximally non-committal description of movement patterns beyond the scale of data collection when correlated random walks characterize observed movements and when there is partial information about landscape and behavioural heterogeneity. This provides a new conceptual basis for Lévy walks that is divorced from optimal searching theory and free from the difficulties with discerning their presence in empirical data.

Exponential and power-law contact distributions represent different atmospheric conditions.

It is well known that the dynamics of plant disease epidemics are very sensitive to the functional form of the contact distribution?the probability distribution function for the distance of viable fungal spore movement until deposition. Epidemics can take the form of a constant-velocity travelling wave when the contact distribution is exponentially bounded. Fat-tailed contact distributions, on the other hand, lead to epidemic spreads that accelerate over time. Some empirical data for contact distributions can be well represented by negative exponentials while other data are better represented by fat-tailed inverse power laws. Here we present data from numerical simulations that suggest that negative exponentials and inverse power laws are not competing candidate forms of the contact distribution but are instead representative of different atmospheric conditions. Contact distributions for atmospheric boundary-layers with stabilities ranging from strongly convective (a hot windless day time scenario) to stable stratification (a cold windy night time scenario) but without precipitation events are calculated using well-established state-of-the-art Lagrangian stochastic (particle tracking) dispersal models. Contact distributions are found to be well represented by exponentials for strongly convective conditions; a -3/2 inverse power law for convective boundary-layers with wind shear; and by a -2/3 inverse power law for stably stratified conditions.

Chemotaxis can provide biological organisms with good solutions to the travelling salesman problem.

The ability to find good solutions to the traveling salesman problem can benefit some biological organisms. Bacterial infection would, for instance, be eradicated most promptly if cells of the immune system minimized the total distance they traveled when moving between bacteria. Similarly, foragers would maximize their net energy gain if the distance that they traveled between multiple dispersed prey items was minimized. The traveling salesman problem is one of the most intensively studied problems in combinatorial optimization. There are no efficient algorithms for even solving the problem approximately (within a guaranteed constant factor from the optimum) because the problem is nondeterministic polynomial time complete. The best approximate algorithms can typically find solutions within 1%-2% of the optimal, but these are computationally intensive and can not be implemented by biological organisms. Biological organisms could, in principle, implement the less efficient greedy nearest-neighbor algorithm, i.e., always move to the nearest surviving target. Implementation of this strategy does, however, require quite sophisticated cognitive abilities and prior knowledge of the target locations. Here, with the aid of numerical simulations, it is shown that biological organisms can simply use chemotaxis to solve, or at worst provide good solutions (comparable to those found by the greedy algorithm) to, the traveling salesman problem when the targets are sources of a chemoattractant and are modest in number (n < 10). This applies to neutrophils and macrophages in microbial defense and to some predators.

Pilot trial of late booster doses of surfactant for ventilated premature infants.

OBJECTIVE: Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant. STUDY DESIGN: A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period. RESULT: For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO(2) × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment. CONCLUSION: Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.

Maze-solving by chemotaxis.

Here, we report on numerical simulations showing that chemotaxis will take a body through a maze via the shortest possible route to the source of a chemoattractant. This is a robust finding that does not depend on the geometrical makeup of the maze. The predictions are supported by recent experimental studies which have shown that by moving down gradients in pH , a droplet of organic solvent can find the shortest of multiple possible paths through a maze to an acid-soaked exit. They are also consistent with numerical and experimental evidence that plant-parasitic nematodes take the shortest route through the labyrinth of air-filled pores within soil to preferred host plants that produce volatile chemoattractants. The predictions support the view that maze-solving is a robust property of chemotaxis and is not specific to particular kinds of maze or to the fractal structure of air-filled channels within soils.

Animals that randomly reorient at cues left by correlated random walkers do the Lévy walk.

For many years, correlated random walks have been the dominant conceptual models used in describing nonoriented animal movements. Here it is shown that Lévy walk movement patterns will arise from animals that randomly reorient on detection of odor trails and/or scent marks left by correlated random walkers. The emergent Lévy walk movement patterns are advantageous when one is randomly searching for sparsely distributed resources. Consequently, there will be strong selection pressures for the aforementioned reorientation process when resources are sparsely distributed within unpredictable environments inhabited by correlated random walkers. This selection pressure may drive the evolution of Lévy walk strategies in these landscapes. The mechanism may account for the Lévy walk movement patterns of microzooplankton in the presence of mobile phytoplankton and those of a species of African jackal that scavenges within landscapes inhabited by other animal species. These findings show that Lévy walks and fractal scaling do not exist outside of the correlated random-walk paradigm, as is widely thought, but are instead natural consequences of it.

Optimising the success of random destructive searches: Lévy walks can outperform ballistic motions.

We re-evaluate the long standing and widely held belief that ballistic movements (i.e. straight-lines movements) outperform Lévy walks when searching for targets that once located are not revisited. The belief stems from the results of analyses of one-dimensional searches, analyses which have not accounted for the fact that target numbers can be continually depleted during the search process. This is a crucial oversight because continual depletion promotes the searching efficiencies of some Lévy walks above that of ballistic motion. The continual depletion effect is not so important for two- and three-dimensional searches. Nevertheless, we show that Lévy walks and ballistic movements can be equally or almost equally effective when searching within two- and three-dimensional environments for randomly and sparsely distributed targets or when searching for targets that are occasionally concealed. We also show that Lévy walks are advantageous when searching for targets that can occasionally evade capture. These situations represent common predator-prey interactions in which predators are involved in 'imperfect destructive' searches. Our model suggests that accounting for coevolutionary arms races at the predator-prey detection/reaction scales can explain to some extent Lévy walk searching patterns of predators at larger scales. This result provides new insights into the Lévy walk movement patterns of some destructive foragers.