Extended hypoxia in the alfalfa leafcutting bee, Megachile rotundata, increases survival but causes sub-lethal effects

AbstractMany insects are tolerant of hypoxic conditions, but survival may come at a cost to long-term health. The alfalfa leaf-cutting bee, Megachile rotundata, develops in brood cells inside natural cavities, and may be exposed to hypoxic conditions for extended periods of time. Whether M. rotundata is tolerant of hypoxia, and whether exposure results in sub-lethal effects, has never been investigated. Overwintering M. rotundata prepupae were exposed to 10%, 13%, 17%, 21% and 24% O2 for 11months. Once adults emerged, five indicators of quality — emergence weight, body size, feeding activity, flight performance, and adult longevity, — were measured to determine whether adult bees that survived past exposure to hypoxia were competent pollinators. M. rotundata prepupae are tolerant of hypoxic condition and have higher survival rates in hypoxia, than in normoxia. Under hypoxia, adult emergence rates did not decrease over the 11months of the experiment. In contrast, bees reared in normoxia had decreased emergence rates by 8months, and were dead by 11months. M. rotundata prepupae exposed to extended hypoxic conditions had similar emergence weight, head width, and cross-thorax distance compared to bees reared in standard 21% oxygen. Despite no significant morphological differences, hypoxia-exposed bees had lower feeding rates and shorter adult lifespans. Hypoxia may play a role in post-diapause physiology of M. rotundata, with prepupae showing better survival under hypoxic conditions. Extended exposure to hypoxia, while not fatal, causes sub-lethal effects in feeding rates and longevity in the adults, indicating that hypoxia tolerance comes at a cost

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model

Treatment with antenatal steroids (ANS) is standard practice for reducing the risk of respiratory distress in the preterm infant. Despite clear overall benefits when appropriately administered, many fetuses fail to derive benefit from ANS therapies. In standardized experiments using a pregnant sheep model, we have demonstrated that around 40% of ANS-exposed lambs did not have functional lung maturation significantly different from that of saline-treated controls. Surfactant protein A is known to play an important role in lung function. In this genotyping study, we investigated the potential correlation between polymorphisms in SFTPA1, messenger RNA and protein levels, and ventilation outcomes in animals treated with ANS. 45 preterm lambs were delivered 48 h after initial ANS therapy and 44 lambs were delivered 8 days after initial ANS therapy. The lambs were ventilated for 30 min after delivery. SFTPA1 mRNA expression in lung tissue was not correlated with arterial blood PaCO2 values at 30 min of ventilation in lambs delivered 48 h after treatment. SFTPA1 protein in lung tissue was significantly correlated with PaCO2 at 30 min of ventilation in lambs ventilated both 48 h and 8 days after ANS treatment. Six different single nucleotide polymorphisms (SNPs) in the Ovis aries SFTPA1 sequence were detected by Sanger Sequencing. No individual SNPs or SNP haplotypes correlated with alterations in PaCO2 at 30 min of ventilation or SFTPA1 protein levels in the lung. For the subset of animals analyzed in the present study, variable lung maturation responses to ANS therapy were not associated with mutations in SFTPA1

Compact phases of polymers with hydrogen bonding

We propose an off-lattice model for a self-avoiding homopolymer chain with two different competing attractive interactions, mimicking the hydrophobic effect and the hydrogen bond formation respectively. By means of Monte Carlo simulations, we are able to trace out the complete phase diagram for different values of the relative strength of the two competing interactions. For strong enough hydrogen bonding, the ground state is a helical conformation, whereas with decreasing hydrogen bonding strength, helices get eventually destabilized at low temperature in favor of more compact conformations resembling $\beta$-sheets appearing in native structures of proteins. For weaker hydrogen bonding helices are not thermodynamically relevant anymore.Comment: 5 pages, 3 figures; revised version published in PR

Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birth weights when administered to pregnant sheep in combination with betamethasone acetate

Background Antenatal corticosteroid (ACS) therapy is standard of care for women at imminent risk of preterm labour. Despite this, much remains to be understood regarding an optimal (maximum benefit, minimal risk of side effects) ACS dosing strategy. Although conveying overall benefit when given to the right patient at the right time, ACS treatment efficacy is highly variable, and is not risk-free. Building on earlier findings, we hypothesized that when administered in combination with slow-release betamethasone acetate, betamethasone phosphate and the high materno-fetal betamethasone concentrations it generates are redundant for fetal lung maturation. Objective Using an established sheep model of prematurity and post-natal ventilation of the preterm lamb, we aimed to compare the pharmacodynamic effects of a low-dose treatment with betamethasone acetate only against a standard dose of betamethasone phosphate and betamethasone acetate as recommended by the American College of Obstetricians and Gynaecologists for women at risk of imminent preterm delivery between 24 and 35+6 weeks’ gestation. Methods Ewes carrying a single fetus at 122±1 d gestational age (term=150d) were randomized to receive either: i) maternal intramuscular injections of sterile saline (the Saline Negative Control Group, n=12), ii) two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + acetate spaced by 24h (the Beta-P+Ac Group, n=12); or iii) two maternal intramuscular injections of 0.125 mg/kg betamethasone acetate spaced by 24h (the Beta-Ac Group, n=11). Fetuses were surgically delivered 48h after treatment initiation and ventilated for 30 minutes to determine functional lung maturation. Fetuses were euthanized after ventilation and lung were collected for analysis using quantitative polymerase chain reaction and western blot assays. Fetal plasma ACTH levels were measured in the cord blood samples taken at delivery. Results Preterm lambs were defined as either ACS treatment responders or non-responders using an arbitrary cut-off, being a PaCO2 level at 30 minutes of ventilation being more extreme than two standard deviations from the mean value of the normally-distributed Saline Control Group values. Relative to Saline Control Group animals, both ACS treatment group animals showed significantly improved lung physiological responses (blood gas and ventilation data) and had a biochemical signature (mRNA and surfactant protein assays) consistent with functional maturation. However, the Beta-Ac Group had a significantly higher treatment response rate than the Beta-P+Ac Group. These physiological results were strongly correlated to the amount of surfactant protein A. Birth weight was lower in Beta-P+Ac Group and the fetal HPA axis was supressed to a greater extent in the Beta-P+Ac Group. Conclusion Low dose ACS therapy solely employing Beta-Ac was sufficient for fetal lung maturation. The elevated materno-fetal betamethasone concentrations associated with the co-administration of betamethasone phosphate did not additionally improve lung maturation, but were associated with greater HPA axis suppression, a lower ACS treatment response rate, and lower birth weight – outcomes not desirable in a clinical setting. These data warrant a clinical investigation of sustained, low-dose ACS treatments that avoid high materno-fetal betamethasone exposures

Numerical comparison of two approaches for the study of phase transitions in small systems

We compare two recently proposed methods for the characterization of phase transitions in small systems. The validity and usefulness of these approaches are studied for the case of the q=4 and q=5 Potts model, i.e. systems where a thermodynamic limit and exact results exist. Guided by this analysis we discuss then the helix-coil transition in polyalanine, an example of structural transitions in biological molecules.Comment: 16 pages and 7 figure

Ground-state properties of tubelike flexible polymers

In this work we investigate structural properties of native states of a simple model for short flexible homopolymers, where the steric influence of monomeric side chains is effectively introduced by a thickness constraint. This geometric constraint is implemented through the concept of the global radius of curvature and affects the conformational topology of ground-state structures. A systematic analysis allows for a thickness-dependent classification of the dominant ground-state topologies. It turns out that helical structures, strands, rings, and coils are natural, intrinsic geometries of such tubelike objects

Variability in the efficacy of a standardized antenatal steroid treatment is not due to maternal or fetal plasma drug levels. Evidence from a sheep model of pregnancy.

Background Antenatal steroids (ANS) are standard of care for women judged to be at imminent risk of preterm delivery. Worldwide, there is significant variation in ANS dosing strategy, selection for treatment criteria, and agent choice. This, combined with very limited optimization of ANS use per se means that treatment efficacy is highly variable and the rate of respiratory distress syndrome is decreased perhaps as little as 40%. In some cases, ANS use is associated with limited benefit and potential harm. Objective We hypothesized that individual differences in maternal and fetal steroid exposure would contribute to observed variability in ANS treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between materno-fetal steroid exposure and ANS treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation. Methods Ewes carrying a single fetus had surgery to catheterize a fetal and maternal jugular vein at 119 days’ gestation. Animals recovered for 24h before being randomized to either: i) a single maternal intramuscular injection (IM) of 2ml saline (Negative Control Group, n=10); or ii) a single maternal IM of 0.25mg/kg betamethasone phosphate + acetate (ANS Group, n=20). Serial maternal and fetal plasma samples were collected from each animal over 48h before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction. Results One animal of the Control Group and one animal from the ANS Group had did not complete their treatment protocol and were removed from analyses. Animals in the ANS Group were divided into a Responder (n=12/19) Sub-Group and a Non-Responder Sub-Group (n=7/19) using a cut-off of a PaCO2 at 30 minutes ventilation within 2SD of the mean value from saline-treated Negative Control Group animals. While ANS improved fetal lung maturation in the undivided ANS group, and in the Responder Sub-Group both physiologically (blood gas and ventilation related data) and biochemically (mRNA expression related to fetal lung maturation), these values were not improved relative to saline-treated Control Group animals in the ANS Non-Responder Sub-Group. Interestingly, no differences in betamethasone distribution, clearance, or protein binding were identified between the ANS Responder and Non-Responder Sub-Groups. Conclusion This study correlated individual materno-fetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation not significantly different to saline-treated Control Group animals. These non-responsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of ANS therapy is not solely determined by materno-fetal drug levels, and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid-driven signaling

Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis

Background Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks’ gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury. We aimed to use an extremely preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela in response to established intra-amniotic (IA) lipopolysaccharide (LPS) exposure. We hypothesized that rytvela would reduce LPS-induced IA inflammation in amniotic fluid (AF) and fetal tissues. Methods Sheep with a single fetus at 95 days gestation (estimated fetal weight 1.0 kg) had surgery to place fetal jugular and IA catheters. Animals were recovered for 48 hours before being randomized to either: i) IA administration of 2 ml saline 24 hours before 2 ml IA and 2 ml fetal intravenous (IV) administration of saline (Saline Group, n = 7); ii) IA administration of 10 mg LPS in 2 ml saline 24 hours before 2 ml IA and 2 ml fetal IV saline (LPS Group, n = 10); 3) IA administration of 10 mg LPS in 2 ml saline 24 hours before 0.3 mg/fetal kg IA and 1 mg/fetal kg fetal IV rytvela in 2 ml saline, respectively (LPS + rytvela Group, n = 7). Serial AF samples were collected for 120 h. Inflammatory responses were characterized by quantitative polymerase chain reaction (qPCR), histology, fluorescent immunohistochemistry, enzyme-linked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis. Results LPS-treated animals had endotoxin and AF monocyte chemoattractant protein (MCP)-1 concentrations that were significantly higher at 24 hours (immediately prior to rytvela administration) relative to values from Saline Group animals. Following rytvela administration, the average MCP-1 concentrations in the AF were significantly lower in the LPS + rytvela Group relative to in the LPS Group. In delivery samples, the expression of IL-1β in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group. Conclusion A single dose of rytvela was associated with partial, modest inhibition in the expression of a panel of cytokines/chemokines in fetal tissues undergoing an active inflammatory response

Effects of intra-amniotic lipopolysaccharide and maternal betamethasone on brain inflammation in fetal sheep

Rationale: Chorioamnionitis and antenatal glucocorticoids are common exposures for preterm infants and can affect the fetal brain, contributing to cognitive and motor deficits in preterm infants. The effects of antenatal glucocorticoids on the brain in the setting of chorioamnionitis are unknown. We hypothesized that antenatal glucocorticoids would modulate inflammation in the brain and prevent hippocampal and white matter injury after intra-amniotic lipopolysaccharide (LPS) exposure. Methods: Time-mated ewes received saline (control), an intra-amniotic injection of 10 mg LPS at 106d GA or 113d GA, maternal intra-muscular betamethasone (0.5 mg/kg maternal weight) alone at 113d GA, betamethasone at 106d GA before LPS or betamethasone at 113d GA after LPS. Animals were delivered at 120d GA (term=150d). Brain structure volumes were measured on T2-weighted MRI images. The subcortical white matter (SCWM), periventricular white matter (PVWM) and hippocampus were analyzed for microglia, astrocytes, apoptosis, proliferation, myelin and pre-synaptic vesicles. Results: LPS and/or betamethasone exposure at different time-points during gestation did not alter brain structure volumes on MRI. Betamethasone alone did not alter any of the measurements. Intra-amniotic LPS at 106d or 113d GA induced inflammation as indicated by increased microglial and astrocyte recruitment which was paralleled by increased apoptosis and hypomyelination in the SCWM and decreased synaptophysin density in the hippocampus. Betamethasone before the LPS exposure at 113d GA prevented microglial activation and the decrease in synaptophysin. Betamethasone after LPS exposure increased microglial infiltration and apoptosis. Conclusion: Intra-uterine LPS exposure for 7d or 14d before delivery induced inflammation and injury in the fetal white matter and hippocampus. Antenatal glucocorticoids aggravated the inflammatory changes in the brain caused by pre-existing intra-amniotic inflammation. Antenatal glucocorticoids prior to LPS reduced the effects of intra-uterine inflammation on the brain. The timing of glucocorticoid administration in the setting of chorioamnionitis can alter outcomes for the fetal brain

Self-control and early adolescent antisocial behavior: A longitudinal analysis

Contains fulltext : 73179.pdf (publisher's version ) (Closed access)The article discusses a three-wave longitudinal study that investigates the relationship between self-control and aggressive and delinquent behavior of early adolescent boys and girls. The sample consists of 1,012 Dutch adolescents (mean age = 12.3) in their first year of secondary education. Structural equation modeling analyses reveal that high levels of self-control consistently decrease aggressive and delinquent behavior in the subsequent 6 months follow-up intervals. Results for the total sample do not support the hypothesis that self-control is influenced by previous levels of aggression or delinquency. For boys, the partial evidence found indicates reciprocal effects of self-control and delinquency.21 p