Mechanism of pH-independent Cleavage and Isomerization of 3′-Ribonucleotide Phosphodiesters

Abstract

The detailed mechanisms of pH-independent cleavage and isomerization reactions of the phosphodiester bond are evaluated by examining kinetics of hydrolytic reactions of selected mono- and dialkyl esters of 3′-uridylic acid. The mechanistic choices are made by comparing LFER's between reaction rates and acidity of the alkyl group of phosphodi- and triesters.     

Background levels of hydrogen cyanide in human breath measured by infrared cavity ring down spectroscopy

Hydrogen cyanide (HCN) in breath has been suggested as a diagnostic tool for cyanide poisoning and for cyanide-producing bacterial infections. To distinguish elevated levels of breath HCN, baseline data are needed. Background levels of HCN were measured in mixed exhaled air from 40 healthy subjects (26 men, 14 women, age 21–61 years; detection limit: 1.5?ppb; median: 4.4?ppb; range <1.5–14?ppb) by near-infrared cavity ring down spectroscopy (CRDS). No correlation was observed with smoking habits, recent meals or age. However, female subjects had slightly higher breath levels of HCN than male subjects. CRDS has not previously been used for this purpose.     

Ecological characteristics associated with high mobility in night-active moths

Mobility is an important factor influencing the range and persistence of local populations. However, mobility is very difficult to measure empirically and thus is poorly known in most taxa. Since ecological characteristics have been suggested as good estimators of mobility, we here explore the association between ecological characteristics and mobility. We surveyed night-active moths on a Swedish island, situated 16 km from the mainland, and compared ecological characteristics of the non-resident moths found on the island with those of a species pool of assumed potential vagrants from the neighbouring mainland. Species associated with high mobility were characterised by a large range, a high population density, an activity period during warm temperatures and by being habitat generalists or preferring open habitats. The generally assumed view of poly- and oligophagous species being more mobile than monophagous species was obscured by the effect of population density. Poly- and oligophagous species had higher population densities than did monophagous species, which probably explain their higher mobility found in this study. Our result highlights the need to consider the influence of ecological characteristics on mobility. This in turn will have implications for an increased understanding of distribution patterns, population persistence and how to prioritise conservation actions, especially since habitats and climate are under dramatic changes. In taxa where data on mobility are poor, ecological characteristics can be used as a proxy for mobility.     

Uncovering Wolbachia Diversity upon Artificial Host Transfer

The common endosymbiotic Wolbachia bacteria influence arthropod hosts in multiple ways. They are mostly recognized for their manipulations of host reproduction, yet, more recent studies demonstrate that Wolbachia also impact host behavior, metabolic pathways and immunity. Besides their biological and evolutionary roles, Wolbachia are new potential biological control agents for pest and vector management. Importantly, Wolbachia-based control strategies require controlled symbiont transfer between host species and predictable outcomes of novel Wolbachia-host associations. Theoretically, this artificial horizontal transfer could inflict genetic changes within transferred Wolbachia populations. This could be facilitated through de novo mutations in the novel recipient host or changes of haplotype frequencies of polymorphic Wolbachia populations when transferred from donor to recipient hosts. Here we show that Wolbachia resident in the European cherry fruit fly, Rhagoletis cerasi, exhibit ancestral and cryptic sequence polymorphism in three symbiont genes, which are exposed upon microinjection into the new hosts Drosophila simulans and Ceratitis capitata. Our analyses of Wolbachia in microinjected D. simulans over 150 generations after microinjection uncovered infections with multiple Wolbachia strains in trans-infected lines that had previously been typed as single infections. This confirms the persistence of low-titer Wolbachia strains in microinjection experiments that had previously escaped standard detection techniques. Our study demonstrates that infections by multiple Wolbachia strains can shift in prevalence after artificial host transfer driven by either stochastic or selective processes. Trans-infection of Wolbachia can claim fitness costs in new hosts and we speculate that these costs may have driven the shifts of Wolbachia strains that we saw in our model system.     

A Phase II,Randomized, Double-Blind,Placebo Controlled,Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects

Background

Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation.

Objective

The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects.

Methods

Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis.

Results

Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R² = 0.492 for HPT, R² = 0.538 for PPT, R² = 0.558 for HPTo and R² = 0.584 for PPTo).

Conclusions

The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre.     

Knee Adduction Moment and Medial Contact Force – Facts about Their Correlation during Gait

The external knee adduction moment is considered a surrogate measure for the medial tibiofemoral contact force and is commonly used to quantify the load reducing effect of orthopedic interventions. However, only limited and controversial data exist about the correlation between adduction moment and medial force. The objective of this study was to examine whether the adduction moment is indeed a strong predictor for the medial force by determining their correlation during gait. Instrumented knee implants with telemetric data transmission were used to measure tibiofemoral contact forces in nine subjects. Gait analyses were performed simultaneously to the joint load measurements. Skeletal kinematics, as well as the ground reaction forces and inertial parameters, were used as inputs in an inverse dynamics approach to calculate the external knee adduction moment. Linear regression analysis was used to analyze the correlation between adduction moment and medial force for the whole stance phase and separately for the early and late stance phase. Whereas only moderate correlations between adduction moment and medial force were observed throughout the whole stance phase (R² = 0.56) and during the late stance phase (R² = 0.51), a high correlation was observed at the early stance phase (R² = 0.76). Furthermore, the adduction moment was highly correlated to the medial force ratio throughout the whole stance phase (R² = 0.75). These results suggest that the adduction moment is a surrogate measure, well-suited to predicting the medial force ratio throughout the whole stance phase or medial force during the early stance phase. However, particularly during the late stance phase, moderate correlations and high inter-individual variations revealed that the predictive value of the adduction moment is limited. Further analyses are necessary to examine whether a combination of other kinematic, kinetic or neuromuscular factors may lead to a more reliable prediction of the force magnitude.     

Hippocampal Feedforward Inhibition Focuses Excitatory Synaptic Signals into Distinct Dendritic Compartments

Feedforward inhibition controls the time window for synaptic integration and ensures temporal precision in cortical circuits. There is little information whether feedforward inhibition affects neurons uniformly, or whether it contributes to computational refinement within the dendritic tree. Here we demonstrate that feedforward inhibition crucially shapes the integration of synaptic signals in pyramidal cell dendrites. Using voltage-sensitive dye imaging we studied the transmembrane voltage patterns in CA1 pyramidal neurons after Schaffer collateral stimulation in acute brain slices from mice. We observed a high degree of variability in the excitation-inhibition ratio between different branches of the dendritic tree. Many dendritic segments showed no depolarizing signal at all, especially the basal dendrites that received predominantly inhibitory signals. Application of the GABA_A receptor antagonist bicuculline resulted in the spread of depolarizing signals throughout the dendritic tree. Tetanic stimulation of Schaffer collateral inputs induced significant alterations in the patterns of excitation/inhibition, indicating that they are modified by synaptic plasticity. In summary, we show that feedforward inhibition restricts the occurrence of depolarizing signals within the dendritic tree of CA1 pyramidal neurons and thus refines signal integration spatially.