Identification and characterization of Kava-derived compounds mediating TNF-alpha suppression

There is a substantial unmet need for new classes of drugs that block TNF-α-mediated inflammation, and particularly for small molecule agents that can be taken orally. We have screened a library of natural products against an assay measuring TNF-α secretion in lipopolysaccharide-stimulated THP-1 cells, seeking compounds capable of interfering with the TNF-α-inducing transcription factor lipopolysaccharide-induced TNF-α factor. Among the active compounds were several produced by the kava plant (Piper mysticum), extracts of which have previously been linked to a range of therapeutic effects. When tested in vivo, a representative of these compounds, kavain, was found to render mice immune to lethal doses of lipopolysaccharide. Kavain displays promising pharmaceutical properties, including good solubility and high cell permeability, but pharmacokinetic experiments in mice showed relatively rapid clearance. A small set of kavain analogs was synthesized, resulting in compounds of similar or greater potency in vitro compared with kavain. Interestingly, a ring-opened analog of kavain inhibited TNF-α secretion in the cell-based assay and suppressed lipopolysaccharide-induced TNF-α factor expression in the same cells, whereas the other compounds inhibited TNF-α secretion without affecting lipopolysaccharide-induced TNF-α factor levels, indicating a potential divergence in mechanism of action.

Frequency, intensity and duration of physical tasks performed by Australian rural firefighters during bushfire suppression

The current study combined, for the first time, video footage of individual firefighters wearing heart rate monitors and personal GPS units to quantify the frequency, duration and intensity of tasks performed by Australian rural fire crews when. suppressing bushfires. Across the four fireground 'shifts', the firefighters performed 34 distinct fireground tasks. Per shift, the task frequency ranged from once (raking fireline in teams, carrying a quick fill pump) to 103 times {lateral repositioning of a 38-mm charged firehose) .. The tasks lasted between 4 ± 2 s (bowling out 3-8-mm firehose) and 461 ± 387 s (raking fireline in teams). The task intensity~ as measured by average heart rate ranged between 97 ± 16 beats·min-1 (55.7 ± 8.7. %HRmax) and 157 ± 15 beats·min-1 (86.2 ± 10.8 %HRmax)· The tasks were performed a speeds that ranged from 0.12 ± 0.08 m·s-1 (manual hose retraction of 38-mm charged firehose) to 0.79 ± 0.40 m·s-1 (carrying a 38-mm coiled hose). Tasks found to be simultaneously frequent, long and intense (or two of these three) are likely to form the basis for job-specific testing of Australian rural firefighters suppressing bushfires.

Medial prefrontal cortex suppression of the hypothalamic–pituitary–adrenal axis response to a physical stressor, systemic delivery of interleukin-1β

Previous studies have shown that the medial prefrontal cortex can suppress the hypothalamic–pituitary–adrenal axis response to stress. However, this effect appears to vary with the type of stressor. Furthermore, the absence of direct projections between the medial prefrontal cortex and corticotropin-releasing factor cells at the apex of the hypothalamic–pituitary–adrenal axis suggest that other brain regions must act as a relay when this inhibitory mechanism is activated. In the present study, we first established that electrolytic lesions involving the prelimbic and infralimbic medial prefrontal cortex increased plasma adrenocorticotropic hormone levels seen in response to a physical stressor, the systemic delivery of interleukin-1β. However, medial prefrontal cortex lesions did not alter plasma adrenocorticotropic hormone levels seen in response to a psychological stressor, noise. To identify brain regions that might mediate the effect of medial prefrontal cortex lesions on hypothalamic–pituitary–adrenal axis responses to systemic interleukin-1β, we next mapped the effects of similar lesions on interleukin-1β-induced Fos expression in regions previously shown to regulate the hypothalamic–pituitary–adrenal axis response to this stressor. It was found that medial prefrontal cortex lesions reduced the number of Fos-positive cells in the ventral aspect of the bed nucleus of the stria terminalis. However, the final experiment, which involved combining retrograde tracing with Fos immunolabelling, revealed that bed nucleus of the stria terminalis-projecting medial prefrontal cortex neurons were largely separate from medial prefrontal cortex neurons recruited by systemic interleukin-1β, an outcome that is difficult to reconcile with a simple medial prefrontal cortex–bed nucleus of the stria terminalis–corticotropin-releasing factor cell control circuit.

Effects of predator control on behaviour of an apex predator and indirect consequences for mesopredator suppression

1. Apex predators can benefit ecosystems through top–down control of mesopredators and herbivores. However, apex predators are often subject to lethal control aimed at minimizing attacks on livestock. Lethal control can affect both the abundance and behaviour of apex predators. These changes could in turn influence the abundance and behaviour of mesopredators.

2. We used remote camera surveys at nine pairs of large Australian rangeland properties, comparing properties that controlled dingoes Canis lupus dingo with properties that did not, to test the effects of predator control on dingo activity and to evaluate the responses of a mesopredator, the feral cat Felis catus.

3. Indices of dingo abundance were generally reduced on properties that practiced dingo control, in comparison with paired properties that did not, although the effect size of control was variable. Dingoes in uncontrolled populations were crepuscular, similar to major prey. In populations subject to control, dingoes became less active around dusk, and activity was concentrated in the period shortly before dawn.

4. Shifts in feral cat abundance indices between properties with and without dingo control were inversely related to corresponding shifts in indices of dingo abundance. There was also a negative relationship between predator visitation rates at individual camera stations, suggesting cats avoided areas where dingoes were locally common. Reduced activity by dingoes at dusk was associated with higher activity of cats at dusk.

5. Our results suggest that effective dingo control not only leads to higher abundance of feral cats, but allows them to optimize hunting behaviour when dingoes are less active. This double effect could amplify the impacts of dingo control on prey species selected by cats. In areas managed for conservation, stable dingo populations may thus contribute to management objectives by restricting feral cat access to prey populations.

6. Synthesis and applications. Predator control not only reduces indices of apex predator abundance but can also modify their behaviour. Hence, indicators other than abundance, such as behavioural patterns, should be considered when estimating a predator's capacity to effectively interact with lower trophic guilds. Changes to apex predator behaviour may relax limitations on the behaviour of mesopredators, providing enhanced access to resources and prey.

Salicylic acid suppression of clubroot in broccoli (Brassicae oleracea var. italica) caused by the obligate biotroph Plasmodiophora brassicae

The obligate soil-borne biotroph Plasmodiophora brassicae has a significant economic impact on Brassicaceae crops. The pathogen severely disrupts the roots by inducing the production of galls which leads to malformation and reduced growth of the roots and a reduced ability to take up water and nutrients. Control of P. brassicae is difficult because it has a number of survival and dissemination strategies that involve both motile and resting stages that need to be targeted by any control agent. We investigated, under controlled conditions and in glasshouse and field experiments, the potential of salicylic acid (SA), a key phytohormone, that is required for defence against certain biotic and abiotic stresses, to reduce infection by P. brassicae in broccoli (Brassicae oleracea var. italica). Under controlled conditions in a growth cabinet exogenous application of SA to roots resulted in its transport systemically to the leaves where it promoted the up-regulation of the pathogenesis related genes PR-1 and PR-2 in an SAR-like response as early as 24 h post-treatment. Concentrations of SA >20 mM reduced significantly both shoot and root weights when applied exogenously but lower concentrations had little measureable effect on plant growth. When SA was applied to plants above 5 mM there was a significant reduction (25-65 %) in gall formation 6 weeks post-inoculation with P. brassicae, indicating that the pathogen was being controlled by the addition of SA. A combination of SA and JA was also shown to reduce severity (25-35 %) of disease associated with P. brassicae. These findings indicate that there may be SA inducible mechanisms in B. oleracea that if fine-tuned could provide enhanced resistance to clubroot disease.

Salivary immunoglobulin A (sIgA) as a biomarker of immune suppression following the combat fitness assessment

SIgA is a potential biomarker for stress. The usual day-to-day and within day variation in sIgA amongst a group of healthy Army reservists was estimated and the acute response of sIgA to moderate intensity exercise (Combat Fitness Assessment) undertaken in both cool-dry and hot-humid conditions was determined. The results indicate that thermal and cardiovascular strain resulting from moderate intensity exercise in hot-humid conditions suppresses sIgA for at least 24 hours post-exercise. Salivary sIgA exhibits a wide biological variation which casts some doubt on its usefulness as a biomarker, however because sIgA has been shown to be sensitive to dietary restriction, alcohol consumption, loss of body mass, fatigue and negative emotions in previous studies and now heat-induced cardiovascular strain, further work is warranted to develop this biomarker.

Trunk postures and upper-body muscle activation during physically demanding wildfire suppression tasks

This study examined the trunk postures and upper-body muscle activations during four physically demanding wildfire suppression tasks. Bilateral, wireless surface electromyography was recorded from the trapezius and erector spinae muscles of nine experienced, wildfire fighters. Synchronised video captured two retroreflective markers to allow for quantification of two-dimensional sagittal trunk flexion. In all tasks, significantly longer time was spent in the mild and severe trunk flexion (p ≤ 0.002) compared to the time spent in a neutral posture. Mean and peak muscle activation in all tasks exceeded previously established safe limits. These activation levels also significantly increased through the performance of each task (p < 0.001). The results suggest that the wildfire suppression tasks analysed impose significant musculoskeletal demand on firefighters. Fire agencies should consider developing interventions to reduce the exposure of their personnel to these potentially injurious musculoskeletal demands.

Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle

The present study examined the acute effects of metformin on fatty acid (FA) metabolism in oxidative soleus (SOL) and glycolytic epitrochlearis (EPT) rodent muscle. SOL and EPT were incubated for either 30 or 180 min in the absence or presence of 2 mM metformin and with or without insulin (10 mU/ml). Metformin did not alter basal FA metabolism but countered the effects of insulin on FA oxidation and incorporation into triacylglyerol (TAG). Specifically, metformin prevented the insulin-induced suppression of FA oxidation in SOL but did not alter FA incorporation into lipid pools. In contrast, in EPT metformin blunted the incorporation of FA into TAG when insulin was present but did not alter FA oxidation. In SOL, metformin resulted in a 50% increase in AMP-activated protein kinase α2 activity and prevented the insulin-induced increase in malonyl-CoA content. In both fiber types, basal and insulin-stimulated glucose oxidation were not significantly altered by metformin. All effects were similar regardless of whether they were measured after 30 or 180 min. Because increased muscle lipid storage and impaired FA oxidation have been associated with insulin resistance in this tissue, the ability of metformin to reverse these abnormalities in muscle FA metabolism may be a part of the mechanism by which metformin improves glucose clearance and insulin sensitivity. The present data also suggest that increased glucose clearance is not due to its enhanced subsequent oxidation. Additional studies are warranted to determine whether chronic metformin treatment has similar effects on muscle FA metabolism.

Sleep restriction during simulated wildfire suppression: effect on physical task performance

OBJECTIVES: To examine the effects of sleep restriction on firefighters' physical task performance during simulated wildfire suppression. METHODS: Thirty-five firefighters were matched and randomly allocated to either a control condition (8-hour sleep opportunity, n = 18) or a sleep restricted condition (4-hour sleep opportunity, n = 17). Performance on physical work tasks was evaluated across three days. In addition, heart rate, core temperature, and worker activity were measured continuously. Rate of perceived and exertion and effort sensation were evaluated during the physical work periods. RESULTS: There were no differences between the sleep-restricted and control groups in firefighters' task performance, heart rate, core temperature, or perceptual responses during self-paced simulated firefighting work tasks. However, the sleep-restricted group were less active during periods of non-physical work compared to the control group. CONCLUSIONS: Under self-paced work conditions, 4 h of sleep restriction did not adversely affect firefighters' performance on physical work tasks. However, the sleep-restricted group were less physically active throughout the simulation. This may indicate that sleep-restricted participants adapted their behaviour to conserve effort during rest periods, to subsequently ensure they were able to maintain performance during the firefighter work tasks. This work contributes new knowledge to inform fire agencies of firefighters' operational capabilities when their sleep is restricted during multi-day wildfire events. The work also highlights the need for further research to explore how sleep restriction affects physical performance during tasks of varying duration, intensity, and complexity.

Suppression of necking in incremental sheet forming

Incremental sheet forming enables sheet metal to deform above a conventional strain-based forming limit. The mechanics reason has not been clearly explained yet. In this work, the stress-based forming limit was utilized for through-thickness necking analysis to explain this uncovered question. Stress-based forming limit which has path-independency shows that the stress states in top, middle and bottom surfaces did not exceed the forming limit curve at the same time and each layer has different stress state in terms of their deformation history to suppress necking. It has been found that it is important to consider the gradient stress profile following the deformation history for the proper forming limit analysis of incremental sheet forming. © 2014 Elsevier Ltd. All rights reserved.

Reduced mu suppression and altered motor resonance in euthymic bipolar disorder: evidence for a dysfunctional mirror system?

Social cognitive difficulties are common in the acute phase of bipolar disorder and, to a lesser extent, during the euthymic stage, and imaging studies of social cognition in euthymic bipolar disorder have implicated mirror system brain regions. This study aimed to use a novel multimodal approach (i.e., including both transcranial magnetic stimulation (TMS) and electroencephalogram (EEG)) to investigate mirror systems in bipolar disorder. Fifteen individuals with euthymic bipolar disorder and 16 healthy controls participated in this study. Single-pulse TMS was applied to the optimal site in the primary motor cortex (M1), which stimulates the muscle of interest during the observation of hand movements (goal-directed or interacting) designed to elicit mirror system activity. Single EEG electrodes (C3, CZ, C4) recorded mu rhythm modulation concurrently. Results revealed that the patient group showed significantly less mu suppression compared to healthy controls. Surprisingly, motor resonance was not significantly different overall between groups; however, bipolar disorder participants showed a pattern of reduced reactivity on some conditions. Although preliminary, this study indicates a potential mirror system deficit in euthymic bipolar disorder, which may contribute to the pathophysiology of the disorder.