A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake

The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia

Regional and temporal changes in AIDS in Europe before HAART

In a prospective observational study 4485 patients from 46 clinical centres in 17 European countries were followed between April 1994 and November 1996. Information on AIDS-defining events (ADEs) were collected together with basic demographic data, treatment history and laboratory results. The centres were divided into four geographical regions (north, central, south-west and south-east) so that it was possible to identify any existing regional differences in ADEs. The regional differences that we observed included a higher risk of all forms of Mycobacterium tuberculosis infections (Tb) and wasting disease in the south-west and an increased risk of infections with the Mycobacterium avium complex (MAC) in the north. In Cox multivariable analyses, where north was used as the reference group, we observed hazard ratios of 6.87, 7.77, 2.29 and 0.16 (P < 0.05 in all cases) for pulmonary Tb, extrapulmonary Tb, wasting disease and MAC respectively in the south-west. Pneumocystis carinii pneumonia (PCP) was less commonly diagnosed in the central region (RH = 0.51, 95% CI 0.32-0.79, P = 0.003) and most common in the south-east (RH = 1.04, 95% CI 0.71-1.51, P = 0.85). Comparisons with a similar 'AIDS in Europe' study that concentrated on the early phase of the epidemic reveal that most of the regional differences that were observed in the 1980s still persist in the mid-1990s

Review of Potential Wind Tunnel Balance Technologies

This manuscript reviews design, manufacture, materials, sensors, and data acquisition technologies that may benefit wind tunnel balances for the aerospace research community. Current state-of-the-art practices are used as the benchmark to consider advancements driven by researcher and facility needs. Additive manufacturing is highlighted as a promising alternative technology to conventional fabrication and has the potential to reduce both the cost and time required to manufacture force balances. Material alternatives to maraging steels are reviewed. Sensor technologies including piezoresistive, piezoelectric, surface acoustic wave, and fiber optic are compared to traditional foil based gages to highlight unique opportunities and shared challenges for implementation in wind tunnel environments. Finally, data acquisition systems that could be integrated into force balances are highlighted as a way to simplify the user experience and improve data quality. In summary, a rank ordering is provided to support strategic investment in exploring the technologies reviewed in this manuscript

The use of a cap-mounted tri-axial accelerometer for measurement of distance, lap times and stroke rates in swim training

This paper will report some of the findings from a trial which recorded accelerometer data from six elite level swimmers (three female and three male, varying primary event stroke and distance) over the course of a regular 15 week training block. Measurements from a headmounted accelerometer are used to determine when the athlete is swimming, marking of turning points (and therefore distance and lap-time measurements), and is processed by frequency analysis to determine stroke-rate. Comparison with video where available, and with training plans and literature where not, have proven this method to be accurate and reliable for determining these performance metrics. The primary objective of this project was to develop a low-cost, simple and highly usable system for use in swim coaching, feedback from elite coaches has indicated that development of this could be an extremely useful addition to their training regime

Predictive ethoinformatics reveals the complex migratory behaviour of a pelagic seabird, the Manx Shearwater

Understanding the behaviour of animals in the wild is fundamental to conservation efforts. Advances in bio-logging technologies have offered insights into the behaviour of animals during foraging, migration and social interaction. However, broader application of these systems has been limited by device mass, cost and longevity. Here, we use information from multiple logger types to predict individual behaviour in a highly pelagic, migratory seabird, the Manx Shearwater (Puffinus puffinus). Using behavioural states resolved from GPS tracking of foraging during the breeding season, we demonstrate that individual behaviours can be accurately predicted during multi-year migrations from low cost, lightweight, salt-water immersion devices. This reveals a complex pattern of migratory stopovers: some involving high proportions of foraging, and others of rest behaviour. We use this technique to examine three consecutive years of global migrations, revealing the prominence of foraging behaviour during migration and the importance of highly productive waters during migratory stopover

Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects.

Cells possess multiple mechanisms that protect against the accumulation of toxic aggregation-prone proteins. Here, we identify a pre-emptive pathway that reduces synthesis of membrane proteins that have failed to properly assemble in the endoplasmic reticulum (ER). We show that loss of the ER membrane complex (EMC) or mutation of the Sec61 translocon causes reduced synthesis of misfolded forms of the yeast ABC transporter Yor1. Synthesis defects are rescued by various ribosomal mutations, as well as by reducing cellular ribosome abundance. Genetic and biochemical evidence point to a ribosome-associated quality-control pathway triggered by ribosome collisions when membrane domain insertion and/or folding fails. In support of this model, translation initiation also contributes to synthesis defects, likely by modulating ribosome abundance on the message. Examination of translation efficiency across the yeast membrane proteome revealed that polytopic membrane proteins have relatively low ribosome abundance, providing evidence for translational tuning to balance protein synthesis and folding. We propose that by modulating translation rates of poorly folded proteins, cells can pre-emptively protect themselves from potentially toxic aberrant transmembrane proteins

Introduced species and extreme weather as key drivers of reproductive output in three sympatric albatrosses

Invasive species present a major conservation threat globally and nowhere are their affects more pronounced than in island ecosystems. Determining how native island populations respond demographically to invasive species can provide information to mitigate the negative effects of invasive species. Using 20 years of mark-recapture data from three sympatric species of albatrosses (black-browed Thalassarche melanophris, grey-headed T. chrysostoma, and light-mantled albatrosses Phoebetria palpebrata), we quantified the influence of invasive European rabbits Oryctolagus cuniculus and extreme weather patterns on breeding probability and success. Temporal variability in rabbit density explained 33–76% of the variability in breeding probability for all three species, with severe decreases in breeding probability observed after a lag period following highest rabbit numbers. For black-browed albatrosses, the combination of extreme rainfall and high rabbit density explained 33% of total trait variability and dramatically reduced breeding success. We showed that invasive rabbits and extreme weather events reduce reproductive output in albatrosses and that eliminating rabbits had a positive effect on albatross reproduction. This illustrates how active animal management at a local breeding site can result in positive population outcomes even for wide ranging animals like albatrosses where influencing vital rates during their at-sea migrations is more challenging

Response to Letter to the Editor from Richard Dorin:Dynamic pituitary-adrenal interactions in the critically ill after cardiac surgery

Diabetes mellitus: pathophysiological changes and therap

Screening current effects in Josephson junction arrays

The purpose of this work is to compare the dynamics of arrays of Josephson junctions in presence of magnetic field in two different frameworks: the so called XY frustrated model with no self inductance and an approach that takes into account the screening currents (considering self inductances only). We show that while for a range of parameters the simpler model is sufficiently accurate, in a region of the parameter space solutions arise that are not contained in the XY model equations.Comment: Figures available from the author

Dynamic pituitary-adrenal interactions in the critically ill after cardiac surgery

Context: Patients with critical illness are thought to be at risk of adrenal insufficiency. There are no models of dynamic hypothalamic-pituitary-adrenal (HPA) axis function in this group of patients and thus current methods of diagnosis are based on aggregated, static models.Objective: To characterize the secretory dynamics of the HPA axis in the critically ill (CI) after cardiac surgery.Design: Mathematical modeling of cohorts.Setting: Cardiac critical care unit.Patients: 20 male patients CI at least 48 hours after cardiac surgery and 19 healthy (H) male volunteers. Interventions: None.Main Outcome Measures: Measures of hormone secretory dynamics were generated from serum adrenocorticotrophic hormone (ACTH) sampled every hour and total cortisol every 10 min for 24 h.Results: All CI patients had pulsatile ACTH and cortisol profiles. CI patients had similar ACTH secretion (1036.4 [737.6] pg/mL/24 h) compared to the H volunteers (1502.3 [1152.2] pg/mL/24 h; P=.20), but increased cortisol secretion (CI: 14 447.0 [5709.3] vs H: 5915.5 [1686.7)] nmol/L/24 h; P<.0001). This increase in cortisol was due to nonpulsatile (CI: 9253.4 [3348.8] vs H: 960 [589.0] nmol/L/24 h, P<.0001), rather than pulsatile cortisol secretion (CI: 5193.1 [3018.5] vs H: 4955.1 [1753.6] nmol/L/24 h; P=.43). Seven (35%) of the 20 CI patients had cortisol pulse nadirs below the current international guideline threshold for critical illness-related corticosteroid insufficiency, but an overall secretion that would not be considered deficient.Conclusions: This study supports the premise that current tests of HPA axis function are unhelpful in the diagnosis of adrenal insufficiency in the CI. The reduced ACTH and increase in nonpulsatile cortisol secretion imply that the secretion of cortisol is driven by factors outside the HPA axis in critical illness.Diabetes mellitus: pathophysiological changes and therap