Global parameter search reveals design principles of the mammalian circadian clock

Background: Virtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/ dark (LD) cycle is abruptly advanced or delayed by several hours. Results: Here, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment. Conclusion: Our work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level

Social identity, social networks and recovery capital in emerging adulthood: a pilot study

Background It has been argued that recovery from substance dependence relies on a change in identity, with past research focused on ‘personal identity’. This study assessed support for a social identity model of recovery in emerging adults through examining associations between social identity, social networks, recovery capital, and quality of life. Methods Twenty participants aged 18–21 in residential treatment for substance misuse were recruited from four specialist youth drug treatment services - three detoxification facilities and one psychosocial rehabilitation facility in Victoria, Australia. Participants completed a detailed social network interview exploring the substance use of groups in their social networks and measures of quality of life, recovery capital, and social identity. Results Lower group substance use was associated with higher recovery capital, stronger identification with non-using groups, and greater importance of non-using groups in the social network. Additionally, greater identification with and importance of non-using groups were associated with better environmental quality of life, whereas greater importance conferred on using groups was associated with reduced environmental quality of life. Conclusions Support was found for the role of social identity processes in reported recovery capital and quality of life. Future research in larger, longitudinal samples is required to improve understanding of social identity processes during treatment and early recovery and its relationship to recovery stability. Keywords Social network Social identity Emerging adult Substance use Treatment Recovery Quality of lif

Factors affecting Removal of Bacterial Pathogens from Healthcare Surfaces during Dynamic Wiping

Wiping of surfaces contaminated with pathogenic bacteria is a key strategy for combatting transmission of healthcare associated infections. It is essential to understand the extent to which removal of bacteria is modulated by fibre properties, biocidal liquid impregnation and applied hand pressure. The influence of intrinsic and extrinsic factors on the removal efficiencies of pathogenic bacteria was studied. Nonwoven wipes made of either hydrophobic (polypropylene) or hygroscopic (lyocell) fibres were manufactured and dynamic removal efficiency of bacteria studied. The single most important parameter affecting bacterial removal efficiency was impregnation with biocidal liquid (p <0.05). For inherently hygroscopic 100% regenerated cellulose (lyocell) wipes impregnated with biocidal liquid, removal of E. coli, S. aureus and E. faecalis improved by increasing the fabric surface density and wiping pressure to their maximal values - 150 g.m-2 and 13.80 kN.m-2 respectively. For inherently hydrophobic 100% polypropylene nonwoven wipes, the same conditions maximised the removal efficiency of S. aureus, but for E. coli and E. faecalis a reduction in the wiping pressure to 4.68 kN.m-2 was required. Best practice involves the use of higher surface density wipes (150 g m-2) containing regenerated cellulose fibres loaded with liquid biocide, and applied with the greatest possible wiping pressure

Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness

&lt;b&gt;Background&lt;/b&gt; In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Discussion&lt;/b&gt; As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Summary&lt;/b&gt; Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Patient Engagement and Coaching for Health: The PEACH study – a cluster randomised controlled trial using the telephone to coach people with type 2 diabetes to engage with their GPs to improve diabetes care: a study protocol

BACKGROUND: The PEACH study is based on an innovative 'telephone coaching' program that has been used effectively in a post cardiac event trial. This intervention will be tested in a General Practice setting in a pragmatic trial using existing Practice Nurses (PN) as coaches for people with type 2 diabetes (T2D). Actual clinical care often fails to achieve standards, that are based on evidence that self-management interventions (educational and psychological) and intensive pharmacotherapy improve diabetes control. Telephone coaching in our study focuses on both. This paper describes our study protocol, which aims to test whether goal focused telephone coaching in T2D can improve diabetes control and reduce the treatment gap between guideline based standards and actual clinical practice. METHODS/DESIGN: In a cluster randomised controlled trial, general practices employing Practice Nurses (PNs) are randomly allocated to an intervention or control group. We aim to recruit 546 patients with poorly controlled T2D (HbA1c >7.5%) from 42 General Practices that employ PNs in Melbourne, Australia. PNs from General Practices allocated to the intervention group will be trained in diabetes telephone coaching focusing on biochemical targets addressing both patient self-management and engaging patients to work with their General Practitioners (GPs) to intensify pharmacological treatment according to the study clinical protocol. Patients of intervention group practices will receive 8 telephone coaching sessions and one face-to-face coaching session from existing PNs over 18 months plus usual care and outcomes will be compared to the control group, who will only receive only usual care from their GPs. The primary outcome is HbA1c levels and secondary outcomes include cardiovascular disease risk factors, behavioral risk factors and process of care measures. DISCUSSION: Understanding how to achieve comprehensive treatment of T2D in a General Practice setting is the focus of the PEACH study. This study explores the potential role for PNs to help reduce the treatment and outcomes gap in people with T2D by using telephone coaching. The intervention, if found to be effective, has potential to be sustained and embedded within real world General Practice

A Low Percent Ethanol Method for Immobilizing Planarians

Planarians have recently become a popular model system for the study of adult stem cells, regeneration and polarity. The system is attractive for both undergraduate and graduate research labs, since planarian colonies are low cost and easy to maintain. Also in situ hybridization, immunofluorescence and RNA-interference (RNAi) gene knockdown techniques have been developed for planarian studies. However, imaging of live worms (particularly at high magnifications) is difficult because animals are strongly photophobic; they quickly move away from light sources and out of frame. The current methods available to inhibit movement in planarians include RNAi injection and exposure to cold temperatures. The former is labor and time intensive, while the latter precludes the use of many fluorescent reporter dyes. Here, we report a simple, inexpensive and reversible method to immobilize planarians for live imaging. Our data show that a short 1 hour treatment with 3% ethanol (EtOH) is sufficient to inhibit both the fine and gross movements of Schmidtea mediterranea planarians, of the typical size used (4–6 mm), with full recovery of movement within 3–4 hours. Importantly, EtOH treatment did not interfere with regeneration, even after repeated exposure, nor lyse epithelial cells (as assayed by H&E staining). We demonstrate that a short exposure to a low concentration of EtOH is a quick and effective method of immobilizing planarians, one that is easily adaptable to planarians of all sizes and will increase the accessibility of live imaging assays to planarian researchers

Epigenetic management of major psychosis

Epigenetic mechanisms are thought to play a major role in the pathogenesis of the major psychoses (schizophrenia and bipolar disorder), and they may be the link between the environment and the genome in the pathogenesis of these disorders. This paper discusses the role of epigenetics in the management of major psychosis: (1) the role of epigenetic drugs in treating these disorders. At present, there are three categories of epigenetic drugs that are being actively investigated for their ability to treat psychosis: drugs inhibiting histone deacetylation; drugs decreasing DNA methylation; and drugs targeting microRNAs; and (2) the role of epigenetic mechanisms in electroconvulsive therapy in these disorders

Quantification of Circadian Rhythms in Single Cells

Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber)