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

Design and feasibility testing of a novel group intervention for young women who binge drink in groups

BackgroundYoung women frequently drink alcohol in groups and binge drinking within these natural drinking groups is common. This study describes the design of a theoretically and empirically based group intervention to reduce binge drinking among young women. It also evaluates their engagement with the intervention and the acceptability of the study methods.MethodsFriendship groups of women aged 18–35 years, who had two or more episodes of binge drinking (>6 UK units on one occasion; 48g of alcohol) in the previous 30 days, were recruited from the community. A face-to-face group intervention, based on the Health Action Process Approach, was delivered over three sessions. Components of the intervention were woven around fun activities, such as making alcohol free cocktails. Women were followed up four months after the intervention was delivered. Results The target of 24 groups (comprising 97 women) was recruited. The common pattern of drinking was infrequent, heavy drinking (mean consumption on the heaviest drinking day was UK 18.1 units). Process evaluation revealed that the intervention was delivered with high fidelity and acceptability of the study methods was high. The women engaged positively with intervention components and made group decisions about cutting down. Twenty two groups set goals to reduce their drinking, and these were translated into action plans. Retention of individuals at follow up was 87%.ConclusionsThis study successfully recruited groups of young women whose patterns of drinking place them at high risk of acute harm. This novel approach to delivering an alcohol intervention has potential to reduce binge drinking among young women. The high levels of engagement with key steps in the behavior change process suggests that the group intervention should be tested in a full randomised controlled trial

Evaluating Active U: an Internet-mediated physical activity program.

Background: Engaging in regular physical activity can be challenging, particularly during the winter months. To promote physical activity at the University of Michigan during the winter months, an eight-week Internet-mediated program (Active U) was developed providing participants with an online physical activity log, goal setting, motivational emails, and optional team participation and competition. Methods: This study is a program evaluation of Active U. Approximately 47,000 faculty, staff, and graduate students were invited to participate in the online Active U intervention in the winter of 2007. Participants were assigned a physical activity goal and were asked to record each physical activity episode into the activity log for eight weeks. Statistics for program reach, effectiveness, adoption, and implementation were calculated using the Re-Aim framework. Multilevel regression analyses were used to assess the decline in rates of data entry and goal attainment during the program, to assess the likelihood of joining a team by demographic characteristics, to test the association between various predictors and the number of weeks an individual met his or her goal, and to analyze server load. Results: Overall, 7,483 individuals registered with the Active U website (≈16% of eligible), and 79% participated in the program by logging valid data at least once. Staff members, older participants, and those with a BMI < 25 were more likely to meet their weekly physical activity goals, and average rate of meeting goals was higher among participants who joined a competitive team compared to those who participated individually (IRR = 1.28, P < .001). Conclusion: Internet-mediated physical activity interventions that focus on physical activity logging and goal setting while incorporating team competition may help a significant percentage of the target population maintain their physical activity during the winter months

Social, environmental and psychological factors associated with objective physical activity levels in the over 65s

Objective: To assess physical activity levels objectively using accelerometers in community dwelling over 65 s and to examine associations with health, social, environmental and psychological factors. Design: Cross sectional survey. Setting: 17 general practices in Scotland, United Kingdom. Participants: Random sampling of over 65 s registered with the practices in four strata young-old (65–80 years), old-old (over 80 years), more affluent and less affluent groups. Main Outcome Measures: Accelerometry counts of activity per day. Associations between activity and Theory of Planned Behaviour variables, the physical environment, health, wellbeing and demographic variables were examined with multiple regression analysis and multilevel modelling. Results: 547 older people (mean (SD) age 79(8) years, 54% female) were analysed representing 94% of those surveyed. Accelerometry counts were highest in the affluent younger group, followed by the deprived younger group, with lowest levels in the deprived over 80 s group. Multiple regression analysis showed that lower age, higher perceived behavioural control, the physical function subscale of SF-36, and having someone nearby to turn to were all independently associated with higher physical activity levels (R2 = 0.32). In addition, hours of sunshine were independently significantly associated with greater physical activity in a multilevel model. Conclusions: Other than age and hours of sunlight, the variables identified are modifiable, and provide a strong basis for the future development of novel multidimensional interventions aimed at increasing activity participation in later life.Publisher PDFPeer reviewe

Clinicians' caseload management behaviours as explanatory factors in patients' length of time on caseloads : a predictive multilevel study in paediatric community occupational therapy

Peer reviewedPublisher PD

Physical activity interventions to improve daily walking activity in cancer survivors

Background Cancer patients may benefit from physical exercise programs. It is unclear, however, how sustained levels of physical activity are best achieved in this population. A systematic review was performed to summarize the current evidence of the effect of physical activity interventions on daily walking activity enhancement in cancer survivors, and to review the literature for its methodological quality. Methods A search in Medline, PEDro and the Cochrane databases was performed for English literature citations (randomized controlled trials; `RCTs`). In a first step, one reviewer abstracted data from the included studies on patients, physical activity interventions and outcomes. Two independent reviewers reviewed the methodological quality of these studies. Data were pooled using random-effects calculations. Results Our search identified 201 citations. Five RCTs that reported changes in daily step activity over time were identified, and were reviewed for methodological quality and substantive results. The median score across studies for methodological quality based on the PEDro criteria was 8. These 5 RCTs evaluated 660 participants with a mean age of 53.6 (SD 4.2) years. The mean change in daily step activity for patients with a physical exercise intervention was 526 daily steps (SD 537), with a range from -92 to 1299 daily steps. The data of three studies reporting the effect of combined physical activity and counseling on daily walking activity in breast cancer survivors were pooled, however; the I2 was 79%, indicating statistical heterogeneity between the three trials. Conclusion The 5 RCTs reviewed were of good methodological quality. Together they suggest that combined physical activity and counseling improves daily step activity in (breast) cancer survivors. Studies that define a step goal appear to be more effective in improving daily walking activity than studies that do not do so. However, the current results should be interpreted with caution because of the observed clinical and statistical heterogeneity. Future studies are warranted to evaluate the effects of goal targeted physical activity, with or without counseling, on daily walking in various cancer populations

Goal setting and self-efficacy among delinquent, at-risk and not at-risk adolescents

Setting clear achievable goals that enhance self-efficacy and reputational status directs the energies of adolescents into socially conforming or non-conforming activities. This present study investigates the characteristics and relationships between goal setting and self-efficacy among a matched sample of 88 delinquent (18 % female), 97 at-risk (20 % female), and 95 not at-risk adolescents (20 % female). Four hypotheses related to this were tested. Findings revealed that delinquent adolescents reported fewest goals, set fewer challenging goals, had a lower commitment to their goals, and reported lower levels of academic and self-regulatory efficacy than those in the at-risk and not at-risk groups. Discriminant function analysis indicated that adolescents who reported high delinquency goals and low educational and interpersonal goals were likely to belong to the delinquent group, while adolescents who reported high educational and interpersonal goals and low delinquency goals were likely to belong to the not at-risk group. The at-risk and not at-risk groups could not be differentiated. A multinomial logistic regression also revealed that adolescents were more likely to belong to the delinquent group if they reported lower self-regulatory efficacy and lower goal commitment. These findings have important implications for the development of prevention and intervention programs, particularly for those on a trajectory to delinquency. Specifically, programs should focus on assisting adolescents to develop clear self-set achievable goals and support them through the process of attaining them, particularly if the trajectory towards delinquency is to be addressed

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

Value Creation from Big Data: Looking Inside the Black Box

The advent of big data is fundamentally changing the business landscape. We open the ‘black box’ of the firm to explore how firms transform big data in order to create value and why firms differ in their abilities to create value from big data. Grounded in detailed evidence from China, the world’s largest digital market, where many firms actively engage in value creation activities from big data, we identify several novel features. We find that it is not the data itself, or individual data scientists, that generate value creation opportunities. Rather, value creation occurs through the process of data management, where managers are able to democratize, contextualize, experiment and execute data insights in a timely manner. We add richness to current theory by developing a conceptual framework of value creation from big data. We also identify avenues for future research and implications for practicing managers

Adult Consequences of Late Adolescent Alcohol Consumption: A Systematic Review of Cohort Studies

In a systematic review of cohort studies of adolescent drinking and later outcomes, Jim McCambridge and colleagues show that although studies suggest links to worse adult physical and mental health and social consequences, existing evidence is of poor quality