Boolean network model predicts cell cycle sequence of fission yeast

A Boolean network model of the cell-cycle regulatory network of fission yeast (Schizosaccharomyces Pombe) is constructed solely on the basis of the known biochemical interaction topology. Simulating the model in the computer, faithfully reproduces the known sequence of regulatory activity patterns along the cell cycle of the living cell. Contrary to existing differential equation models, no parameters enter the model except the structure of the regulatory circuitry. The dynamical properties of the model indicate that the biological dynamical sequence is robustly implemented in the regulatory network, with the biological stationary state G1 corresponding to the dominant attractor in state space, and with the biological regulatory sequence being a strongly attractive trajectory. Comparing the fission yeast cell-cycle model to a similar model of the corresponding network in S. cerevisiae, a remarkable difference in circuitry, as well as dynamics is observed. While the latter operates in a strongly damped mode, driven by external excitation, the S. pombe network represents an auto-excited system with external damping.Comment: 10 pages, 3 figure

Feedback control architecture and the bacterial chemotaxis network.

PMCID: PMC3088647This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Bacteria move towards favourable and away from toxic environments by changing their swimming pattern. This response is regulated by the chemotaxis signalling pathway, which has an important feature: it uses feedback to 'reset' (adapt) the bacterial sensing ability, which allows the bacteria to sense a range of background environmental changes. The role of this feedback has been studied extensively in the simple chemotaxis pathway of Escherichia coli. However it has been recently found that the majority of bacteria have multiple chemotaxis homologues of the E. coli proteins, resulting in more complex pathways. In this paper we investigate the configuration and role of feedback in Rhodobacter sphaeroides, a bacterium containing multiple homologues of the chemotaxis proteins found in E. coli. Multiple proteins could produce different possible feedback configurations, each having different chemotactic performance qualities and levels of robustness to variations and uncertainties in biological parameters and to intracellular noise. We develop four models corresponding to different feedback configurations. Using a series of carefully designed experiments we discriminate between these models and invalidate three of them. When these models are examined in terms of robustness to noise and parametric uncertainties, we find that the non-invalidated model is superior to the others. Moreover, it has a 'cascade control' feedback architecture which is used extensively in engineering to improve system performance, including robustness. Given that the majority of bacteria are known to have multiple chemotaxis pathways, in this paper we show that some feedback architectures allow them to have better performance than others. In particular, cascade control may be an important feature in achieving robust functionality in more complex signalling pathways and in improving their performance

Breastfeeding Is Associated with a Maternal Feeding Style Low in Control from Birth

Background: The influence of maternal child-feeding style upon child weight and eating style for children over the age of twelve months is well established. However there is little empirical evidence examining maternal child-feeding style during milk feeding despite evidence that mothers who breastfeed exert lower levels of control over later diet. The aim of this paper was to examine variation in maternal child-feeding style during the first six months postpartum and to explore associations with mode of milk feeding and infant weight. Methods: The Child Feeding Questionnaire (CFQ) is frequently used to measure maternal child-feeding style in preschool children. 390 mothers with an infant aged 0–6 months completed an adapted version of the CFQ to measure maternal child-feeding style during milk feeding. Participants reported breastfeeding duration, infant weight and perceived size. Results: Principle components analysis of questionnaire items produced six factors; encouraging feeding, feeding to a routine, limiting intake, concern for weight, monitoring and perceived responsibility. Breastfeeding was associated with lower levels of control compared to formula feeding. Infant birth weight was significantly inversely associated with concern for weight, monitoring and encouraging feeding. Discussion: Formula feeding is associated with greater maternal control of child-feeding from birth whilst a lower birth weight is linked to concerns for infant weight and pressure to eat. As early maternal child-feeding relationships may impac

Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells

The innate immune system, acting as the first line of host defense, senses and adapts to foreign challenges through complex intracellular and intercellular signaling networks. Endotoxin tolerance and priming elicited by macrophages are classic examples of the complex adaptation of innate immune cells. Upon repetitive exposures to different doses of bacterial endotoxin (lipopolysaccharide) or other stimulants, macrophages show either suppressed or augmented inflammatory responses compared to a single exposure to the stimulant. Endotoxin tolerance and priming are critically involved in both immune homeostasis and the pathogenesis of diverse inflammatory diseases. However, the underlying molecular mechanisms are not well understood. By means of a computational search through the parameter space of a coarse-grained three-node network with a two-stage Metropolis sampling approach, we enumerated all the network topologies that can generate priming or tolerance. We discovered three major mechanisms for priming (pathway synergy, suppressor deactivation, activator induction) and one for tolerance (inhibitor persistence). These results not only explain existing experimental observations, but also reveal intriguing test scenarios for future experimental studies to clarify mechanisms of endotoxin priming and tolerance.Comment: 15 pages, 8 figures, submitte

The Formation and Evolution of the First Massive Black Holes

The first massive astrophysical black holes likely formed at high redshifts (z>10) at the centers of low mass (~10^6 Msun) dark matter concentrations. These black holes grow by mergers and gas accretion, evolve into the population of bright quasars observed at lower redshifts, and eventually leave the supermassive black hole remnants that are ubiquitous at the centers of galaxies in the nearby universe. The astrophysical processes responsible for the formation of the earliest seed black holes are poorly understood. The purpose of this review is threefold: (1) to describe theoretical expectations for the formation and growth of the earliest black holes within the general paradigm of hierarchical cold dark matter cosmologies, (2) to summarize several relevant recent observations that have implications for the formation of the earliest black holes, and (3) to look into the future and assess the power of forthcoming observations to probe the physics of the first active galactic nuclei.Comment: 39 pages, review for "Supermassive Black Holes in the Distant Universe", Ed. A. J. Barger, Kluwer Academic Publisher

Microdroplet-Enabled Highly Parallel Co-Cultivation of Microbial Communities

Microbial interactions in natural microbiota are, in many cases, crucial for the sustenance of the communities, but the precise nature of these interactions remain largely unknown because of the inherent complexity and difficulties in laboratory cultivation. Conventional pure culture-oriented cultivation does not account for these interactions mediated by small molecules, which severely limits its utility in cultivating and studying “unculturable” microorganisms from synergistic communities. In this study, we developed a simple microfluidic device for highly parallel co-cultivation of symbiotic microbial communities and demonstrated its effectiveness in discovering synergistic interactions among microbes. Using aqueous micro-droplets dispersed in a continuous oil phase, the device could readily encapsulate and co-cultivate subsets of a community. A large number of droplets, up to ∼1,400 in a 10 mm×5 mm chamber, were generated with a frequency of 500 droplets/sec. A synthetic model system consisting of cross-feeding E. coli mutants was used to mimic compositions of symbionts and other microbes in natural microbial communities. Our device was able to detect a pair-wise symbiotic relationship when one partner accounted for as low as 1% of the total population or each symbiont was about 3% of the artificial community

Design and validation of the Health Professionals' Attitudes Toward the Homeless Inventory (HPATHI)

BACKGROUND: Recent literature has called for humanistic care of patients and for medical schools to begin incorporating humanism into medical education. To assess the attitudes of health-care professionals toward homeless patients and to demonstrate how those attitudes might impact optimal care, we developed and validated a new survey instrument, the Health Professional Attitudes Toward the Homeless Inventory (HPATHI). An instrument that measures providers' attitudes toward the homeless could offer meaningful information for the design and implementation of educational activities that foster more compassionate homeless health care. Our intention was to describe the process of designing and validating the new instrument and to discuss the usefulness of the instrument for assessing the impact of educational experiences that involve working directly with the homeless on the attitudes, interest, and confidence of medical students and other health-care professionals. METHODS: The study consisted of three phases: identifying items for the instrument; pilot testing the initial instrument with a group of 72 third-year medical students; and modifying and administering the instrument in its revised form to 160 health-care professionals and third-year medical students. The instrument was analyzed for reliability and validity throughout the process. RESULTS: A 19-item version of the HPATHI had good internal consistency with a Cronbach's alpha of 0.88 and a test-retest reliability coefficient of 0.69. The HPATHI showed good concurrent validity, and respondents with more than one year of experience with homeless patients scored significantly higher than did those with less experience. Factor analysis yielded three subscales: Personal Advocacy, Social Advocacy, and Cynicism. CONCLUSIONS: The HPATHI demonstrated strong reliability for the total scale and satisfactory test-retest reliability. Extreme group comparisons suggested that experience with the homeless rather than medical training itself could affect health-care professionals' attitudes toward the homeless. This could have implications for the evaluation of medical school curricula

A Mathematical Model of Mitotic Exit in Budding Yeast: The Role of Polo Kinase

Cell cycle progression in eukaryotes is regulated by periodic activation and inactivation of a family of cyclin–dependent kinases (Cdk's). Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins. Mitotic exit in budding yeast is known to involve the interplay of mitotic kinases (Cdk and Polo kinases) and phosphatases (Cdc55/PP2A and Cdc14), as well as the action of the anaphase promoting complex (APC) in degrading specific proteins in anaphase and telophase. To understand the intricacies of this mechanism, we propose a mathematical model for the molecular events during mitotic exit in budding yeast. The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains. The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network

The acceptance of the clinical photographic posture assessment tool (CPPAT)

Abstract Background There is a lack of evidence-based quantitative clinical methods to adequately assess posture. Our team developed a clinical photographic posture assessment tool (CPPAT) and implemented this tool in clinical practice to standardize posture assessment. The objectives were to determine the level of acceptance of the CPPAT and to document predictors as well as facilitators of and barriers to the acceptance of this tool by clinicians doing posture re-education. Methods This is a prospective study focussing on technology acceptance. Thirty-two clinician participants (physical therapists and sport therapists) received a 3–5 h training workshop explaining how to use the CPPAT. Over a three-month trial, they recorded time-on-task for a complete posture evaluation (photo - and photo-processing). Subsequently, participants rated their acceptance of the tool and commented on facilitators and barriers of the clinical method. Results Twenty-three clinician participants completed the trial. They took 22 (mean) ± 10 min (SD) for photo acquisition and 36 min ± 19 min for photo-processing. Acceptance of the CPPAT was high. Perceived ease of use was an indirect predictor of intention to use, mediated by perceived usefulness. Analysis time was an indirect predictor, mediated by perceived usefulness, and a marginally significant direct predictor. Principal facilitators were objective measurements, visualization, utility, and ease of use. Barriers were time to do a complete analysis of posture, quality of human-computer interaction, non-automation of posture index calculation and photo transfer, and lack of versatility. Conclusion The CPPAT is perceived as useful and easy to use by clinicians and may facilitate the quantitative analysis of posture. Adapting the user-interface and functionality to quantify posture may facilitate a wider adoption of the tool