Transcriptional Dynamics of the Embryonic Stem Cell Switch

Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4–SOX2–NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4–SOX2–NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched on/off by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is on, the self-renewal genes are on and the differentiation genes are off. The opposite holds when the switch is off. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains on even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG

Robustness of circadian clocks to daylight fluctuations: hints from the picoeucaryote Ostreococcus tauri

The development of systemic approaches in biology has put emphasis on identifying genetic modules whose behavior can be modeled accurately so as to gain insight into their structure and function. However most gene circuits in a cell are under control of external signals and thus quantitative agreement between experimental data and a mathematical model is difficult. Circadian biology has been one notable exception: quantitative models of the internal clock that orchestrates biological processes over the 24-hour diurnal cycle have been constructed for a few organisms, from cyanobacteria to plants and mammals. In most cases, a complex architecture with interlocked feedback loops has been evidenced. Here we present first modeling results for the circadian clock of the green unicellular alga Ostreococcus tauri. Two plant-like clock genes have been shown to play a central role in Ostreococcus clock. We find that their expression time profiles can be accurately reproduced by a minimal model of a two-gene transcriptional feedback loop. Remarkably, best adjustment of data recorded under light/dark alternation is obtained when assuming that the oscillator is not coupled to the diurnal cycle. This suggests that coupling to light is confined to specific time intervals and has no dynamical effect when the oscillator is entrained by the diurnal cycle. This intringuing property may reflect a strategy to minimize the impact of fluctuations in daylight intensity on the core circadian oscillator, a type of perturbation that has been rarely considered when assessing the robustness of circadian clocks

Evolutionary relationships among barley and <i>Arabidopsis</i> core circadian clock and clock-associated genes

The circadian clock regulates a multitude of plant developmental and metabolic processes. In crop species, it contributes significantly to plant performance and productivity and to the adaptation and geographical range over which crops can be grown. To understand the clock in barley and how it relates to the components in the Arabidopsis thaliana clock, we have performed a systematic analysis of core circadian clock and clock-associated genes in barley, Arabidopsis and another eight species including tomato, potato, a range of monocotyledonous species and the moss, Physcomitrella patens. We have identified orthologues and paralogues of Arabidopsis genes which are conserved in all species, monocot/dicot differences, species-specific differences and variation in gene copy number (e.g. gene duplications among the various species). We propose that the common ancestor of barley and Arabidopsis had two-thirds of the key clock components identified in Arabidopsis prior to the separation of the monocot/dicot groups. After this separation, multiple independent gene duplication events took place in both monocot and dicot ancestors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00239-015-9665-0) contains supplementary material, which is available to authorized users

Humanities for medical students? A qualitative study of a medical humanities curriculum in a medical school program

BACKGROUND: Today, there is a trend towards establishing the medical humanities as a component of medical education. However, medical humanities programs that exist within the context of a medical school can be problematic. The aim of this study was to explore problems that can arise with the establishment of a medical humanities curriculum in a medical school program. METHODS: Our theoretical approach in this study is informed by derridean deconstruction and by post-structuralist analysis. We examined the ideology of the Humanities and Medicine program at Lund University, Sweden, the practical implementation of the program, and how ideology and practice corresponded. Examination of the ideology driving the humanities and medicine program was based on a critical reading of all available written material concerning the Humanities and Medicine project. The practice of the program was examined by means of a participatory observation study of one course, and by in-depth interviews with five students who participated in the course. Data was analysed using a hermeneutic editing approach. RESULTS: The ideological language used to describe the program calls it an interdisciplinary learning environment but at the same time shows that the conditions of the program are established by the medical faculty's agenda. In practice, the "humanities" are constructed, defined and used within a medical frame of reference. Medical students have interesting discussions, acquire concepts and enjoy the program. But they come away lacking theoretical structure to understand what they have learned. There is no place for humanities students in the program. CONCLUSION: A challenge facing cross-disciplinary programs is creating an environment where the disciplines have equal standing and contribution

The meaning of quality work from the general practitioner's perspective: an interview study

BACKGROUND: The quality of health care and its costs have been a subject of considerable attention and lively discussion. Various methods have been introduced to measure, assess, and improve the quality of health care. Many professionals in health care have criticized quality work and its methods as being unsuitable for health care. The aim of the study was to obtain a deeper understanding of the meaning of quality work from the general practitioner's perspective. METHODS: Fourteen general practitioners, seven women and seven men, were interviewed with the aid of a semi-structured interview guide about their experience of quality work. The interviews were tape-recorded and transcribed verbatim. Data collection and analysis were guided by a phenomenological approach intended to capture the essence of the statements. RESULTS: Two fundamentally different ways to view quality work emerged from the statements: A pronounced top-down perspective with elements of control, and an intra-profession or bottom-up perspective. From the top-down perspective, quality work was described as something that infringes professional freedom. From the bottom-up perspective the statements described quality work as a self-evident duty and as a professional attitude to the medical vocation, guided by the principles of medical ethics. Follow-up with a bottom-up approach is best done in internal processes, with the profession itself designing structures and methods based on its own needs. CONCLUSIONS: The study indicates that general practitioners view internal follow-up as a professional obligation but external control as an imposition. This opposition entails a difficulty in achieving systematism in follow-up and quality work in health care. If the statutory standards for systematic quality work are to gain a real foothold, they must be packaged in such a way that general practitioners feel that both perspectives can be reconciled

The 'PUCE CAFE' Project: the First 15K Coffee Microarray, a New Tool for Discovering Candidate Genes correlated to Agronomic and Quality Traits

Background: Understanding the genetic elements that contribute to key aspects of coffee biology will have an impact on future agronomical improvements for this economically important tree. During the past years, EST collections were generated in Coffee, opening the possibility to create new tools for functional genomics. Results: The "PUCE CAFE" Project, organized by the scientific consortium NESTLE/IRD/CIRAD, has developed an oligo-based microarray using 15,721 unigenes derived from published coffee EST sequences mostly obtained from different stages of fruit development and leaves in Coffea Canephora (Robusta). Hybridizations for two independent experiments served to compare global gene expression profiles in three types of tissue matter (mature beans, leaves and flowers) in C. canephora as well as in the leaves of three different coffee species (C. canephora, C. eugenoides and C. arabica). Microarray construction, statistical analyses and validation by Q-PCR analysis are presented in this study. Conclusion: We have generated the first 15 K coffee array during this PUCE CAFE project, granted by Genoplante (the French consortium for plant genomics). This new tool will help study functional genomics in a wide range of experiments on various plant tissues, such as analyzing bean maturation or resistance to pathogens or drought. Furthermore, the use of this array has proven to be valid in different coffee species (diploid or tetraploid), drastically enlarging its impact for high-throughput gene expression in the community of coffee research

General practitioners' conceptions about treatment of depression and factors that may influence their practice in this area. A postal survey

BACKGROUND: The way GPs work does not appear to be adapted to the needs of depressive patients. Therefore we wanted to examine Swedish GPs' conceptions of depressive disorders and their treatment and GPs' ideas of factors that may influence their manner of work with depressive patients. METHODS: A postal questionnaire to a stratified sample of 617 Swedish GPs. RESULTS: Most respondents assumed antidepressive drugs effective and did not assume that psychotherapy can replace drugs in depression treatment though many of them looked at psychotherapy as an essential complement. Nearly all respondents thought that clinical experiences had great importance in decision situations, but patients' own preferences and official clinical guidelines were also regarded as essential. As influences on their work, almost all surveyed GPs regarded experiences from general practice very important, and a majority also emphasised experiences from private life. Courses arranged by pharmaceutical companies were seen as essential sources of knowledge. A majority thought that psychiatrists did not provide sufficient help, while most respondents perceived they were well backed up by colleagues. CONCLUSION: GPs tend to emphasize experiences, both from clinical work and private life, and overlook influences of collegial dealings and ongoing CME as well as the effects of the pharmaceutical companies' marketing activities. Many GPs appear to need more evidence based knowledge about depressive disorders. Interventions to improve depression management have to be supporting and interactive, and should be combined with organisational reforms to improve co-operation with psychiatrists

Gradient Descent Optimization in Gene Regulatory Pathways

BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example

Commercial Arctic shipping through the Northeast Passage:routes, resources, governance, technology, and infrastructure

The Russian and Norwegian Arctic are gaining notoriety as an alternative maritime route connecting the Atlantic and Pacific Oceans and as sources of natural resources. The renewed interest in the Northeast Passage or the Northern Sea Route is fueled by a recession of Arctic sea ice coupled with the discovery of new natural resources at a time when emerging and global markets are in growing demand for them. Driven by the expectation of potential future economic importance of the region, political interest and governance has been rapidly developing, mostly within the Arctic Council. However, this paper argues that optimism regarding the potential of Arctic routes as an alternative to the Suez Canal is overstated. The route involves many challenges: jurisdictional disputes create political uncertainties; shallow waters limit ship size; lack of modern deepwater ports and search and rescue (SAR) capabilities requires ships to have higher standards of autonomy and safety; harsh weather conditions and free-floating ice make navigation more difficult and schedules more variable; and more expensive ship construction and operation costs lessen the economic viability of the route. Technological advances and infrastructure investments may ameliorate navigational challenges, enabling increased shipping of natural resources from the Arctic to global markets.Albert Buixadé Farré, Scott R. Stephenson, Linling Chen, Michael Czub, Ying Dai, Denis Demchev, Yaroslav Efimov, Piotr Graczyk, Henrik Grythe, Kathrin Keil, Niku Kivekäs, Naresh Kumar, Nengye Liu, Igor Matelenok, Mari Myksvoll, Derek O'Leary, Julia Olsen, Sachin Pavithran.A.P., Edward Petersen, Andreas Raspotnik, Ivan Ryzhov, Jan Solski, Lingling Suo, Caroline Troein, Vilena Valeeva, Jaap van Rijckevorsel and Jonathan Wightin