On the analysis of straight line data in pharmacology and biochemistry

The determination of drug potency, efficacy and receptor affinity constants, common calculations in pharmacology and biochemistry, require estimates of the slope and intercept of a linear regression line obtained from measured points (x_i, y_i). Three questions not explicitly covered in the basic statistical literature and, consequently, answered differently by scientists, arise often. (1) When there exist several y's corresponding to each value of the controlled parameter x, should all of these be used as points or only their average value at that x in constructing the line? (2) What are precise confidence limits of an abscissa corresponding to a specified ordinale? (3) What are confidence limits for the intercepts of a regression line whose slope is constrained to +1 or -1? In this paper we show that all the data should be used (question 1) and provide derivations for the formulas used to get the confidence limits mentioned in questions (2) and (3).     

Electron transfer between cytochromec and cytochromec peroxidase

The reaction between cytochromec (CC) and cytochromec peroxidase (CcP) is a very attractive system for investigating the fundamental mechanism of biological electron transfer. The resting ferric state of CcP is oxidized by hydrogen peroxide to compound I (CMPI) containing an oxyferryl heme and an indolyl radical cation on Trp-191. CMPI is sequentially reduced to CMPII and then to the resting state CcP by two molecules of CC. In this review we discuss the use of a new ruthenium photoreduction technique and other rapid kinetic techniques to address the following important questions: (1) What is the initial electron acceptor in CMPI? (2) What are the true rates of electron transfer from CC to the radical cation and to the oxyferryl heme? (3) What are the binding domains and pathways for electron transfer from CC to the radical cation and the oxyferryl heme? (4) What is the mechanism for the complete reaction under physiological conditions?     

Valéry et l’automatisme psychologique

While the name of Paul Valery is usually associated with that of Leonardo da Vinci or the character, Monsieur Teste, most people are unaware of Valery’s posthumous work, which he considered the most significant of his writings: Cahiers/Notebooks, a voluminous and dense work, in its dimensions (around 30,000 pages) as well as in what it discloses about the daily ponderings of a man who considered himself — in spite of himself — a philosopher. It is a multifaceted work, touching on all fields of thought: history, politics, and the sciences, in all their diversity, from mathematics to physics, and biology to the theory of evolution. Neither philosophy, nor theology, nor linguistics is left in the dark. But he clearly expressed a preference for psychology and, more specifically, the question of mental function: What is it to think? How does the mind link ideas? What is abstraction? What role do feelings play? What is the relationship between the mind and the machine? Must we concede the existence of the unconscious mind. These are some of the questions we address in elucidating the concept of automatism through what makes it work as well as its failings.     

Applications in brain proteomics: 8(th) HUPO Brain Proteome Project Workshop 7 October 2007, Seoul, Korea

What are the current approaches in brain proteomics? Can we combine different, but complementary study designs to obtain better results concerning brain diseases? What are the neuro‐hotspots, especially in Korea? These were some of the questions the participants of the 8^th HUPO Brain Proteome Project Workshop tried to answer prior to the 6^th HUPO World Congress in Seoul, Korea. Around 100 scientists came together during the afternoon of 7 October, 2007, to discuss and to catch up on the latest results and strategies concerning Huntington's disease, glioblastoma and standardization.     

Evaluation of the rates of biological processes from tracer kinetic data. IV. Digital simulation of nucleic acid metabolism in bacteria

A flexible computer program was set up to simulate the kinetics of the amounts of radioactivity and the amounts of substance in various classes of nucleic acids for a generalized biological system. This program works by transferring numbers from registers to other registers corresponding to the amounts of isotope label or the amount of substance moving from one pool or compartment to another for each successive time interval. It is practical to choose the time interval small enough so that the same results are accurately obtained with this type of computation as with the analytical solution for the most realistic and complicated case previously formulated. Much more complicated situations now can be treated with this recursion program and questions of relevance to current molecular biology can be answered. The questions treated in this paper are directed to enteric microorganisms and are as follows. (1) What are the conditions under which a short pulse reflects net synthesis and what are the conditions where it reflects total synthesis? (2) What are the conditions that measurement of intermediate pool specific activity can yield information about the turnover and concentration of unstable macromolecules in the system? (3) How prolonged can a pulse be and still label the species of RNA substantially in proportion to their rates of synthesis? (4) What are the amounts and rates of synthesis and degradation of ribosomal precursors best fitting data in the literature?     

Endpiece: Three different talks

ObjectivesTo characterise the information needs of family doctors by collecting the questions they asked about patient care during consultations and to classify these in ways that would be useful to developers of knowledge bases.DesignObservational study in which investigators visited doctors for two half days and collected their questions. Taxonomies were developed to characterise the clinical topic and generic type of information sought for each question.SettingEastern Iowa.ParticipantsRandom sample of 103 family doctors.ResultsParticipants asked a total of 1101 questions. Questions about drug prescribing, obstetrics and gynaecology, and adult infectious disease were most common and comprised 36% of all questions. The taxonomy of generic questions included 69 categories; the three most common types, comprising 24% of all questions, were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?” Answers to most questions (702, 64%) were not immediately pursued, but, of those pursued, most (318, 80%) were answered. Doctors spent an average of less than 2 minutes pursuing an answer, and they used readily available print and human resources. Only two questions led to a formal literature search.ConclusionsFamily doctors in this study did not pursue answers to most of their questions. Questions about patient care can be organised into a limited number of generic types, which could help guide the efforts of knowledge base developers.

Key messages

• Questions that doctors have about the care of their patients could help guide the content of medical information sources and medical training
• In this study of US family doctors, participants frequently had questions about patient care but did not pursue answers to most questions (64%)
• On average, participants spent less than 2 minutes seeking an answer to a question
• The most common resources used to answer questions included textbooks and colleagues; formal literature searches were rarely performed
• The most common generic questions were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?”

     

Schema-based learning of adaptable and flexible prey-catching in anurans I. The basic architecture

A motor action often involves the coordination of several motor synergies and requires flexible adjustment of the ongoing execution based on feedback signals. To elucidate the neural mechanisms underlying the construction and selection of motor synergies, we study prey-capture in anurans. Experimental data demonstrate the intricate interaction between different motor synergies, including the interplay of their afferent feedback signals (Weerasuriya 1991; Anderson and Nishikawa 1996). Such data provide insights for the general issues concerning two-way information flow between sensory centers, motor circuits and periphery in motor coordination. We show how different afferent feedback signals about the status of the different components of the motor apparatus play a critical role in motor control as well as in learning. This paper, along with its companion paper, extend the model by Liaw et al. (1994) by integrating a number of different motor pattern generators, different types of afferent feedback, as well as the corresponding control structure within an adaptive framework we call Schema-Based Learning. We develop a model of the different MPGs involved in prey-catching as a vehicle to investigate the following questions: What are the characteristic features of the activity of a single muscle? How can these features be controlled by the premotor circuit? What are the strategies employed to generate and synchronize motor synergies? What is the role of afferent feedback in shaping the activity of a MPG? How can several MPGs share the same underlying circuitry and yet give rise to different motor patterns under different input conditions? In the companion paper we also extend the model by incorporating learning components that give rise to more flexible, adaptable and robust behaviors. To show these aspects we incorporate studies on experiments on lesions and the learning processes that allow the animal to recover its proper functioning     

Fire,Heroes and the Cosmic: Aesthetic Resonances of Fire‐walking in Northern Greece

In the Greek village of Mavrolefki in Thrace, a small number of women and men. about ten in number, once a year, on the feast day of St. Constantine, undertake a series of rites, ranging from dancing to the icons, blood sacrifice, to the most spectacular fire‐walking (pyrovasia). It is the last which brings spectators from all over Greece and further afield. The principal participants, however, are known as the anastenarides (shakers, tremblers). Several concerns are addressed in the paper. Given the peculiar mix of proceedings, the first is to lay out the components of the affair, asking what's going on? Furthermore, there are the conceptual issues. What aesthetic is being implicated? What emotions are being brought into play? What does the event amount to? In addressing such questions the paper draws on certain aesthetic formulations of the Hindu rasa theory.     

Abduction: Can Non-human Animals Make Discoveries?

The aim of this paper is to investigate the relationship between information and abductive reasoning in the context of problem-solving, focusing on non-human animals. Two questions guide our investigation: (1) What is the relation between information and abductive reasoning in the context of human and non-human animals? (2) Do non-human animals perform discovery based on inferential processes such as abductive reasoning? In order to answer these questions, we discuss the semiotic concept of information in relation to the concept of abductive reasoning and, more specifically, to the notion of manipulative abduction proposed by Magnani (2009). Finally, we investigate a case study of corvids’ intelligence, namely, their capacity of causal cognition.     

EMPIRICAL ETHICS AS DIALOGICAL PRACTICE

In this article, we present a dialogical approach to empirical ethics, based upon hermeneutic ethics and responsive evaluation. Hermeneutic ethics regards experience as the concrete source of moral wisdom. In order to gain a good understanding of moral issues, concrete detailed experiences and perspectives need to be exchanged. Within hermeneutic ethics dialogue is seen as a vehicle for moral learning and developing normative conclusions. Dialogue stands for a specific view on moral epistemology and methodological criteria for moral inquiry. Responsive evaluation involves a structured way of setting up dialogical learning processes, by eliciting stories of participants, exchanging experiences in (homogeneous and heterogeneous) groups and drawing normative conclusions for practice. By combining these traditions we develop both a theoretical and a practical approach to empirical ethics, in which ethical issues are addressed and shaped together with stakeholders in practice. Stakeholders' experiences are not only used as a source for reflection by the ethicist; stakeholders are involved in the process of reflection and analysis, which takes place in a dialogue between participants in practice, facilitated by the ethicist. This dialogical approach to empirical ethics may give rise to questions such as: What contribution does the ethicist make? What role does ethical theory play? What is the relationship between empirical research and ethical theory in the dialogical process? In this article, these questions will be addressed by reflecting upon a project in empirical ethics that was set up in a dialogical way. The aim of this project was to develop and implement normative guidelines with and within practice, in order to improve the practice concerning coercion and compulsion in psychiatry.     

Primatology: the beginning

The journal Primates was founded by Kinji Imanishi (1902–1992) in 1957: It is the oldest and longest-running international primatology journal in the world. In this series of dialogues between Tetsuro Matsuzawa, Editor-in-Chief of Primates and the General Director of the Japan Monkey Centre (JMC) and Juichi Yamagiwa, former Editor-in-Chief of Primates and the Museum Director of the JMC, we look back at the achievements of our spiritual ancestors in primate research and talk about the back story of Imanishi and his fellow primatologists: founding the JMC as a research institute focused on primates and launching this journal. What was their motivation? What challenges did they face? What is their continued influence on the field right up to the present? What will be the legacy of our influence on the discipline?     

Pathogen recognition and signal transduction by the Pto kinase

In tomato, the disease resistance genePto confers resistance to bacterial speck disease by recognizing the expression of a corresponding avirulence gene,avrPto, in the pathogenPseudomonas syringae pv.tomato (Martinet al. 1993). Similar “gene-for-gene” interactions occur in many plant-pathogen associations (Flor 1971). Such recognition events often lead to the activation in the plant of a variety of defense responses including a rapid induction of localized necrosis at the site of infection (the hypersensitive response, HR), increased expression of defense-related genes, production of antimicrobial compounds, lignin formation, and the oxidative burst (Lambet al. 1989, Mehdy 1994). As a result, the pathogen is contained at the infection site and its growth is inhibited.Pto encodes a serine/threonine protein kinase and belongs to a clustered multigene family. Another member of thePto family calledFen confers no known disease resistance, but mediates a hypersensitive-like reaction in the plant to the insecticide fenthion (Martinet al. 1994). We are interested in a number of fundamental questions concerning the Pto signaling pathways. What is the molecular basis of thePto-avrPto gene-for-gene interaction? What are the components involved in thePto-mediated signal transduction chain? How does thePto kinase activate complex defense responses? This paper summarizes our recent progress towards understanding these questions.     

Class II phosphoinositide 3-kinase C2alpha: what we learned so far

More than fifteen years after the first identification of a class II isoform of phosphoinositide 3-kinase (PI3K) in Drosophila melanoǵaster this subfamily remains the most enigmatic among all PI3Ks. What are the functions of these enzymes? What are their mechanisms of activation? Which downstream effectors are specifically regulated by these isoforms? Are class I and class II PI3Ks redundant or do they control different intracellular processes? And, more important, do class II PI3Ks have a role in human diseases? The recent increased interest on class II PI3Ks has started providing some answers to these questions but still a lot needs to be done to completely uncover the contribution of these enzymes to physiological processes and possibly to pathological conditions. Here we will summarise the recent findings on the alpha isoform of mammalian class II PI3Ks (PI3K-C2α ) and we will discuss the potential involvement of this enzyme in human diseases.     

L’anonymat dans l’insémination avec don de sperme: un regard éthique

Which is the link between secret and anonymity in the case of donor insemination? Do we need to know the name of our donor in order to understand our own personal history? What does the term origin mean? This article aims to analyze such questions from a philosophical point of view, in order to show the difference existing between secret — which concerns conception — and anonymity, which deals with the name of the sperm donor.     

Early prehistory of South America and population dynamics: Issues and hypotheses

People were in the Americas before, during, and immediately after the Last Glacial Maximum. Multiple data converge toward a deep chronology model for Homo genre exploration, dispersal, occupation, and settlement across the continent. South America is not an exception. This paper is an attempt to think of South America record in terms of population dynamics within a Paleolithic reflection: What are the anthropological implications of a longer and therefore slower peopling process? What modes of expansion, rhythms, adaptations, routes could be traced base especially in lithic records? What kind of archaeological manifestations should we expect in the different environments that make up an immense and highly diverse geography? What modes of technological continuity and change could be linked to these manifestations? Although further research is still needed to address these questions, our goal is to contribute to posing the problem in the most holistic way possible, linking climate, environment, and techno-cultural data within and beyond South America, in order to model how populations might have expanded and contracted at different periods throughout this subcontinent.     

Interactions between intrinsic membrane protein and electric field. An approach to studying nerve excitability

We have approached the problem of nerve excitability through three questions: (a) What is the diagram for a channel? That is, what conformational states can the protein assume, and what transitions between these conformations are permitted? (b) What is the channel conductance associated with each conformation the channel can assume? (c) How do the rates for conformational transition depend upon membrane potential? These three questions arise from a standard statistical mechanical treatment of a nerve membrane containing several classes of identical, independent channels. Gating of channels, in this view, is associated with conformational changes of the channel protein, and it is assumed these conformations are distinct. The precise formulation of these questions is presented in terms of the theoretical treatment, and the approaches we have taken to answer the questions are indicated. Our present results indicate: Transition rates should depend exponentially on membrane potential over a limited voltage range, but probably will show a more complex dependence for extremes of the range; channels probably can take on only two conductances, open and shut, but more complicated situations are not entirely excluded; the diagram for a channel cannot be determined from standard voltage clamp data alone, but by studying gating currents and conductance fluctuations, it should be possible to select between alternative plausible physical mechanisms.     

Is affordable and cost-effective assisted reproductive technology in low-income countries possible? What should we know to answer the question?

¹ Correspondence address. E-mail: j.d.f.habbema{at}erasmusmc.nl Decision making on infertility treatment in low-income countries(LIC) assumes answers to quite a few questions: how should theinfertility problem be defined? How often does infertility occur?What is the burden-of-disease of infertility? What is the incomein LIC, and what can be spend on health care? How cheap shouldIVF be in order to be accessible to a considerable part of thepopulation? With what alternative health interventions shouldinfertility treatment be compared? How cost-effective shouldIVF be in order to compete with those other interventions? Thesequestions will be discussed. The emphasis is on the situationin Sub-Saharan Africa (SSA). It is concluded that a place forART in a health care package is not straightforward. Many ofthe questions are not or only partially answered. Moreover,cheap and effective ART has yet to be developed and tested.From the limited evidence available for each of the questions,it could be calculated that an IVF cycle should cost between50 and 75 dollar in order to be a candidate for the inclusionin a health package in SSA. This estimate can easily changeconsiderably when in the future the calculations will be basedon thorough research. Thus, a targeted research programme foranswering the open questions, especially on quality-of-lifeimplications of infertility in different societies, is the preferredoption for facilitating the future evaluation of ART in LIC.     

Involvement of autophagy and mitochondrial dynamics in determining the fate and effects of irreparable mitochondrial DNA damage

Mitochondrial DNA (mtDNA) is different in many ways from nuclear DNA. A key difference is that certain types of DNA damage are not repaired in the mitochondrial genome. What, then, is the fate of such damage? What are the effects? Both questions are important from a health perspective because irreparable mtDNA damage is caused by many common environmental stressors including ultraviolet C radiation (UVC). We found that UVC-induced mtDNA damage is removed slowly in the nematode Caenorhabditis elegans via a mechanism dependent on mitochondrial fusion, fission, and autophagy. However, knockdown or knockout of genes involved in these processes—many of which have homologs involved in human mitochondrial diseases—had very different effects on the organismal response to UVC. Reduced mitochondrial fission and autophagy caused no or small effects, while reduced mitochondrial fusion had dramatic effects.     

Research versus practice: The dilemmas of research ethics in the era of learning health‐care systems

In this article we attempt to answer the question of how the ethical and conceptual framework (ECF) for a learning health‐care system (LHS) affects some of the main controversies in research ethics by addressing five key problems of research ethics: (a) What is the difference between practice and research? (b) What is the relationship between research ethics and clinical ethics? (c) What is the ethical relevance of the principle of clinical equipoise? (d) Does participation in research require a higher standard of informed consent than the practice of medicine? and (e) What ethical principle should take precedence in medicine? These questions allow us to construct two opposite idealized positions on the distinction between research and practice: the integration model and the segregation model of research and practice. We then compare the ECF for an LHS with these two idealized positions. We argue that the ECF for a LHS does not, in fact, solve these problems, but that it is a third, separate position in the relationship between research ethics and clinical ethics. Moreover, we suggest that the ECF for a LHS raises new ethical problems that require additional ethical analysis and justification. Our article contributes to the discussion on the relationship between research ethics and clinical ethics, revealing that although a learning health‐care system may significantly change the landscape of health care, some ethical dilemmas still require resolving on both theoretical and policy‐making levels.     

Fifteen compelling open questions in plant cell biology

As scientists, we are at least as excited about the open questions—the things we do not know—as the discoveries. Here, we asked 15 experts to describe the most compelling open questions in plant cell biology. These are their questions: How are organelle identity, domains, and boundaries maintained under the continuous flux of vesicle trafficking and membrane remodeling? Is the plant cortical microtubule cytoskeleton a mechanosensory apparatus? How are the cellular pathways of cell wall synthesis, assembly, modification, and integrity sensing linked in plants? Why do plasmodesmata open and close? Is there retrograde signaling from vacuoles to the nucleus? How do root cells accommodate fungal endosymbionts? What is the role of cell edges in plant morphogenesis? How is the cell division site determined? What are the emergent effects of polyploidy on the biology of the cell, and how are any such “rules” conditioned by cell type? Can mechanical forces trigger new cell fates in plants? How does a single differentiated somatic cell reprogram and gain pluripotency? How does polarity develop de-novo in isolated plant cells? What is the spectrum of cellular functions for membraneless organelles and intrinsically disordered proteins? How do plants deal with internal noise? How does order emerge in cells and propagate to organs and organisms from complex dynamical processes? We hope you find the discussions of these questions thought provoking and inspiring.

We asked 15 experts to address what they consider to be the most compelling open questions in plant cell biology and these are their questions.