Rethinking the role of theory in exploratory experimentation

To explain their role in discovery and contrast them with theory-driven research, philosophers of science have characterized exploratory experiments in terms of what they lack: namely, that they lack direction from what have been called “local theories” of the target system or object under investigation. I argue that this is incorrect: it’s not whether or not there is direction from a local theory that matters, but instead how such a theory is used to direct an experiment that matters. Appealing to contemporary exploratory experiments that involve the use of experimental techniques—specifically, examples where scientists explore the interaction of neural activity and human behavior by magnetically stimulating brains—I argue that local theories of a target system can inform auxiliary hypotheses in exploratory experiments, which direct these experiments. These examples illustrate how local theories can direct the exploration of target systems where researchers do not aim to evaluate these theories.     

Explanation and Falsification in Phylogenetic Inference: Exercises in Popperian Philosophy

Deduction leads to causal explanation in phylogenetic inference when the evidence, the systematic character, is conceptualized as a transformation series. Also, the deductive entailment of modus tollens is satisfied when those kinds of events are operationalized as patristic difference. Arguments to the contrary are based largely on the premise that character-states are defined intensionally as objects, in terms of similarity relations. However, such relations leave biologists without epistemological access to the causal explanation and explanatory power of historical statements. Moreover, the prediction-making to which those kinds of relations are limited in practice can lead to a category error—the mental conversion of an abstraction (the classes defined in terms of similarity relations) into a thing (such as an historical individual). The latter practices and problems characterize pattern cladistics, taxa being interpreted as homeostatic property cluster natural kinds, and other instrumentalist research programs.     

Meet the new mammoth,same as the old? Resurrecting the <Emphasis Type="Italic">Mammuthus primigenius</Emphasis>

Media reporters often announce that we are on the verge of bringing back the woolly mammoth, even while there is growing consensus among scientists that resurrecting the mammoth is unlikely. In fact, current “de-extinction” efforts are not designed to bring back a mammoth, but rather adaptations of the mammoth using close relatives. For example, Harvard scientists are working on creating an Asian elephant with the thick coat of a mammoth by merging mammoth and elephant DNA. But how should such creatures be classified? Are they elephants, mammoths, or both? Answering these questions requires getting clear about the concept of reproduction. What I hope to show is that with an appropriate notion of reproduction—one for which I will argue—resurrecting a member of Mammuthus primigenius is a genuine possibility.     

A hybrid systems framework for cellular processes

With the availability of technologies that allow us to obtain stimulus-response time series data for modeling and system identification, there is going to be an increasing need for conceptual frameworks in which to formulate and test hypotheses about intra- and inter-cellular dynamics, in general and not just dependent on a particular cell line, cell type, organism, or technology. While the semantics can be quite different, biologists and systems scientists use in many cases a similar language (notion of feedback, regulation, etc.). A more abstract system-theoretic framework for signals, systems, and control could provide the biologist with an interface between the domains. Apart from recent examples to identify functional elements and describing them in engineering terms, there have been various more abstract developments to describe dynamics at the cell level in the past. This includes Rosen's (M,R)-systems. This paper presents an abstract and general compact mathematical framework of intracellular dynamics, regulation and regime switching inspired by (M,R)-theory and based on hybrid automata.     

Finding the good: Reactive modernity among the Gebusi,in the Pacific,and elsewhere

Conditions of being left behind in economic and political terms are keenly felt in many areas of Melanesia and the wider Pacific Islands—as is more generally the case in many developing and also developed countries. Insofar as modern expectations portend a future that should be improving, it is unsurprising that modern expectations or entitlements are throttled by economic and political downturns across many cultural and class conditions. Ensuing circumstances are not so much ‘post’ modern—since ideals of modern progress are not given up—as they are ‘reactively’ modern in cultural terms. In this context, a poignant and longstanding sense of backwardness in many areas of the insular Pacific arguably provides a cultural bellwether of increasingly widespread perceptions and reactions elsewhere. Among the Gebusi of Papua New Guinea prolonged economic downturn under conditions of marginality and remoteness has thrown people back on their own material and cultural resources. Despite a general absence of cash economy, monetisation or fiscalisation of ‘work’ increasingly orchestrates social relations. So, too, in the absence of government presence, police, or courts, mechanisms of dispute mediation have become locally developed and effectively elaborated, including through rhetorics of monetary compensation that were previously undeveloped in indigenous contexts of person‐for‐person exchange both in marriage and in death. In selected ways, reactive modernity among Gebusi has features that seem salutary—evoking an ‘anthropology of the good’—despite and even because of Gebusi's politicoeconomic marginality. Drawing on work by Ortner, Robbins, and others, the larger relevance of this development reframes the relevance of Dark Anthropology and an Anthropology of the Good.     

Application of dynamic flux balance analysis to an industrial Escherichia coli fermentation

We have developed a reactor-scale model of Escherichia coli metabolism and growth in a 1000L process for the production of a recombinant therapeutic protein. The model consists of two distinct parts: (1) a dynamic, process specific portion that describes the time evolution of 37 process variables of relevance and (2) a flux balance based, 123-reaction metabolic model of E. coli metabolism. This model combines several previously reported modeling approaches including a growth rate-dependent biomass composition, maximum growth rate objective function, and dynamic flux balancing. In addition, we introduce concentration-dependent boundary conditions of transport fluxes, dynamic maintenance demands, and a state-dependent cellular objective. This formulation was able to describe specific runs with high-fidelity over process conditions including rich media, simultaneous acetate and glucose consumption, glucose minimal media, and phosphate depleted media. Furthermore, the model accurately describes the effect of process perturbations—such as glucose overbatching and insufficient aeration—on growth, metabolism, and titer.     

What mechanisms can’t do: Explanatory frameworks and the function of the p53 gene in molecular oncology

What has been called the new mechanistic philosophy conceives of mechanisms as the main providers of biological explanation. We draw on the characterization of the p53 gene in molecular oncology, to show that explaining a biological phenomenon (cancer, in our case) implies instead a dynamic interaction between the mechanistic level—rendered at the appropriate degree of ontological resolution—and far more general explanatory tools that perform a fundamental epistemic role in the provision of biological explanations. We call such tools “explanatory frameworks”. They are called frameworks to stress their higher level of generality with respect to bare mechanisms; on the other hand, they are called explanatory because, as we show in this paper, their importance in explaining biological phenomena is not secondary with respect to mechanisms. We illustrate how explanatory frameworks establish selective and local criteria of causal relevance that drive the search for, characterisation and usage of biological mechanisms. Furthermore, we show that explanatory frameworks allow for changes of scientific perspective on the causal relevance of mechanisms going beyond the account provided by the new mechanistic philosophy.     

A two-sex life history model of handicap signaling

The males of many species (such as peacocks) develop excessively large traits, which appear to interfere with their agility and hence survival probability. Moreover, it is also observed that females seem to prefer mating males with such clumsy traits. Zahavi (1975) proposed a handicap theory to explain this phenomenon, suggesting that this trait/preference interaction is a way in which strong males can signal their viability by yielding a handicap in terms of a clumsy trait size. This paper presents a two-sex model of selfish genes that generates this particular male-female interaction, and characterizes the conditions behind a handicap equilibrium. We first show the female dominance result of Bateman (1948) in this two-sex model, and then specify the relevant equilibrium conditions, including the incentive compatibility condition for females, the individual rationality condition for males, and the stability condition of population composition. Identifying these conditions helps us understand the various features of the searching/signaling of sex selection in evolution.     

Effect size measures and their benchmark values for quantifying benefit or risk of medicinal products

The standardized mean difference is a well‐known effect size measure for continuous, normally distributed data. In this paper we present a general basis for important other distribution families. As a general concept, usable for every distribution family, we introduce the relative effect, also called Mann–Whitney effect size measure of stochastic superiority. This measure is a truly robust measure, needing no assumptions about a distribution family. It is thus the preferred tool for assumption‐free, confirmatory studies. For normal distribution shift, proportional odds, and proportional hazards, we show how to derive many global values such as risk difference average, risk difference extremum, and odds ratio extremum. We demonstrate that the well‐known benchmark values of Cohen with respect to group differences—small, medium, large—can be translated easily into corresponding Mann–Whitney values. From these, we get benchmarks for parameters of other distribution families. Furthermore, it is shown that local measures based on binary data (2 × 2 tables) can be associated with the Mann–Whitney measure: The concept of stochastic superiority can always be used. It is a general statistical value in every distribution family. It therefore yields a procedure for standardizing the assessment of effect size measures. We look at the aspect of relevance of an effect size and—introducing confidence intervals—present some examples for use in statistical practice.     

Exergy‐Based Population Dynamics

This article discusses whether “sustainability” has a physical meaning in applied thermodynamics. If it has, then it should be possible to derive general principles and rules for devising “sustainable systems.” If not, then other sides of the issue retain their relevance, but thermodynamic laws are not appropriate by themselves to decide whether a system or a scenario is sustainable. Here, we make use of a single axiom: that final consumption (material or immaterial) can be quantified solely in terms of equivalent primary exergy flows. On this basis, we develop a system theory that shows that if “simple” systems are based solely on the exploitation of fossil resources, they cannot be thermodynamically “sustainable.” But as renewable resources are brought into the picture and the system complexity grows, there are thresholds below or beyond which the system exhibits an ability to maintain itself (perhaps through fluctuations), in a self‐preserving (i.e., a sustainable) state. It appears that both complexity and the degree of nonlinearity of the transfer functions of the systems play a major role and—even for some of the simplest cases—lead to nontrivial solutions in phase space. Therefore, even if the examples presented in the article can be considered rather crude approximations to real, complex systems at best, the results show a trend that is worth further consideration.     

Annual rhythms that underlie phenology: biological time-keeping meets environmental change

Seasonal recurrence of biological processes (phenology) and its relationship to environmental change is recognized as being of key scientific and public concern, but its current study largely overlooks the extent to which phenology is based on biological time-keeping mechanisms. We highlight the relevance of physiological and neurobiological regulation for organisms’ responsiveness to environmental conditions. Focusing on avian and mammalian examples, we describe circannual rhythmicity of reproduction, migration and hibernation, and address responses of animals to photic and thermal conditions. Climate change and urbanization are used as urgent examples of anthropogenic influences that put biological timing systems under pressure. We furthermore propose that consideration of Homo sapiens as principally a ‘seasonal animal’ can inspire new perspectives for understanding medical and psychological problems.     

HMB supplementation: clinical and athletic performance-related effects and mechanisms of action

Amino acids such as leucine and its metabolite α-ketoisocaproate (KIC), are returning to be the focus of studies, mainly because of their anti-catabolic properties, through inhibition of muscle proteolysis and enhancement of protein synthesis. It is clear that these effects may counteract catabolic conditions, as well as enhance skeletal muscle mass and strength in athletes. Moreover, beta-hydroxy-beta-methylbutyrate (HMB) has been shown to produce an important effect in reducing muscle damage induced by mechanical stimuli of skeletal muscle. This review aims to describe the general scientific evidence of KIC and HMB supplementation clinical relevance, as well as their effects (e.g., increases in skeletal muscle mass and/or strength), associated with resistance training or other sports. Moreover, the possible mechanisms of cell signaling regulation leading to increases and/or sparing (during catabolic conditions) of skeletal muscle mass are discussed in detail based on the recent literature.     

Testosterone increases perceived dominance but not attractiveness in human males

Recent evidence suggests that certain features on the human face indicate hormonal levels during growth, and that women judge the attractiveness of potential partners based on the appearance of these features. One entrenched notion is male facial features that are affected by testosterone are used as direct cues in mate preference. Testosterone may be particularly revealing as it is purported to be an honest indicator of male fitness. Increased testosterone may impose an immunocompetence handicap on the bearer and only the best males can carry this handicap. To date, tests of this theory have been indirect, and have relied on digital manipulations that represent unrealistic continuums of masculine and feminine faces. We provide a much more direct test by manipulating digitally male faces to mimic known shape variation, caused by varying levels of testosterone through puberty. We produced a continuum of faces that ranged from low to high levels of testosterone in male faces and asked women to choose the points on the continuum that appeared most attractive and most physically dominant. Our data indicate that high testosterone faces reveal dominance. However, there is no evidence of directional selection for increased (or decreased) testosterone in terms of attractiveness to the opposite sex. We discuss the relevance and applicability of evolutionary interpretations of our data and, contrary to predictions, provide evidence of stabilizing selection acting on testosterone through mate preferences.     

Tarsiers,adapids and the integrity of Strepsirhini

Although strepsirhine primates can be described by their narial configuration, this and most other definable features are probably primitive retentions; only the development of a grooming claw of the second pedal digit and of a toothcomb (the latter of which has been lost in Daubentonia) emerge as potential apomorphies of the group. Within this assemblage lemurids, Lepilemur, the indriids, and Daubentonia can be argued to constitute a monophyletic group whose relationships cladistically are in the sequence listed; Lemuridae and Indriidae can themselves be delineated as monophyletic groups. The remaining strepsirhine primates—the cheirogaleids, galagids, and lorisids—also appear to constitute a definable clade, with the former group representing the sister taxon of the latter two families; cach family can be united on the basis of distinct synapomorphies. Although there are features—especially of the ear region—which present themselves as potentially reflective of the sister relationship of Tarsius + Anthropoidea, other characters, including the possession of the grooming claw, are suggestive of an alternative scheme: Tarsius may be the sister of the extant lorisiform group, thereby reconstituting, albeit in a novel form, the primate suborder Prosimii. It also appears that fossil “tarsioids” may in fact be more closely related to the extant lorisiforms than to Tarsius. A reconsideration of the so-called fossil lemurs, the adapids, leads to the conclusion that Adapis-like primates are a clade apart from Pelycodus, Notharctus, Smilodectes and their most immediate relatives, and may themselves constitute a clade that is related as the primitive sister to all other “prosimians” by virtue of the development of the so-called free intrabullar tympanic ring.     

Perspectives on setting success criteria for wetland restoration

The task of determining the success of wetland restoration has long been challenging and sometimes contentious because success is an imprecise term that means different things in different situations and to different people. Compliance success is determined by evaluating compliance with the terms of an agreement, e.g. a contract or permit, whereas functional success is determined by evaluating whether the ecological functions of the system have been restored. Compliance and functional success have historically focused on the individual project (the site being restored); we are only beginning to consider another important factor, the success of restoration at the landscape scale. Landscape success is a measure of how restoration (or management, in general) has contributed to the ecological integrity of the region or landscape and to achievement of goals such as the maintenance of biodiversity. The utility of all definitions of success is ultimately constrained by the current status of the science of restoration ecology and by our ability to use that information to make sound management decisions and to establish measurable success criteria. Measurements of vegetation are most commonly used in evaluations of restoration projects, with less frequent analysis of soils, fauna, and hydrologic characteristics. Although particular characteristics of projects, such as vegetative cover and production, can resemble those in similar naturally occurring wetlands, overall functional equivalency has not been demonstrated. However, ongoing research is providing information on what can and cannot be accomplished, valuable insights on how to correct mistakes, and new approaches to defining success. The challenge is how to recognize and deal with the uncertainty, given that projects are ecologically young and that our knowledge of the process of restoration is evolving. One way to deal with the uncertainty is to use scientific principles of hypothesis testing and model building in an adaptive management framework. In this way, options can be systematically evaluated and needs for corrective actions identified when a project is not progressing toward goals. By taking such an approach we can improve our ability to reliably restore wetlands while contributing to our understanding of the basic structure and function of ecosystems.     

Minimization of intermediate concentrations as a suggested optimality principle for biochemical networks

The criterion of minimum intermediate concentrations in steady states is suggested to be of essential relevance in the evolution of biochemical reaction networks. This extremum principle is phrased in two different ways, firstly in terms of total osmolarity of intermediates and, secondly, as a multiple criterion problem. The relationships between the two problems are elucidated and a solving method for the latter is then given. It turns out that in each optimal state, the network can be subdivided into a slow and a fast subsystem. The notion of convex conservation relations is introduced and the implications of such relations for the optimization problem are investigated.     

A Massively Parallel Pipeline to Clone DNA Variants and Examine Molecular Phenotypes of Human Disease Mutations

Understanding the functional relevance of DNA variants is essential for all exome and genome sequencing projects. However, current mutagenesis cloning protocols require Sanger sequencing, and thus are prohibitively costly and labor-intensive. We describe a massively-parallel site-directed mutagenesis approach, “Clone-seq”, leveraging next-generation sequencing to rapidly and cost-effectively generate a large number of mutant alleles. Using Clone-seq, we further develop a comparative interactome-scanning pipeline integrating high-throughput GFP, yeast two-hybrid (Y2H), and mass spectrometry assays to systematically evaluate the functional impact of mutations on protein stability and interactions. We use this pipeline to show that disease mutations on protein-protein interaction interfaces are significantly more likely than those away from interfaces to disrupt corresponding interactions. We also find that mutation pairs with similar molecular phenotypes in terms of both protein stability and interactions are significantly more likely to cause the same disease than those with different molecular phenotypes, validating the in vivo biological relevance of our high-throughput GFP and Y2H assays, and indicating that both assays can be used to determine candidate disease mutations in the future. The general scheme of our experimental pipeline can be readily expanded to other types of interactome-mapping methods to comprehensively evaluate the functional relevance of all DNA variants, including those in non-coding regions.     

Mutant mice: Experimental organisms as materialised models in biomedicine

Animal models have received particular attention as key examples of material models. In this paper, we argue that the specificities of establishing animal models—acknowledging their status as living beings and as epistemological tools—necessitate a more complex account of animal models as materialised models. This becomes particularly evident in animal-based models of diseases that only occur in humans: in these cases, the representational relation between animal model and human patient needs to be generated and validated. The first part of this paper presents an account of how disease-specific animal models are established by drawing on the example of transgenic mice models for Alzheimer’s disease. We will introduce an account of validation that involves a three-fold process including (1) from human being to experimental organism; (2) from experimental organism to animal model; and (3) from animal model to human patient. This process draws upon clinical relevance as much as scientific practices and results in disease-specific, yet incomplete, animal models. The second part of this paper argues that the incompleteness of models can be described in terms of multi-level abstractions. We qualify this notion by pointing to different experimental techniques and targets of modelling, which give rise to a plurality of models for a specific disease.