From Fertilization to Adult Sexual Behavior

Research has established the broad mammalian developmental plan that genes on the sex chromosomes influence gonad development which determines gonadal hormone production (or its absence) leading to modification of the genitalia and simultaneously biasing the nervous system to organize adult sexual behavior. This might be considered the “gonad to hormones to behavior” model. It is clear, however, that although this model generally works well it is incomplete. The model does not account for behavioral influences attributed to the environment or to genetic but nongonadal or hormonal factors. In this essay we probe those areas of sexual development that are neither differentiated by hormones nor activated by them. The concept of the environment used for our discussion is very broad; it incorporates considerations of both the molar and the molecular levels. The general sense of the word “environment” as something exterior to the person is retained, even if that something influences intraperson processes. In addition, we focus directly on molecular events themselves. Here the “environment” involved can be that within a DNA segment. We also expand the notion of “biologically based sex differences.” Although many, and perhaps most, important sex differences arise from gonadal and hormonal development, also important are sex differences which are neither gonadal nor hormonal. All these factors affect the internal workings of the individual and intervene in structuring how the social environment might or might not modify sexual behavior. This discourse calls attention to features that are central to the so-called nature–nurture discussion.     

Levels of biological plausibility

Notions of mechanism, emergence, reduction and explanation are all tied to levels of analysis. I cover the relationship between lower and higher levels, suggest a level of mechanism approach for neuroscience in which the components of a mechanism can themselves be further decomposed and argue that scientists'' goals are best realized by focusing on pragmatic concerns rather than on metaphysical claims about what is ‘real''. Inexplicably, neuroscientists are enchanted by both reduction and emergence. A fascination with reduction is misplaced given that theory is neither sufficiently developed nor formal to allow it, whereas metaphysical claims of emergence bring physicalism into question. Moreover, neuroscience''s existence as a discipline is owed to higher-level concepts that prove useful in practice. Claims of biological plausibility are shown to be incoherent from a level of mechanism view and more generally are vacuous. Instead, the relevant findings to address should be specified so that model selection procedures can adjudicate between competing accounts. Model selection can help reduce theoretical confusions and direct empirical investigations. Although measures themselves, such as behaviour, blood-oxygen-level-dependent (BOLD) and single-unit recordings, are not levels of analysis, like levels, no measure is fundamental and understanding how measures relate can hasten scientific progress.This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity''.     

Mechanistic models of population-level phenomena

This paper is about mechanisms and models, and how they interact. In part, it is a response to recent discussion in philosophy of biology regarding whether natural selection is a mechanism. We suggest that this debate is indicative of a more general problem that occurs when scientists produce mechanistic models of populations and their behaviour. We can make sense of claims that there are mechanisms that drive population-level phenomena such as macroeconomics, natural selection, ecology, and epidemiology. But talk of mechanisms and mechanistic explanation evokes objects with well-defined and localisable parts which interact in discrete ways, while models of populations include parts and interactions that are neither local nor discrete in any actual populations. This apparent tension can be resolved by carefully distinguishing between the properties of a model and those of the system it represents. To this end, we provide an analysis that recognises the flexible relationship between a mechanistic model and its target system. In turn, this reveals a surprising feature of mechanistic representation and explanation: it can occur even when there is a mismatch between the mechanism of the model and that of its target. Our analysis reframes the debate, providing an alternative way to interpret scientists’ “mechanism-talk”, which initially motivated the issue. We suggest that the relevant question is not whether any population-level phenomenon such as natural selection is a mechanism, but whether it can be usefully modelled as though it were a particular type of mechanism.     

Genic homozygosity in an ancient reptile (Alligator mississippiensis)

Proteins assayed electrophoretically showed variation at only three of 49 presumed genetic loci in alligators from southwestern Louisiana. Average heterozygosity per individual was 0.021±0.012; proportion of polymorphic loci was 0.06. Data on the history, structure, and ecology of this alligator population are consistent with natural selection as the primary factor accounting for this low genetic variability. However, neither a historic population bottleneck nor some genetic mechanism limiting variability can be dismissed as a possible factor.The study was supported by NSF Grant BMS 73-0125 to H.C.D.     

The Ecology of Defensive Medicine and Malpractice Litigation

Using an evolutionary game, we show that patients and physicians can interact with predator-prey relationships. Litigious patients who seek compensation are the ‘predators’ and physicians are their ‘prey’. Physicians can adapt to the risk of being sued by performing defensive medicine. We find that improvements in clinical safety can increase the share of litigious patients and leave unchanged the share of physicians who perform defensive medicine. This paradoxical result is consistent with increasing trends in malpractice claims in spite of safety improvements, observed for example in empirical studies on anesthesiologists. Perfect cooperation with neither defensive nor litigious behaviors can be the Pareto-optimal solution when it is not a Nash equilibrium, so maximizing social welfare may require government intervention.     

Hormone receptor mobility and catecholamine binding in membranes. A theoretical model

[³ H]-Catecholamine binding to intact cells, isolated cell membranes, and to several isolated macromolecules has been shown by several laboratories to be neither stereospecific nor inhibited by known β-antagonists. Since additional evidence indicates that this binding is not an artifact (i.e. due neither to the binding of a catecholamine oxidation product nor hormone binding to a catabolic enzyme such as COMT), the question remains as to whether this represents binding to a bona fide membrane receptor. Because all ligands which bind strongly or compete for this binding possess a catechol group, one possible explanation is that the binding affinity is primarily determined by the catechol moiety, whereas the correct stereoisomer of the side chain is necessary to activate the receptor. Thus, although binding is a necessary condition for hormone action, the necessary and sufficient condition for activation of adenyl cyclase is both the catechol group and the correct stereoisomer of the side chain. A theoretical model is developed here to provide a quantitative basis for this hypothesis. This model extends the current concept of distinct subunits in the adenyl cyclase system by separating the receptors from the catalytic sites and placing them at separate locations within the membrane. Utilizing the spare receptor model of Furchgott, and the mobility of macromolecules within a “lipid sea,” the appropriate equations to predict both hormone binding and enzyme activation are derived. Using the observed affinity constants from catecholamine binding studies, it is then shown that this model can predict the experimental observations and hence explain the apparent dichotomy arising from binding and enzyme activation studies.     

The nonexistence of “hermaphoroditic” tracer systems

This communiction argues that so-called “hermaphroditic” tracer systems, which are neither open nor closed, do not exist physically. The argument is based on the assumption that any observable (possibly nonhomogeneous) macroscopic compartment can be approximated by a compartmentC with a finite number of entry points for the tracer, each associated with an abstract subcompartment ofC. It is shown that the “hermaphroditic” property requires that the mean waiting time be infinite in at least one of the subcompartments, or in a subcompartment elsewhere in the system. A subcompartment with infinite mean waiting time must have some sort of memory, of infinite duration, which knows how long a given particle has been retained, however long that is, and thereby determines its probability of departure. Assuming, as seems likely, that no physical basis exists for such an infinite memory, it follows that “hermaphroditic” systems do not exist. Supported in part by U.S. Public Health Service Research Grant GM 21269 from the National Institute of General Medical Sciences, and in part by Biomedical Research Support Grant S07 RR 05392 from the National Institutes of Health.     

The Utility of the Proximate-Ultimate Dichotomy in Ethology

We defend the organizing principle that there are fundamentally different levels of analysis in biology, notably proximate and ultimate. Despite recent claims to the contrary, the proximate-ultimate distinction is a true dichotomy, not an artificial division of a continuum. Acceptance of this dichotomy does not imply that ultimate questions are of greater importance than those dealing with proximate mechanisms, nor does it result in confusion of current reproductive consequences with evolutionary causes.     

To be Makiran is to see like Mr Parrot: the anthropology of wonder in Solomon Islands

This article lays out a general thesis for the development of a comparative ethnographic approach to the anthropology of wonder. It suggests that wonder is both an index and a mode of challenge to existing ontological premises. Through analytical engagement with the theme of wonder in Western philosophy and the anthropology of ontology, it extends this thesis to include the corollary that different ontological premises give rise to different wonders. Ethnographically, the article supports these claims via analysis of wonder discourses among the Arosi of Solomon Islands. These discourses, it is argued, both respond to and promote ontological transformations in a context where the premises at stake are neither those of the Cartesian dualism commonly ascribed to modernity nor of the relational non‐dualism commonly ascribe to anthropology's ethnographic ‘others’, but of a non‐Cartesian pluralism termed poly‐ontology.     

Retrospective analysis of sequential dose-finding designs

The continual reassessment method (CRM) is a dose-finding design using a dynamic sequential updating scheme. In common with other dynamic schemes the method estimates a current dose level corresponding to some target percentile for experimentation. The estimate is based on all included subjects. This continual reevaluation is made possible by the use of a simple model. As it stands, neither the CRM, nor any of the other dynamic schemes, allow for the correct estimation of some target percentile, based on retrospective data apart from the exceptional situation in which the simplified model exactly generates the observations. In this article we focus on the very specific issue of retrospective analysis of data generated by some arbitrary mechanism and subsequently analyzed via the continual reassessment method. We show how this can be done consistently. The proposed methodology is not restricted to that particular design and is applicable to any sequential updating scheme in which dose levels are associated with percentiles via model inversion.     

A Theoretical Foundation for Life-Cycle Assessment

The presence of value judgments in life-cycle impact assessment (LCIA) has been a constant source of controversy. According to a common interpretation, the international standard on LCIA requires that the assessment methods used in published comparisons be "value free." Epistemologists argue that even natural science rests on "constitutive" and "contextual" value judgments. The example of the equivalency potential for climate change, the global warming potential (GWP), demonstrates that any impact assessment method inevitably contains not only constitutive and contextual values, but also preference values. Hence, neither life-cycle assessment (LCA) as a whole nor any of its steps can be "value free." As a result, we suggest a more comprehensive definition of objectivity in LCA that allows arguments about values and their relationship to facts. We distinguish three types of truth claims: factual claims, which are based on natural science; normative claims, which refer to preference values; and relational claims, which address the proper relation between factual knowledge and values. Every assessment method, even the GWP, requires each type of claim. Rational arguments can be made about each type of claim. Factual truth claims can be assessed using the scientific method. Normative claims can be based on ethical arguments. The values of individuals or groups can be elicited using various social science methods. Relational claims must follow the rules of logic. Relational claims are most important for the development of impact assessment methods. Because LCAs are conducted to satisfy the need of decision makers to consider environmental impacts, relational claims about impact assessment methods should refer to this goal. This article introduces conditions that affect environmental decision making and discusses how LCA—values and all—can be defended as a rational response to the challenge of moving uncertain scientific information into the policy arena.     

Regression Calibration in Semiparametric Accelerated Failure Time Models

Summary In large cohort studies, it often happens that some covariates are expensive to measure and hence only measured on a validation set. On the other hand, relatively cheap but error‐prone measurements of the covariates are available for all subjects. Regression calibration (RC) estimation method ( Prentice, 1982 , Biometrika 69 , 331–342) is a popular method for analyzing such data and has been applied to the Cox model by Wang et al. (1997, Biometrics 53 , 131–145) under normal measurement error and rare disease assumptions. In this article, we consider the RC estimation method for the semiparametric accelerated failure time model with covariates subject to measurement error. Asymptotic properties of the proposed method are investigated under a two‐phase sampling scheme for validation data that are selected via stratified random sampling, resulting in neither independent nor identically distributed observations. We show that the estimates converge to some well‐defined parameters. In particular, unbiased estimation is feasible under additive normal measurement error models for normal covariates and under Berkson error models. The proposed method performs well in finite‐sample simulation studies. We also apply the proposed method to a depression mortality study.     

The Quantitative Genetic Consequences of Pleiotropy under Stabilizing and Directional Selection

The independence of two phenotypic characters affected by both pleiotropic and nonpleiotropic mutations is investigated using a generalization of M. Slatkin's stepwise mutation model of 1987. The model is used to determine whether predictions of either the multivariate normal model introduced in 1980 by R. Lande or the house-of-cards model introduced in 1985 by M. Turelli can be regarded as typical of models that are intermediate between them. We found that, under stabilizing selection, the variance of one character at equilibrium may depend on the strength of stabilizing selection on the other character (as in the house-of-cards model) or not (as in the multivariate normal model) depending on the types of mutations that can occur. Similarly, under directional selection, the genetic covariance between two characters may increase substantially (as in the house-of-cards model) or not (as in the multivariate normal model) depending on the kinds of mutations that are assumed to occur. Hence, even for the simple model we consider, neither the house-of-cards nor the multivariate normal model can be used to make predictions, making it unlikely that either could be used to draw general conclusions about more complex and realistic models.     

Effect of pore structure on energy barriers and applied voltage profiles. II. Unsymmetrical channels.

This paper examines "realistic" pores, i.e., ones that are neither symmetric nor of uniform diameter. Methods are described that permit estimation of the image potential for an ion in an aqueous pore spanning a lipid membrane and for the electric field produced in such a pore when a transmembrane potential is applied. They are used to model features of the delayed rectifier potassium channel. Constraints on the geometry of the exterior mouth, the dielectric properties of the narrow part of the pore and the conduction mechanism are determined for this channel.     

Subset controllers in agreement relations

Agreement relations are interpreted asymmetrically, in that phi-features restrict the interpretation of the controller, but not the target. In this paper we explore whether this semantic asymmetry corresponds to a syntactic asymmetry. We will argue that it does not: phi-features are generated independently on target and controller. The evidence comes from cases of what we term ‘subset control’, in which the controller has fewer features than the target. We will argue that there are genuine cases of subset control that cannot be explained away, neither by assuming the controller contains non-realised features, nor by assuming that the underspecified category is not the actual controller, the latter being a fully specified null element. Our main evidence comes from Spanish ‘unagreement’.     

Effects of persister formation on bacterial response to dosing

Almost all moist surfaces are colonized by microbial biofilms. Biofilms are implicated in cross-contamination of food products, biofouling and various human infections such as dental cavities, ulcerative colitis and chronic respiratory infections. The recalcitrance of biofilms to typical antibiotic and antimicrobial treatments is one focus of current investigations. Neither reaction-diffusion limitation nor heterogeneities in growth-rate explain the observed tolerance. Another hypothesis is that specialized 'persister' cells, which are extremely tolerant of antimicrobials, are the source of resistance. In this investigation, we describe the formation of 'persister' cells which neither grow nor die in the presence of antibiotics. We propose that these cells are of a different phenotype whose expression is regulated by the growth rate and the antibiotic concentration. Based on several experiments describing the dynamics of persister cells, we introduce a mathematical model that is used to describes the effect of a periodic dosing regiment. Results from our analysis indicate that the relative dose/withdrawal times are important in determining the effectiveness of such a treatment. A reduced model is also introduced and the similar behavior is demonstrated analytically.     

The estimator of the optimal measure of allelic association: mean, variance and probability distribution when the sample size tends to infinity

The allelic association or linkage disequilibrium between two loci is a parameter of fundamental interest in modern population genetics for evolutionary inference and association mapping studies. Among the many measures available, the optimal measure of allelic association rho presents a strong evolutionary theory basis and is modeled on the physical distance along the chromosome with the Malécot equation for isolation by distance. Moreover, rho is equal to the absolute value of D', the standardized measure of gametic disequilibrium. We studied here the statistical properties of the rho sample estimator. We derived its asymptotic probability distribution and showed that it is neither asymptotically normal nor unbiased when rho=0 or when allelic frequencies are equal at both loci, in contrast to previous claims. This asymptotic study leads to propose a new test for absence of linkage disequilibrium. We compared it to Pearson's Chi2 test for independence in a contingency table and showed by simulations that the range in power of these two tests depends on the sign of D'. The new test outperformed slightly the Chi2 test, when D', polarized with respect to major alleles, is negative. Finally, we derived the asymptotic bias and information of the rho estimator that are due to the experimental sampling and showed by simulation that its bias is large in small samples. The consequences of these findings on applications using the rho measure are then discussed in particular for constructing LD unit maps, and call for a revised statistical treatment.     

Early Mecopterida and the systematic position of the Microptysmatidae (Insecta: Endopterygota)

In recent times many authors have regarded the Protomeropidae and Microptysmatidae - two essentially Permian groups - as either early trichopteran lineages or members of the stem-group of the Amphiesmenoptera (basically: Trichoptera+Lepidoptera). Actually none of these families possesses, in its ground plan, the most significant derived trait of the amphiesmenopteran forewing, namely a true ‘double-Y loop’ arrangement of the anal veins. Since ‘Carpenter’s organs’, small rounded structures in the costal area of the hindwing, are only known to occur in certain members of the Permochoristidae, Kaltanidae and Protomeropidae, these three families should belong to a fossil clade, which we ascribe to the Mecoptera, suborder Pistillifera sensu lato, mainly on account of a few venational features. Although we maintain the Microptysmatidae in the Mecopterida (=Panorpida, i.e. Amphiesmenoptera, Mecoptera, Diptera, and relatives), we propose to place this family in a separate order: the Permotrichoptera, n. status. Indeed, apparently, Microptysmatidae can be ascribed neither to the Amphiesmenoptera nor to the Antliophora (=Mecoptera-Diptera complex).