Hypotheses Derived from Morphological Data: When and How They Are Useful

SYNOPSIS. This paper discusses the validity of hypotheses basedon morphological data,and distinguishes between hypotheses,which are testable, and speculation, which is not. Specificexamples from the mammalian auditory system are examined: arecently evolved, highly derived character (enlarged middleears in desert rodents); and an older, more general character(the inner and outer hair cells of the mammalian organ of Corti).It is concluded that morphologically-based hypotheses are powerfuland important when accompanied by experimental data.     

How a Poliovirus Might Cause Schizophrenia: A Commentary on Eagles' Hypothesis

John M. Eagles suggested that polioviruses might cause schizophrenia because 1) several reports of a recent decline in the incidence of schizophrenia coinciding with the introduction of polio vaccination, 2) the observed winter excesses in schizophrenic births (in temperate climates) could be explained by fetal exposure to poliovirus during the second trimester of gestation which would occur during the summer when polio epidemics are most frequent, 3) there are increased rates of schizophrenia among immigrants to the UK from regions of the world with low frequencies if immunity to polioviruses, 4) there may be genetic variants in the poliovirus receptor gene that could increase susceptibility to poliovirus infection (1). The large discordance rates for schizophrenia in monozygotic twin pairs indicate the existence of both genetic and environmental factors. Numerous genetic studies indicate an interaction of several genes in the etiology of schizophrenia. These genes may encode a family of poliovirus receptor subunits, various active combinations of which are expressed on T-immunocytes, monocytes, endothelial cells, and limited populations of (glutamatergic?) neurons. The poliovirus receptor on the T-cell may require both a specific combination of V segments of the T-cell antigen receptor, as well as a specific major histocompatibility (MHC) antigen, acting in concert to infect monocytes, the primary transporter of poliovirus from blood into the brain. The very large discordance rates for schizophrenia that probably exist for dichorionic-monozygotic twins (about 90%), as well as the much smaller discordance rates for monochorionic-monozygotic twins (about 40%), may be due to several allelic exclusion events expressed both in T-cells and possibly in certain neurons. A child who has lost some glutamatergic neurons due to viral infection during the second trimester of gestation, may be able to compensate for this deficit to a large extent by the super-abundance of excitatory synapses that exists in the brain until sexual maturity, at which time a selective loss of excitatory (mainly glutamatergic) synapses occurs together with hormonally induced changes in behavior, leading to a much increased risk of a psychotic episode.

     

Variable Parental Care in a Labrid Fish: How Care Might Evolve

Hypotheses for the evolution of parental care suggest several intermediate stages between no care and full care. To shed light on how care might evolve, I describe intermediate stages within one species. These include spawning behavior ranging from out-of-nest spawning, (which involves no parental care) to algal nests and associated male parental care (plus intermediate stages between the two previous categories), all observed in the same individual males of the peacock wrasse, Symphodus tinca. About 20% of males go through transitional stages from no care to full care as the season progresses. These stages are: 1) following females over large areas, 2) focusing on an area about 10 × 10 m, 3) chasing other fish, (both con- and heterospecific) from this area, 4) focusing spawns into a 1–2 m² area that he modifies by adding algae, and 5) remaining with the site day and night until the eggs hatch and the young disperse. This sequence of stages is similar to the evolutionary sequence suggested by previous theory, but differs in that site limitation is not necessary in order to lead to site attachment.     

How Disruption of Cell Cycle Regulators Might Predispose to Sun-Induced Skin Cancer

The Ink4a/Arf ( CDKN2a) locus encodes two proteins that regulate distinct important tumor suppressor pathways represented by p53 and Rb. Loss of either p16^INK4a or p19^ARF was recently reported to reduce the ability of mouse cells to repair UV-induced DNA damage and to induce a UV-mutator phenotype. This observation was independent of cell cycle effects incurred by either p16INK4a and/or p19ARF loss, as it was demonstrable in unirradiated cells using UV-treated DNA. We suggest that this might explain why germ line mutations of INK4a/ARF predispose mainly to malignant melanoma, a UV-induced skin cancer, and provides a molecular explanation for the link between melanoma-genesis and impaired DNA repair. It also further demonstrates that regulation of cell cycle check points and DNA repair in response to genomic insults, such as ultraviolet irradiation are intricately interwoven processes. Differences in the apoptotic response to ultraviolet light between melanocytes and keratinocytes might explain why INK4a/ARF mutations predispose to malignant melanoma, but not to keratinocyte-derived skin cancers.     

How Sugars Might Coordinate Chloroplast and Nuclear Gene Expression during Acclimation to High Light Intensities

The concept of retrograde control of nuclear gene expression assumes the generation of signals inside the chloroplasts, which are either released from or sensed inside of the organelle. In both cases, downstream signaling path- ways lead eventually to a differential regulation of nuclear gene expression and the production of proteins required in the chloroplast. This concept appears reasonable as the majority of the over 3000 predicted plastidial proteins are encoded by nuclear genes. Hence, the nucleus needs information on the status of the chloroplasts, such as during acclimation responses, which trigger massive changes in the protein composition of the thylakoid membrane and in the stroma. Here, we propose an additional control mechanism of nuclear- and plastome-encoded photosynthesis genes, taking advantage of pathways involved in sugar- or hormonal signaling. Sugars are major end products of photosynthesis and their con- tents respond very sensitively to changes in light intensities. Based on recent findings, we ask the question as to whether the carbohydrate status outside the chloroplast can be directly sensed within the chloroplast stroma. Sugars might syn- chronize the responsiveness of both genomes and thereby help to coordinate the expression of piastome- and nuclear- encoded photosynthesis genes in concert with other, more specific retrograde signals.     

How Changes in Extracellular Matrix Mechanics and Gene Expression Variability Might Combine to Drive Cancer Progression

Changes in extracellular matrix (ECM) structure or mechanics can actively drive cancer progression; however, the underlying mechanism remains unknown. Here we explore whether this process could be mediated by changes in cell shape that lead to increases in genetic noise, given that both factors have been independently shown to alter gene expression and induce cell fate switching. We do this using a computer simulation model that explores the impact of physical changes in the tissue microenvironment under conditions in which physical deformation of cells increases gene expression variability among genetically identical cells. The model reveals that cancerous tissue growth can be driven by physical changes in the microenvironment: when increases in cell shape variability due to growth-dependent increases in cell packing density enhance gene expression variation, heterogeneous autonomous growth and further structural disorganization can result, thereby driving cancer progression via positive feedback. The model parameters that led to this prediction are consistent with experimental measurements of mammary tissues that spontaneously undergo cancer progression in transgenic C3(1)-SV40Tag female mice, which exhibit enhanced stiffness of mammary ducts, as well as progressive increases in variability of cell-cell relations and associated cell shape changes. These results demonstrate the potential for physical changes in the tissue microenvironment (e.g., altered ECM mechanics) to induce a cancerous phenotype or accelerate cancer progression in a clonal population through local changes in cell geometry and increased phenotypic variability, even in the absence of gene mutation.     

How Nanopore Translocation Experiments Can Measure RNA Unfolding

Electrokinetic translocation of biomolecules through solid-state nanopores represents a label-free single-molecule technique that may be used to measure biomolecular structure and dynamics. Recent investigations have attempted to distinguish individual transfer RNA (tRNA) species based on the associated pore translocation times, ion-current noise, and blockage currents. By manufacturing sufficiently smaller pores, each tRNA is required to undergo a deformation to translocate. Accordingly, differences in nanopore translocation times and distributions may be used to infer the mechanical properties of individual tRNA molecules. To bridge our understanding of tRNA structural dynamics and nanopore measurements, we apply molecular dynamics simulations using a simplified “structure-based” energetic model. Calculating the free-energy landscape for distinct tRNA species implicates transient unfolding of the terminal RNA helix during nanopore translocation. This provides a structural and energetic framework for interpreting current experiments, which can aid the design of methods for identifying macromolecules using nanopores.     

Selection and Preparation of Leaf Epidermis for Experiments on Stomatal Physiology

A simple method for reproducibly peeling leaf epidermis tissueis described. Epidermis was obtained from eight species usingthe method, and its properties of value in research on stomatalphysiology evaluated. Effects of the method of peeling on cellviability and mesophyll contamination were quantified, and acomparison was made between the effects of peeling and subsequenttreatments on a plant with morphologically distinct subsidiarycells, Commelina communis, and one without, Vicia faba. Theresults indicate that artefacts in experiments on stomatal physiologyinvolving leaf epidermis could arise not only from the peelingmethod, but also the plant species chosen.     

How Sex Selection Undermines Reproductive Autonomy

Non-medical sex selection is premised on the notion that the sexes are not interchangeable. Studies of individuals who undergo sex selection for non-medical reasons, or who have a preference for a son or daughter, show that they assume their child will conform to the stereotypical roles and norms associated with their sex. However, the evidence currently available has not succeeded in showing that the gender traits and inclinations sought are caused by a “male brain” or a “female brain”. Therefore, as far as we know, there is no biological reason why parents cannot have the kind of parenting experience they seek with a child of any sex. Yet gender essentialism, a set of unfounded assumptions about the sexes which pervade society and underpin sexism, prevents parents from realising this freedom. In other words, unfounded assumptions about gender constrain not only a child’s autonomy, but also the parent’s. To date, reproductive autonomy in relation to sex selection has predominantly been regarded merely as the freedom to choose the sex of one’s child. This paper points to at least two interpretations of reproductive autonomy and argues that sex selection, by being premised on gender essentialism and/or the social pressure on parents to ensure their children conform to gender norms, undermines reproductive autonomy on both accounts.