Progress toward a general species concept

New insights in the speciation process and the nature of "species" that accumulated in the past decade demand adjustments of the species concept. The standing of some of the most broadly accepted or most innovative species concepts in the light of the growing evidence that reproductive barriers are semipermeable to gene flow, that species can differentiate despite ongoing interbreeding, that a single species can originate polyphyletically by parallel evolution, and that uniparental organisms are organised in units that resemble species of biparental organisms is discussed. As a synthesis of ideas in existing concepts and the new insights, a generalization of the genic concept is proposed that defines species as groups of individuals that are reciprocally characterized by features that would have negative fitness effects in other groups and that cannot be regularly exchanged between groups upon contact. The benefits of this differential fitness species concept are that it classifies groups that keep differentiated and keep on differentiating despite interbreeding as species, that it is not restricted to specific mutations or mechanisms causing speciation, and that it can be applied to the whole spectrum of organisms from uni- to biparentals.     

Dissociation of conditioned taste avoidance from conditioned disgust reactions induced by wheel running in rats

It is well established that wheel running in rats produces conditioned taste avoidance; that is, rats that run in wheels after consuming a novel-tasting solution later consume less of that solution than rats that do not run. In experiment 1, we found that wheel running also produces conditioned disgust reactions, indicated by gapes elicited by both the taste and context that were experienced before running. Experiment 2 showed that the conditioned disgust reactions were likely not due to running itself but to a by-product of running, the rocking of the wheel that occurs when the running stops. When rocking was reduced, the disgust reactions were also reduced, but consumption of the taste solution was not changed, showing dissociation of conditioned taste avoidance and disgust. These findings indicate that the taste avoidance induced by wheel running itself is more like the taste avoidance produced by rewarding drugs than that produced by nausea-inducing drugs.     

The neural and cognitive correlates of aimed throwing in chimpanzees: a magnetic resonance image and behavioural study on a unique form of social tool use

It has been hypothesized that neurological adaptations associated with evolutionary selection for throwing may have served as a precursor for the emergence of language and speech in early hominins. Although there are reports of individual differences in aimed throwing in wild and captive apes, to date there has not been a single study that has examined the potential neuroanatomical correlates of this very unique tool-use behaviour in non-human primates. In this study, we examined whether differences in the ratio of white (WM) to grey matter (GM) were evident in the homologue to Broca's area as well as the motor-hand area of the precentral gyrus (termed the KNOB) in chimpanzees that reliably throw compared with those that do not. We found that the proportion of WM in Broca's homologue and the KNOB was significantly higher in subjects that reliably throw compared with those that do not. We further found that asymmetries in WM within both brain regions were larger in the hemisphere contralateral to the chimpanzee's preferred throwing hand. We also found that chimpanzees that reliably throw show significantly better communication abilities than chimpanzees that do not. These results suggest that chimpanzees that have learned to throw have developed greater cortical connectivity between primary motor cortex and the Broca's area homologue. It is suggested that during hominin evolution, after the split between the lines leading to chimpanzees and humans, there was intense selection on increased motor skills associated with throwing and that this potentially formed the foundation for left hemisphere specialization associated with language and speech found in modern humans.     

Effects of pore mutations and permeant ion concentration on the spontaneous gating activity of OmpC porin

Porins are trimers of beta-barrels that form channels for ions and other hydrophilic solutes in the outer membrane of Gram-negative bacteria. The X-ray structures of OmpF and PhoE show that each monomeric pore is constricted by an extracellular loop that folds into the channel vestibule, a motif that is highly conserved among bacterial porins. Electrostatic calculations have suggested that the distribution of ionizable groups at the constriction zone (or eyelet) may establish an intrinsic transverse electrostatic field across the pore, that is perpendicular to the pore axis. In order to study the role that electrostatic interactions between pore residues may have in porin function, we used spontaneous mutants and engineered site-directed mutants that have an altered charge distribution at the eyelet and compared their electrophysiological behavior with that of wild-type OmpC. We found that some mutations lead to changes in the spontaneous gating activity of OmpC porin channels. Changes in the concentration of permeant ions also altered this activity. These results suggest that the ionic interactions that exist between charged residues at the constriction zone of porin may play a role in the transitions between the channel's closed and open states.     

GABA and “neuro-cardiovascular” mechanisms

One has only to recall that GABA appears to be a major inhibitory neurotransmitter in the vertebrate central nervous system (CNS), that it exerts a hypotensive action upon systemic administration, that it is present in the blood, that its actions are antagonized by bicuculline and picrotoxin and facilitated by benzodiazepines, and that receptors for GABA exist in cerebral blood vessels, to consider that GABA is somehow involved in cardiovascular regulation. One might even postulate that influences upon GABA-ergic mechanisms are involved in that dangerous sequence of biological activities: environmental stress → anxiety → atherosclerosis and hypertension, the latter of which represent major health problems of man. Herein, some evidence that appears to support this view will be presented.     

The anarchist's guide to ecological theory. Or, we don't need no stinkin' laws

Several ecologists have recently suggested that ecology has several laws. This conclusion contrasts with the views of some philosophers of science, who have suggested that biology cannot have laws. I argue that the debate has been confused because two very different types of law can be recognised: correlative and causal laws. Once we recognise that there is a difference, the argument against causal laws becomes stronger, and instead I suggest that ecologists should recognise that they can and do produce generalisations that are used to build models – nomological machines – that describe the ecological systems they are studying.     

Surface changes of the mechanosensitive channel MscS upon its activation, inactivation, and closing

MscS is a bacterial mechanosensitive channel that shows voltage dependence. The crystal structure of MscS revealed that the channel is a homoheptamer with a large chamber on the intracellular site. Our previous experiments indicated that the cytoplasmic chamber of the channel is not a rigid structure and changes its conformation upon the channel activation. In this study, we have applied various sized cosolvents that are excluded from protein surfaces. It is well known that such cosolvents induce compaction of proteins and prevent thermal fluctuations. It is also known that they shift channel equilibrium to the state of lower volume. We have found that large cosolvents that cannot enter the channel interior accelerate channel inactivation when applied from the cytoplasmic side, but they slow down inactivation when applied from the extracellular side. We have also found that small cosolvents that can enter the channel cytoplasmic chamber prevent the channel from opening, unlike the large ones. These data support our idea that the channel cytoplasmic chamber shrinks upon inactivation but also give new clues about conformational changes of the channel upon transitions between its functional states.     

Reliable sampling method for analysis of the ecology of the human alimentary tract

An intubation method has been developed that allows removal of a sample of human intestinal fluid within a short period of time, that avoids contamination, and that minimizes exposure of the sample to air. Preliminary results obtained with this method have shown that the stomach and duodenum are essentially sterile and that the bacterial population present in the remainder of the small intestine is similar to that described by previous workers except that Veillonella species were encountered frequently and Haemophilus species were also detected in the lower jejunum and ileum of some individuals.     

Why Selective Publication of Statistically Significant Results Can Be Effective

Concerns exist within the medical and psychological sciences that many published research findings are not replicable. Guidelines accordingly recommend that the file drawer effect should be eliminated and that statistical significance should not be a criterion in the decision to submit and publish scientific results. By means of a simulation study, we show that selectively publishing effects that differ significantly from the cumulative meta-analytic effect evokes the Proteus phenomenon of poorly replicable and alternating findings. However, the simulation also shows that the selective publication approach yields a scientific record that is content rich as compared to publishing everything, in the sense that fewer publications are needed for obtaining an accurate meta-analytic estimation of the true effect. We conclude that, under the assumption of self-correcting science, the file drawer effect can be beneficial for the scientific collective.     

Identification of a Gene That Shortens Clonal Life Span of Paramecium Tetraurelia

We have isolated a Paramecium tetraurelia mutant that divides slowly in daily reisolation cultures and repeats short clonal life spans after successive autogamies. Here we show, using breeding analysis, that a recessive mutation is responsible for the low fission rate and that this low rate is closely related to the short clonal life span. We conclude that a single pleiotropic gene controls these traits and have named it jumyo. In an attempt to further characterize the jumyo mutant, we have revealed that it has a culture life span similar to that of the wild-type cells and that, when mass cultured, it can divide as rapidly as wild-type cells. There was strong evidence that the mutant cells excreted into culture medium some substance that promotes their cell division. These findings may not only present supporting evidence for the hypothesis that the cellular life span is genetically programmed but also give a material basis for the study of the controlling mechanism of cell division in relation to the clonal life span.     

A Quantitative Measure of the Mitotic Pairing of Alleles in Drosophila Melanogaster and the Influence of Structural Heterozygosity

In Drosophila there exist several examples of gene expression that can be modified by an interaction between alleles; this effect is known as transvection. The inference that alleles interact comes from the observations that homologous chromosomes pair in mitotically dividing cells, and that chromosome rearrangements can alter the phenotype produced by a pair of alleles. It is thought that heterozygous rearrangements impede the ability of alleles to pair and interact. However, because the existing data are inconsistent, this issue is not fully settled. By measuring the frequency of site-specific recombination between homologous chromosomes, we show that structural heterozygosity inhibits the pairing of alleles that lie distal to a rearrangement breakpoint. We suggest that some of the apparent conflicts may owe to variations in cell-cycle lengths in the tissues where the relevant allelic interactions occur. Cells with a longer cell cycle have more time to establish the normal pairing relationships that have been disturbed by rearrangements. In support, we show that Minute mutations, which slow the rate of cell division, partially restore a transvection effect that is disrupted by inversion heterozygosity.     

Isoform-specific interaction of C-RAF with mitochondria

The proteins of the RAF family (A-RAF, B-RAF, and C-RAF) are serine/threonine kinases that play important roles in development, mature cell regulation, and cancer. Although it is widely held that their localization on membranes is an important aspect of their function, there are few data that address this aspect of their mode of action. Here, we report that each member of the RAF family exhibits a specific distribution at the level of cellular membranes and that C-RAF is the only isoform that directly targets mitochondria. We found that the RAF kinases exhibit intrinsic differences in terms of mitochondrial affinity and that C-RAF is the only isoform that binds this organelle efficiently. This affinity is conferred by the C-RAF amino-terminal domain and does not depend on the presence of RAS GTPases on the surface of mitochondria. Finally, we analyzed the consequences of C-RAF activation on mitochondria and observed that this event dramatically changes their morphology and their subcellular distribution. Our observations indicate that: (i) RAF kinases exhibit different localizations at the level of cellular membranes; (ii) C-RAF is the only isoform that directly binds mitochondria; and (iii) through its functional coupling with MEK, C-RAF regulates the shape and the cellular distribution of mitochondria.     

Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch

Recent findings suggest that Delta/Serrate/Lag2 (DSL) signals activate Notch by an unprecedented mechanism that requires the ligands to be endocytosed in signal-sending cells to activate the receptor in signal-receiving cells. Here, we show that cells devoid of Epsin, a conserved adaptor protein for Clathrin-mediated endocytosis, behave normally except that they cannot send DSL signals. Surprisingly, we find that Epsin is not required for bulk endocytosis of DSL proteins. Instead, Epsin appears to be essential for targeting DSL proteins to a special endocytic pathway that they must enter to acquire signaling activity. We present evidence that DSL proteins must be mono-ubiquitinated to be targeted by Epsin to this pathway. Furthermore, we show that the requirements for both Epsin and mono-ubiquitination can be bypassed by introducing the internalization signal that mediates endocytosis and recycling of the Low Density Lipoprotein (LDL) receptor. We propose that Epsin is essential for DSL signaling because it targets mono-ubiquitinated DSL proteins to an endocytic recycling compartment that they must enter to be converted into active ligands. Alternatively Epsin may be required to target mono-ubiquitinated DSL proteins to a particular subclass of coated pits that have special properties essential for Notch activation.     

Feature-based attention: it is all bottom-up priming

Feature-based attention (FBA) enhances the representation of image characteristics throughout the visual field, a mechanism that is particularly useful when searching for a specific stimulus feature. Even though most theories of visual search implicitly or explicitly assume that FBA is under top-down control, we argue that the role of top-down processing in FBA may be limited. Our review of the literature indicates that all behavioural and neuro-imaging studies investigating FBA suffer from the shortcoming that they cannot rule out an effect of priming. The mere attending to a feature enhances the mandatory processing of that feature across the visual field, an effect that is likely to occur in an automatic, bottom-up way. Studies that have investigated the feasibility of FBA by means of cueing paradigms suggest that the role of top-down processing in FBA is limited (e.g. prepare for red). Instead, the actual processing of the stimulus is needed to cause the mandatory tuning of responses throughout the visual field. We conclude that it is likely that all FBA effects reported previously are the result of bottom-up priming.     

Primary amphipathic cell-penetrating peptides: structural requirements and interactions with model membranes

To identify rules for the design of efficient cell-penetrating peptides that deliver therapeutic agents into subcellular compartments, we compared the properties of two closely related primary amphipathic peptides that mainly differ by their conformational state. On the basis of a peptide Pbeta that is nonstructured in water and that promotes efficient cellular uptake of nucleic acids through noncovalent association, we have designed a peptide [Palpha] that is predicted to adopt a helical conformation. We show that [Pbeta] undergoes a lipid-induced conformational transition into a sheet structure, while [Palpha] remains helical. Penetration experiments show that both peptides can spontaneously insert into phospholipid membranes. Analysis of compression isotherms indicates that both peptides interact with phospholipids in the liquid expanded and liquid condensed states. AFM observations reveal that the peptides strongly disrupt the lipid organization of the monolayers and that the conformational state can influence the uptake by model membranes.     

Courtship in S. cerevisiae: both cell types choose mating partners by responding to the strongest pheromone signal

We demonstrate that during the courtship stage of conjugation, S. cerevisiae a cells choose the alpha cell producing the highest level of pheromone from among potential mating partners. From this result and that for alpha cells we conclude that both a and alpha cells act as signaling cells during courtship, that both cell types respond by discriminating different levels of signal, and that the signals are the mating pheromones. Responding cells that are supersensitive to signal fail to discriminate pheromone-producing from nonproducing cells to an extent that depends on their degree of supersensitivity. We propose that partner selection in S. cerevisiae results from polarized morphogenesis of a responding cell in the direction of highest pheromone concentration and that cells defective in discriminating this gradient execute a default pathway in which an adjacent cell is selected at random.     

S-laminin expression in adult and developing retinae: a potential cue for photoreceptor morphogenesis.

The development of the neural retina follows a stereotyped time course that begins with an undifferentiated neuroepithelium populated by multipotential progenitor cells and ends with a highly differentiated tissue containing diverse cell types. The identities of the factors that guide this differentiation have remained elusive; a likely location for such factors, however, is the extracellular environment. Here, we show that the extracellular matrix component s-laminin is present in the neural retina, that s-laminin expression parallels the differentiation of rod photoreceptors, that photoreceptors interact with s-laminin in vitro, and that antibodies to s-laminin profoundly reduce the appearance of cells that express rhodopsin in vitro. These data suggest that s-laminin plays a role in the differentiation of the neural retina and provide evidence that the composition of the extracellular matrix may be an important determinant of retinal differentiation.     

Nebulin regulation of actin filament lengths: new angles

The highly organized arrays of thick and thin filaments found in striated muscles continue to be the subject of studies that yield groundbreaking concepts regarding cell motility. One example is the idea that massive, linearly extended polypeptides function as molecular rulers that set the length of polymeric filaments. Actin filaments that are polymerized in vitro exhibit wide variations in length, but many cells can assemble structures that contain actin filaments that are remarkably uniform. In striated muscles, the giant nebulin polypeptide extends the length of the actin filaments, and nebulin size has been correlated with actin filament lengths in muscles from different species. Here, I discuss a recent study by Gregorio and colleagues that demonstrates that nebulin knockdown leads to loss of actin filament-length regulation in cardiomyocytes, providing functional evidence that is consistent with the molecular ruler concept.     

A calpain-like proteolytic activity produces the limited cleavage at the N-terminal regulatory domain of rabbit skeletal muscle AMP deaminase: evidence of a protective molecular mechanism

On storage at 4 degrees C, rabbit skeletal muscle AMP deaminase undergoes limited proteolysis with the conversion of the native 85-kDa enzyme subunit to a 75-kDa core that is resistant to further proteolysis. Further studies have shown that limited proteolysis of AMP deaminase with trypsin, removing the 95-residue N-terminal fragment, converts the native enzyme to a species that exhibits hyperbolic kinetics even at low K+ concentration. The results of this report show that a 21-residue synthetic peptide, when incubated with the purified enzyme, is cleaved with a specificity identical to that reported for ubiquitous calpains. In addition, the cleavage of a specific fluorogenic peptide substrate by rabbit m-calpain is inhibited by a synthetic peptide that corresponds to residues 10-17 of rabbit skeletal muscle AMP deaminase; this peptide contains a sequence (K-E-L-D-D-A) that is present in the fourth subdomain A of rabbit calpastatin, suggesting that the N-terminus of AMP deaminase shares with calpastatin a regulatory sequence that might exert a protective role against the fragmentation-induced activation of AMP deaminase. These observations suggest that a calpain-like proteinase present in muscle removes from AMP deaminase a domain that holds the enzyme in an inactive conformation and which also contains a regulatory region that protects against unregulated proteolysis. We conclude that proteolysis of AMP deaminase is the basis of the large ammonia accumulation that occurs in skeletal muscle subjected to strong tetanic contraction or passing into rigor mortis.     

Rationality, biology and optimality*

A historical theory of rational norms claims that, if we are supposed to think rationally, this is because it is biologically normal for us to do so. The historical theorist is committed to the view that we are supposed to think rationally only if, in the past, adult humans sometimes thought rationally. I consider whether there is any plausible model of rational norms that can be adopted by the historical theorist that is compatible with the claim that adult human beings are subject to rational norms, given certain plausible empirical assumptions about our history and capabilities. I suggest that there is one such model: this model centres on the idea that a procedure is rational if it has been endorsed (or at least not rejected) by mechanisms that have the function to ensure that the subject learns to reason in a way that approaches a certain kind of optimality. This revised version was published online in July 2006 with corrections to the Cover Date.