Endosomal microdomains: Formation and function

It is widely recognized that after endocytosis, internalized cargo is delivered to endosomes that act as sorting stations. The limiting membrane of endosomes contain specialized subregions, or microdomains, that represent distinct functions of the endosome, including regions competing for cargo capture leading to degradation or recycling. Great progress has been made in defining the endosomal protein coats that sort cargo in these domains, including Retromer that recycles transmembrane cargo, and ESCRT (endosomal sorting complex required for transport) that degrades transmembrane cargo. In this review, we discuss recent work that is beginning to unravel how such coat complexes contribute to the creation and maintenance of endosomal microdomains. We highlight data that indicates that adjacent microdomains do not act independently but rather interact to cross-regulate. We posit that these interactions provide an agile means for the cell to adjust sorting in response to extracellular signals and intracellular metabolic cues.     

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.     

Relative rates of synonymous substitutions in the mitochondrial, chloroplast and nuclear genomes of seed plants

Previous studies have estimated that, in angiosperms, the synonymous substitution rate of chloroplast genes is three times higher than that of mitochondrial genes and that of nuclear genes is twelve times higher than that of mitochondrial genes. Here we used 12 genes in 27 seed plant species to investigate whether these relative rates of substitutions are common to diverse seed plant groups. We find that the overall relative rate of synonymous substitutions of mitochondrial, chloroplast and nuclear genes of all seed plants is 1:3:10, that these ratios are 1:2:4 in gymnosperms but 1:3:16 in angiosperms and that they go up to 1:3:20 in basal angiosperms. Our results show that the mitochondrial, chloroplast and nuclear genomes of seed plant groups have different synonymous substitutions rates, that these rates are different in different seed plant groups and that gymnosperms have smaller ratios than angiosperms.     

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.     

Stem cells' centrosomes: How can organelles identified 130 years ago contribute to the future of regenerative medicine?

At the core of regenerative medicine lies the expectation of repair or replacement of damaged tissues or whole organs. Donor scarcity and transplant rejection are major obstacles, and exactly the obstacles that stem cell based therapy promises to overcome. These therapies demand a comprehensive understanding of the asymmetric division of stem cells, i.e. their ability to produce cells with identical potency or differentiated cells. It is believed that with better understanding, researchers will be able to direct stem cell differentiation. Here, we describe extraordinary advances in manipulating stem cell fate that show that we need to focus on the centrosome and the centrosome-derived primary cilium. This belief comes from the fact that this organelle is the vehicle that coordinates the asymmetric division of stem cells. This is supported by studies that report the significant role of the centrosome/cilium in orchestrating signaling pathways that dictate stem cell fate. We anticipate that there is sufficient evidence to place this organelle at the center of efforts that will shape the future of regenerative medicine.     

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.     

The parental obligation to expand a child's range of open futures when making genetic trait selections for their child

As parents become increasingly able to make genetic trait selections on behalf of their children, they will need ethical guidance in deciding what genetic traits to select. Dena Davis has argued that parents act unethically if they make selections that constrain their child's range of futures. But some selections may expand the child's range of futures. And other selections may shift the child's range of futures, without either constraining or expanding that range. I contend that not only would parents act unethically if they make selections that constrain the range of their child's futures, they would act unethically if they make selections that shift the range of their child's futures, because selections that shift the range of the child's futures would allow parents to over-determine their child's futures. Thus, I contend that parents would act ethically only if they make selections that expand their child's range of futures.     

The genetic architecture of disease resistance in plants and the maintenance of recombination by parasites

Parasites represent strong selection on host populations because they are ubiquitous and can drastically reduce host fitness. It has been hypothesized that parasite selection could explain the widespread occurrence of recombination because it is a coevolving force that favours new genetic combinations in the host. A review of deterministic models for the maintenance of recombination reveals that for recombination to be favoured, multiple genes that interact with each other must be under selection. To evaluate whether parasite selection can explain the maintenance of recombination, we review 85 studies that investigated the genetic architecture of plant disease resistance and discuss whether they conform to the requirements that emerge from theoretical models. General characteristics of disease resistance in plants and problems in evaluating resistance experimentally are also discussed. We found strong evidence that disease resistance in plants is determined by multiple loci. Furthermore, in most cases where loci were tested for interactions, epistasis between loci that affect resistance was found. However, we found weak support for the idea that specific allelic combinations determine resistance to different host genotypes and there was little data on whether epistasis between resistance genes is negative or positive. Thus, the current data indicate that it is possible that parasite selection can favour recombination, but more studies in natural populations that specifically address the nature of the interactions between resistance genes are necessary. The data summarized here suggest that disease resistance is a complex trait and that environmental effects and fitness trade-offs should be considered in future models of the coevolutionary dynamics of host and parasites.     

Energy allocation in the cladoceran Daphnia magna Straus,under starvation and refeeding

Summary Models incorporating the energetics of individual daphnids (Cladocera) have been developed to predict the effect of environmental variables, particularly food availability, on population dynamics. One of them, that of Kooijman (1986), assumes that all assimilated energy enters a storage compartment prior to use in production and metabolism, and that under starvation the stores are used to support maintenance, reproduction and somatic growth, in that order of priority. This predicts that, under starvation, reproduction and growth will continue for a time, and that after they cease death will be immediate. Another model, that of McCauley et al. (1990), assumes that assimilated energy is used directly for maintenance and production, and that stores are accumulated to support maintenance metabolism under starvation. This predicts that growth and reproduction should cease immediately upon starvation and that death will not be immediate. We have carried out laboratory experiments, manipulating starvation time, on Daphnia magna to distinguish between these two models. The results support features of both models in that reproduction, but not growth, ceases upon starvation. We therefore developed a third model in which both maintenance and growth are supported from stores under starvation, with maintenance taking priority over growth under these conditions.     

Simulated morphogenesis of developmental folds due to proliferative pressure

We present a simulation that models individual cells as spherical particles that can migrate, interact, divide and differentiate. We simulate the evolution of a progenitor layer of cells that reproduce, leading either to more progenitors or to differentiated daughters. We find that this simplified model produces spontaneous folds whose lengths depend linearly on the ratio of rates of production of progenitors to differentiated daughters. We also find that folds grow approximately exponentially in time, and that larger folds can be placed via patterning events that perturb the positions of selected progenitor cells early in the developmental process.     

Serendipity and Vision: Two Methods for Discovery Comments on Nickles

Thomas Nickles challenges my thesis that innovative discoveries can be based on deliberately chosen problems and research strategies. He suggests that all significant innovation can be seen as such only in retrospect and that its generation must be serendipitous. Here I argue in response that significant innovations can and do often arise from self conscious critical appraisal of orthodox practice combined with regulated though speculative abductive argumentation to alternative explanatory schemata. Orthodox practice is not based upon monolithic systems of belief about the subject of inquiry. Rather major domains of scientific practice often are approached from different conceptualizations that provide grounds for critical dialectic and consilient empirical information. Abductive arguments that meet appropriate conditions of likelihood, probability and analogy are an important means of justifying allocating resources to innovative practices that have yet to produce products that can rival those of established orthodoxy.     

Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum

Colostrum provides essential nutrients and immunologically active factors that are beneficial to newborns. Our previous work demonstrated that milk contains large amounts of miRNA that is largely stored in milk-derived microvesicles (MVs). In the present study, we found that the MVs from colostrum contain signifi cantly higher levels of several immune-related miRNAs. We hypothesized that the colostrum MVs may transfer the immune-related miRNAs into cells, which contribute to its immune modulatory feature. We isolated colostrum MVs by ultracentrifugation and demonstrated several immune modulation features associated with miRNAs. We also provide evidence that the physical structure of milk-derived MVs is essential for transfer miRNAs and following immune modulation effect. Moreover, we found that colostrum powder-derived MVs also contains higher levels of immune-related miRNAs that display similar immune modulation effects. Taken together, these results show that MV-containing immunerelated miRNAs may be a novel mechanism by which colostrum modulates body immune response.     

Adaptation of prey and predators between patches

Mathematical models are proposed to simulate migrations of prey and predators between patches. In the absence of predators, it is shown that the adaptation of prey leads to an ideal spatial distribution in the sense that the maximal capacity of each patch is achieved. With the introduction of co-adaptation of predators, it is proved that both prey and predators achieve ideal spatial distributions when the adaptations are weak. Further, it is shown that the adaptation of prey and predators increases the survival probability of predators from the extinction in both patches to the persistence in one patch. It is also demonstrated that there exists a pattern that prey and predators cooperate well through adaptations such that predators are permanent in every patch in the case that predators become extinct in each patch in the absence of adaptations. For strong adaptations, it is proved that the model admits periodic cycles and multiple stability transitions.     

Execution by lethal injection, euthanasia, organ-donation and the proper goals of medicine

In a recent issue of this journal, David Silver and Gerald Dworkin discuss the physicians' role in execution by lethal injection. Dworkin concludes that discussion by stating that, at that point, he is unable to think of an acceptable set of moral principles to support the view that it is illegitimate for physicians to participate in execution by lethal injection that would not rule out certain other plausible moral judgements, namely that euthanasia is under certain conditions legitimate and that organ-donation surgery is sometimes permissible. This article draws attention to some problems in the views of Silver and Dworkin and suggests moral principles which support the three moral views just mentioned.     

Inner-membrane proteins PMI/TMEM11 regulate mitochondrial morphogenesis independently of the DRP1/MFN fission/fusion pathways

Mitochondria are highly dynamic organelles that can change in number and morphology during cell cycle, development or in response to extracellular stimuli. These morphological dynamics are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Genetic approaches have identified a cohort of conserved proteins that form the core of mitochondrial remodelling machineries. Mitofusins (MFNs) and OPA1 proteins are dynamin-related GTPases that are required for outer- and inner-mitochondrial membrane fusion respectively whereas dynamin-related protein 1 (DRP1) is the master regulator of mitochondrial fission. We demonstrate here that the Drosophila PMI gene and its human orthologue TMEM11 encode mitochondrial inner-membrane proteins that regulate mitochondrial morphogenesis. PMI-mutant cells contain a highly condensed mitochondrial network, suggesting that PMI has either a pro-fission or an anti-fusion function. Surprisingly, however, epistatic experiments indicate that PMI shapes the mitochondria through a mechanism that is independent of drp1 and mfn. This shows that mitochondrial networks can be shaped in higher eukaryotes by at least two separate pathways: one PMI-dependent and one DRP1/MFN-dependent.     

Age‐dependent mutational effects curtail the evolution of senescence by antagonistic pleiotropy

One of the two main hypotheses to account for ageing is antagonistic pleiotropy (AP). This model requires alleles that increase vital rates (reproduction or survival) at early age at the expense of vital rates at late age. An important focus of evolutionary studies has been to assess the relative abundance of AP‐type aging alleles that arise through mutation. Here, we develop theory that predicts that senescence per se reduces the probability that these alleles arise by mutation. A direct result is that these mutations should arise with extremely low frequencies in already senescing populations. This has profound implications for the evolution of life histories because it implies that the adaptive evolution of aging via AP will experience negative feedback. This theory also clarifies the previously inexplicable epistatic patterns of genetic covariance across age‐specific vital rates that are observed in mutation accumulation experiments. We show that this epistasis is an emergent property of aging.     

The fallacy of the Principle of Procreative Beneficence

The claim that we have a moral obligation, where a choice can be made, to bring to birth the 'best' child possible, has been highly controversial for a number of decades. More recently Savulescu has labelled this claim the Principle of Procreative Beneficence. It has been argued that this Principle is problematic in both its reasoning and its implications, most notably in that it places lower moral value on the disabled. Relentless criticism of this proposed moral obligation, however, has been unable, thus far, to discredit this Principle convincingly and as a result its influence shows no sign of abating. I will argue that while criticisms of the implications and detail of the reasoning behind it are well founded, they are unlikely to produce an argument that will ultimately discredit the obligation that the Principle of Procreative Beneficence represents. I believe that what is needed finally and convincingly to reveal the fallacy of this Principle is a critique of its ultimate theoretical foundation, the notion of impersonal harm. In this paper I argue that while the notion of impersonal harm is intuitively very appealing, its plausibility is based entirely on this intuitive appeal and not on sound moral reasoning. I show that there is another plausible explanation for our intuitive response and I believe that this, in conjunction with the other theoretical criticisms that I and others have levelled at this Principle, shows that the Principle of Procreative Beneficence should be rejected.     

Time-calibrated phylogeny of the woody Australian genus Hakea (Proteaceae) supports multiple origins of insect-pollination among bird-pollinated ancestors

? Premise of the study: A past study based on morphological data alone showed that the means by which plants of the Australian genus Hakea reduce florivory is related to the evolution of bird pollination. For example, bird pollination was shown to have arisen only in insect-pollinated lineages that already produced greater amounts of floral cyanide, a feature that reduces florivory. We examine a central conclusion of that study, and a common assumption in the literature, that bird pollination arose in insect-pollinated lineages, rather than the reverse. ? Methods: We combined morphological and DNA data to infer the phylogeny and age of the Australian genus Hakea, using 9.2 kilobases of plastid and nuclear DNA and 46 morphological characters from a taxonomically even sampling of 55 of the 149 species. ? Key results: Hakea is rooted confidently in a position that has not been suggested before. The phylogeny implies that bird pollination is primitive in Hakea and that multiple shifts to insect pollination have occurred. The unexpectedly young age of Hakea (a crown age of ca. 10 Ma) makes it coincident with its primary bird pollinators (honeyeaters) throughout its history. ? Conclusions: Our study demonstrates that Hakea is an exception to the more commonly described shift from insect to bird pollination. However, we note that only one previous phylogenetic study involved Australian plants and their honeyeater pollinators and that our finding might prove to be more common on that continent.     

Innate Ideas as a Naturalistic Source of Metaphysical Knowledge

This article starts from the assumption that there are various innate contributions to our view of the world and explores the epistemological implications that follow from this. Specifically, it explores the idea that if certain components of our worldview have an evolutionary origin, this implies that these aspects accurately depict the world. The simple version of the argument for this conclusion is that if an aspect of mind is innate, it must be useful, and the most parsimonious explanation for its usefulness is that it accurately depicts the world. There are a number of important criticisms of this argument. These include the idea that evolutionary justifications are circular, that evolved mental content and principles are not necessarily accurate, and that, if the argument is taken seriously, it has some highly dubious consequences. These criticisms necessitate various qualifications to the initial argument. Nonetheless, it is argued that, in some cases, important conclusions can be drawn about the world from an analysis of evolved contributions to our view of the world. An evolutionary approach cannot provide an ultimate justification for any belief; however, in certain circumstances, it supports the conclusion that a given belief is a reasonable first approximation. To the extent that innate content and principles pertain to topics in metaphysics, they can be viewed as a naturalistic source of metaphysical knowledge.