Unconventional bed mates: Gaia and the selfish gene

In this forum, David M. Wilkinson argued that Gaia-type phenomena can be explained by conventional ecological ideas meaning that such phenomena do not require major changes to existing ecological or evolutionary theory. Overstating my case a little, I will argue that a reconciliation between Gaia and Darwinism will not be conventional in the sense of mainstream ecology. The main addition of this essay is an exploration in how far the claim that the atmosphere is an extension of life on Earth is logically correct. In a thought experiment, the idea of extended phenotypes by Richard Dawkins can be integrated with the one of Gaia. The problem of cheats remains pertinent, however, because the atmosphere will not select differentially between cheats and non-cheats. Conclusion: Gaia-type phenomena will be by-products of naturally selected traits. As such they are not jeopardised by cheats, because side effects can be free to self-organise, while the main effects will be naturally selected for evolutionarily stable states. Understanding the laws of self-organisation of such side effects will be of major importance to all environmental sciences.     

Extracellular ATP as a signaling molecule for epithelial cells

The charge of this invited review is to present a convincing case for the fact that cells release their ATP for physiological reasons. Many of our "purinergic" colleagues as well as ourselves have experienced resistance to this concept, because it is teleologically counter-intuitive. This review serves to integrate the three main tenets of extracellular ATP signaling: ATP release from cells, ATP receptors on cells, and ATP receptor-driven signaling within cells to affect cell or tissue physiology. First principles will be discussed in the Introduction concerning extracellular ATP signaling. All possible cellular mechanisms of ATP release will then be presented. Use of nucleotide and nucleoside scavengers as well as broad-specificity purinergic receptor antagonists will be presented as a method of detecting endogenous ATP release affecting a biological endpoint. Innovative methods of detecting released ATP by adapting luciferase detection reagents or by using "biosensors" will be presented.Because our laboratory has been primarily interested in epithelial cell physiology and pathophysiology for several years, the role of extracellular ATP in regulation of epithelial cell function will be the focus of this review. For ATP release to be physiologically relevant, receptors for ATP are required at the cell surface. The families of P2Y G protein-coupled receptors and ATP-gated P2X receptor channels will be introduced. Particular attention will be paid to P2X receptor channels that mediate the fast actions of extracellular ATP signaling, much like neurotransmitter-gated channels versus metabotropic heptahelical neurotransmitter receptors that couple to G proteins. Finally, fascinating biological paradigms in which extracellular ATP signaling has been implicated will be highlighted. It is the goal of this review to convert and attract new scientists into the exploding field of extracellular nucleotide signaling and to convince the reader that extracellular ATP is indeed a signaling molecule.     

Antiresorptive agents and osteoclast apoptosis

Antiresorptive agents have proven to be effective therapies for the treatment of bone diseases associated with excessive osteoclast activity. Decreased osteoclast formation, inhibition of osteoclast actions, and reduced osteoclast survival represent mechanisms by which antiresorptive agents could act. The goals of this article are to present the evidence that antiresorptive agents can decrease osteoclast survival through apoptosis, to review the mechanisms by which they are thought to activate the apoptotic process, and to consider whether the actions on apoptosis fully account for the antiresorptive effects. As background, the apoptotic process will be briefly summarized together with the evidence that factors that promote osteoclast survival affect steps in the process. Following this, therapeutic agents that are both antiresorptive and can stimulate osteoclast apoptosis will be discussed. Other bone therapeutic agents that are either antiresorptive or apoptotic, but not both, will be described. Finally, newer antiresorptive compounds that elicit apoptosis and could represent potential therapeutic agents will be noted.     

Use of antibodies to the lipopolysaccharide core region in the treatment of gram-negative sepsis and shock

In this paper we review evidence in favor of a protective role for antibodies directed at the lipopolysaccharide (LPS) core region of Gram-negative bacilli. It will be shown that, given the right animal model, polyclonal antisera raised against O-antigen lacking, rough mutant strains, can be shown to protect animals against lethal sepsis due to a variety a bacterial species. Evidence for a protective role obtained from clinical studies will also be discussed. It will be stressed how difficult it is to prove that the antibodies directed against the LPS-core, and not other proteins present in the polyclonal anti-rough strain antisera, were responsible for the observed protective effects. The solution to some of these problems is the production of monoclonal antibodies (Mabs). We will discuss the findings that purified anti-core Mabs may give false-positive outcomes of protection studies, due to the induction of tolerance by small amounts of contaminating endotoxin, present in the antibody preparation. The need to administer the Mab therapeutically instead of prophylactically to the test animals, will be stressed. It will be shown how we succeeded in determining the epitope-specificities of several anti-core antibodies. It will be shown also that use of Elisa alone for characterization of anti-core Mabs may lead to false conclusions concerning epitope specificities. We will prove that synthetic KDO-(=ketodeoxycctanate) and lipid A-containing antigens are indispensable tools for thorough characterization of Mabs. Using this methodology we were able to discriminate between specific antigen-antibody interactions, and the ability of some Mabs to bind “non-specifically” to hydrophobic surfaces. The relationship between epitope specificity and protective effects of anti-core Mabs will be described. Finally, we will demonstrate that a KDO-specific Mabs is capable of protecting mice against lethal sepsis; in other words, it will be shown conclusively that Mabs to defined epitopes in LPS core region are cross-protective.     

NuMA/centrophilin: sequence analysis of the coiled-coil rod domain.

Nuclear mitotic apparatus protein (NuMA), also known as centrophilin, has been shown in previous work to contain a centrally located sequence of length 1485 residues that has both a heptad substructure and a high propensity for alpha-helix formation. Further analysis of this sequence here has revealed that NuMA will form a two-stranded coiled-coil structure with multiple (18) points at which the conformation is interrupted either by proline-containing segments or by discontinuities in the phasing of the heptad substructure. It has also been shown that the two chains will be parallel (rather than antiparallel), that they will lie in axial register, and that this arrangement will be stabilized by a large number of interchain ionic interactions. Interestingly the coiled-coil rod domain is also shown to lack any significant long-range periodicity in the linear distribution of either its acidic or its basic residues. Hence there is no direct evidence from the sequence data that NuMA molecules will aggregate to form closely packed filaments within nuclear space.     

Diabetes mellitus: a potential target for stem cell therapy

Type 1 diabetes mellitus has received much attention recently as a potential target for the emerging science of stem cell medicine. In this autoimmune disease, the insulin-secreting beta-cells of the pancreas are selectively and irreversibly destroyed by autoimmune assault. Advances in islet transplantation procedures now mean that patients with the disease can be cured by transplantation of primary human islets of Langerhans. A major drawback in this therapy is the availability of donor islets, and the search for substitute transplant tissues has intensified in the last few years. This review will describe the essential requirements of a material designed as a replacement beta-cell and will look at the potential sources of such replacements. These include embryonic stem (ES) cells and multipotent adult stem/progenitor cells from a range of tissues including the pancreas, intestine, liver, bone marrow and brain. These stem cell populations will be evaluated and the different experimental approaches that have been employed to derive functional insulin-expressing cells will be discussed. The review will also look at the capability of human ES (hES) cells generated by somatic cell nuclear transfer and some adult stem cell populations such as bone marrow-derived stem cells, to offer autologous transplant material that would remove the need for immunosuppression. In patients with Type 1 diabetes, auto-reactive T-cells are programmed to recognise the insulin-producing beta-cells. As a result, for therapeutic replacement tissues, it may be more sensible to derive cells that behave like beta-cells but are immunologically distinct. Thus, the potential of cells derived from non-beta-cell origin to avoid the autoimmune response will also be discussed. Finally, the review will summarise the future prospects for stem cell therapies for diabetes and will highlight some of the problems that may be faced by researchers working in this area, such as malignancy, irreproducible differentiation strategies, immune-system rejection and social and ethical concerns over the use of hES cells.     

Collective motion in DNA and its role in drug intercalation

The effects of collective motion in DNA as reflected by resonance coupling among its intact segments have been discussed for both linear and circular DNA molecules. The results indicate that due to the effects of this kind of internal collective motion, the energy will be at times highly concentrated at some spots. As a result of the overfocus of energy, the stress built up along the direction of hydrogen bonds between complementary base pairs will be dramatically increased, rupturing a series of consecutive hydrogen bonds simultaneously and resulting in a suddenly free jerk, such that the DNA molecule will undergo a local “quake.” The “hole” formed by this kind of quake-like motion will be large enough for bulky drugs to gain entrance and intercalate into DNA. Even for smaller drugs, this local quake-like motion can also provide a significant mode of entry for intercalation. Energy minimizations carried out for DNA–drug complexes indicate that, for most drugs, a distortion or disruption of 2 to 4 base pairs occurs at the intercalation site in DNA molecules.     

A bioinformatics approach to investigating developmental pathways in the kidney and other tissues.

Over the past few years, large amounts of data linking gene-expression (GE) patterns and other genetic data with the development of the mouse kidney have been published, and the next task will be to integrate these data with the molecular networks responsible for the emergence of the kidney phenotype. This paper discusses how a start to this task can be made by using the kidney database and its associated search tools, and shows how the data generated by such an approach can be used as a guide to future experimentation. Many of the events taking place as the kidney develops do, of course, also take place in other tissues and organisms and it will soon be possible to incorporate relevant information from these systems into analyses of kidney data as well as the new information from microarray technology. The key to success here will be the ability to access over the internet data from the textual and graphical databases for the mouse and other organisms now being established. In order to do this, informatic tools will be needed that will allow a user working with one database to query another. This paper also considers both the types of tools that will be necessary and the databases on which they will operate.     

O-GlcNAc glycosylation: a signal for the nuclear transport of cytosolic proteins?

Year 2004 marks the 20th anniversary of the discovery of O-linked N-acetylglucosamine (O-GlcNAc) by Gerald W. Hart. Despite interest for O-GlcNAc, the functions played by this single monosaccharide remain poorly understood, though numerous roles have been suggested, among which is the involvement of O-GlcNAc in the nuclear transport of cytosolic proteins. This idea was first sustained by studies on bovine serum albumin that showed that the protein could be actively carried to the nucleus when it was modified with sugars. In this paper, we will review data on this puzzling problem. We will first describe the well-established nuclear localisation signal (NLS)-dependent nuclear transport by presenting the different factors involved, and then, we will examine where and how O-GlcNAc could be involved in nuclear transport. Whereas it has been suggested that O-GlcNAc could interfere at two levels in the nuclear transport both by modifying proteins to be translocated to the nucleus and by modifying the nucleoporins of the nuclear pore complex, according to us, this second idea seems unlikely. Part of this study will also be dedicated to a relatively new concept in the nuclear transport: the role of the 70-kDa heat shock proteins (HSP70). The action of the chaperone in nuclear translocation was put forward 10 years ago, but new findings suggest that this mechanism could be linked to O-GlcNAc glycosylation.     

Brief intervention for alcohol misuse in people attending sexual health clinics: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Over the last 30 years the number of people who drink alcohol at harmful levels has increased in many countries. There have also been large increases in rates of sexually transmitted infections. Available evidence suggests that excessive alcohol consumption and poor sexual health may be linked. The prevalence of harmful alcohol use is higher among people attending sexual health clinics than in the general population, and a third of those attending clinics state that alcohol use affects whether they have unprotected sex. Previous research has demonstrated that brief intervention for alcohol misuse in other medical settings can lead to behavioral change, but the clinical- and cost-effectiveness of this intervention on sexual behavior have not been examined. METHODS: We will conduct a two parallel-arm, randomized trial. A consecutive sample of people attending three sexual health clinics in London and willing to participate in the study will be screened for excessive alcohol consumption. Participants identified as drinking excessively will then be allocated to either active treatment (Brief Advice and referral for Brief Intervention) or control treatment (a leaflet on healthy living). Randomization will be via an independent and remote telephone randomization service and will be stratified by study clinic. Brief Advice will comprise feedback on the possible health consequences of excessive alcohol consumption, written information about alcohol and the offer of an appointment for further assessment and Brief Intervention. Follow-up data on alcohol use, sexual behavior, health related quality of life and service use will be collected by a researcher masked to allocation status six months later. The primary outcome for the study is mean weekly alcohol consumption during the previous three months, and the main secondary outcome is the proportion of participants who report unprotected sex during this period. DISCUSSION: Opportunistic intervention for excessive alcohol use has been shown to be effective in a range of medical settings. The SHEAR study will examine whether delivering such interventions in sexual health clinics results in reductions in alcohol consumption and will explore whether this is associated with changes in sexual behavior.     

Haltung und Zucht von Schläfenfleckspechten (Melanerpes pucherani)

Many unique natural habitats have already been disturbed by mankind. At the same time a lot of animal- and plant species have reach the point of no return and so their extinction. The human private efforts for conservation are becoming more and more important.In these efforts zoological gardens as international conservation organisations and private initiatives should go hand in hand.About the breeding of woodpeckers for instance, literature does not show that much. In this case it would be of highly importance in publishing any experience in this matter.The breeding of the Black-cheeked woodpecker is more or less uncomplicated. In spite of his tropical origin, this species is not that sensitive against coldness as other South-American birds. Soft food, fruit and mealworms will be a decent basic food. Even during the breeding-season this kind of food will be totally ok. In the birds enclosure, only a single bird or a couple should be put in. Probably because of their territorial claim, they will become aggressive otherwise. Also very important for this species will be to keep them out of sight from each other. Even housing at hearing distance could be problematic for the brood. To keep this species with other bird species in a community will be possible. In literature until four eggs per brood could be possible. However, even in separated enclosures as mentioned above, these results have never been reached until now.     

Hepcidin, the iron watcher

Hepcidin, a peptide hormone produced by the liver, constitutes the master regulator of iron homeostasis in mammals allowing iron adaptation according to the body iron needs. In recent years there has been important breakthrough in our knowledge of hepcidin regulation that has also implications for understanding the physiopathology of human iron disorders. Different aspects of hepcidin regulation will be considered in this review, including regulation by the iron status and the BMP6/HJV/SMAD pathway. Hepcidin dysregulation in iron disorders will be also discussed. Although much can already be accomplished for treating iron disorders using the knowledge that has currently been developed, additional issues will be challenging for the coming years.     

Evolutionary genomics of animal personality

Research on animal personality can be approached from both a phenotypic and a genetic perspective. While using a phenotypic approach one can measure present selection on personality traits and their combinations. However, this approach cannot reconstruct the historical trajectory that was taken by evolution. Therefore, it is essential for our understanding of the causes and consequences of personality diversity to link phenotypic variation in personality traits with polymorphisms in genomic regions that code for this trait variation. Identifying genes or genome regions that underlie personality traits will open exciting possibilities to study natural selection at the molecular level, gene-gene and gene-environment interactions, pleiotropic effects and how gene expression shapes personality phenotypes. In this paper, we will discuss how genome information revealed by already established approaches and some more recent techniques such as high-throughput sequencing of genomic regions in a large number of individuals can be used to infer micro-evolutionary processes, historical selection and finally the maintenance of personality trait variation. We will do this by reviewing recent advances in molecular genetics of animal personality, but will also use advanced human personality studies as case studies of how molecular information may be used in animal personality research in the near future.     

Clutch size evolution under sexual conflict enhances the stability of mating systems.

Models of optimal clutch size often implicitly assume a situation with uniparental care. However, the evolutionary conflict between males and females over the division of parental care will have a major influence on the evolution of clutch size. Since clutch size is a female trait, a male has little possibility of directly influencing it. However, the optimal clutch size from a female's perspective will depend on the amount of paternal care her mate is expected to provide. The sexual conflict over parental care will in its turn be affected by clutch size, since a larger clutch makes male care more valuable. Hence, there will be joint evolution of mating system and clutch size. In this paper, we demonstrate that this joint evolution will tend to stabilize the mating system. In a situation with conventional sex roles, this joint evolution might result in either increased clutch size and biparental care or reduced clutch size and uniparental female care. Under some circumstances the initial conditions might determine which will be the outcome. These results demonstrate that it may be difficult to deduce whether biparental care evolved because of few opportunities for breeding males increasing their fitness by attracting additional mates or because of the importance of male care for offspring fitness by studying prevailing mating systems using, for example, male removals or manipulation of males' opportunities for finding additional mates. In general terms, we demonstrate that models of life-history evolution have to consider the social context in which they evolve.     

Effects of kinetic coupling on experimentally determined electron transfer parameters

Coupled electron transfer (ET) occurs when a relatively slow nonadiabatic ET reaction is preceded by a rapid but unfavorable adiabatic reaction that is required to activate the system for ET. As a consequence of this, the observed ET rate constant (k(ET)) is an apparent value equal to the product of the true k(ET) and the equilibrium constant for the preceding reaction step. Analysis of such reactions by ET theory may yield erroneous values for the reorganizational energy (lambda), electronic coupling (H(AB)), and ET distance that are associated with the true k(ET). If the DeltaG degrees dependence of the rate of a coupled ET reaction is analyzed, an accurate value of lambda will be obtained but the experimentally determined H(AB) will be less than the true H(AB) and the ET distance will be greater than the true distance. If the temperature dependence of the rate of a coupled ET reaction is analyzed, the experimentally determined value of lambda will be greater than the true lambda. The magnitude of this apparent lambda will depend on the magnitude of DeltaH degrees for the unfavorable reaction step that precedes ET. The experimentally determined values of H(AB) and distance will be accurate if DeltaS degrees for the preceding reaction is zero. If DeltaS degrees is positive, then H(AB) will be greater than the true value and the distance will be less than the true value. If DeltaS degrees is negative, then H(AB) will be less than the true value and the distance will be greater than the true value. Data sets for coupled ET reactions have been simulated and analyzed by ET theory to illustrate these points.     

Structural and regulatory evolution of cellular electrophysiological systems

SUMMARY Cellular electrophysiological systems, like developmental systems, appear to evolve primarily by means of regulatory evolution. It is suggested that electrophysiological systems share two key features with developmental systems that account for this dependence on regulatory evolution. For both systems, structural evolution has the potential to create significant problems of pleiotropy and both systems are predominantly computational in nature. It is concluded that the relative balance of physical and computational tasks that a biological system has to perform, combined with the probability that these tasks may have to change significantly during the course of evolution, will be major factors in determining the relative mix of regulatory and structural evolution that is observed for a given system. Physiological systems that directly interface with the environment will almost always perform some low-level physical task. In the majority of cases this will require evolution of protein function in order for the tasks themselves to evolve. For complex physiological systems a large fraction of their function will be devoted to high-level control functions that are predominantly computational in nature. In most cases regulatory evolution will be sufficient in order for these computational tasks to evolve.     

The consent problem within DNA biobanks

Large prospective biobanks are being established containing DNA, lifestyle and health information in order to study the relationship between diseases, genes and environment. Informed consent is a central component of research ethics protection. Disclosure of information about the research is an essential element of seeking informed consent. Within biobanks, it is not possible at recruitment to describe in detail the information that will subsequently be collected because people will not know which disease they will develop. It will also be difficult to describe the specific research that will be performed using the biobank, other than to stipulate categories of research or diseases that are not included. Potential subjects can only be given information about the sorts of research that will be performed and by whom. Organisations responsible for biobanks usually argue that this disclosure of information is adequate when seeking informed consent, especially if coupled with a right to withdraw, as it would not be feasible or it would be too expensive to seek consent renewal on a regular basis. However, there are concerns about this 'blanket consent' approach'. Consent waivers have also been proposed in which research subjects entrust their consent with an independent third party to decide whether subsequent research using the biobank is consistent with the original consent provided by the subject.     

Haltung und Zucht von Schläfenfleckspechten (Melanerpes pucherani)

Many unique natural habitats have already been disturbed by mankind. At the same time a lot of animal- and plant species have reach the point of no return and so their extinction. The human private efforts for conservation are becoming more and more important.In these efforts zoological gardens as international conservation organisations and private initiatives should go hand in hand.About the breeding of woodpeckers for instance, literature does not show that much. In this case it would be of highly importance in publishing any experience in this matter.The breeding of the Black-cheeked woodpecker is more or less uncomplicated. In spite of his tropical origin, this species is not that sensitive against coldness as other South-American birds. Soft food, fruit and mealworms will be a decent basic food. Even during the breeding-season this kind of food will be totally ok. In the birds enclosure, only a single bird or a couple should be put in. Probably because of their territorial claim, they will become aggressive otherwise. Also very important for this species will be to keep them out of sight from each other. Even housing at hearing distance could be problematic for the brood. To keep this species with other bird species in a community will be possible. In literature until four eggs per brood could be possible. However, even in separated enclosures as mentioned above, these results have never been reached until now.