Statistical analysis and prediction of protein-protein interfaces

Predicting protein-protein interfaces from a three-dimensional structure is a key task of computational structural proteomics. In contrast to geometrically distinct small molecule binding sites, protein-protein interface are notoriously difficult to predict. We generated a large nonredundant data set of 1494 true protein-protein interfaces using biological symmetry annotation where necessary. The data set was carefully analyzed and a Support Vector Machine was trained on a combination of a new robust evolutionary conservation signal with the local surface properties to predict protein-protein interfaces. Fivefold cross validation verifies the high sensitivity and selectivity of the model. As much as 97% of the predicted patches had an overlap with the true interface patch while only 22% of the surface residues were included in an average predicted patch. The model allowed the identification of potential new interfaces and the correction of mislabeled oligomeric states.     

Environments and evolution: interactions between stress, resource inadequacy and energetic efficiency

Evolutionary change is interpreted in terms of the near-universal ecological scenario of stressful environments. Consequently, there is a premium on the energetically efficient exploitation of resources in a resource-inadequate world. Under this environmental model, fitness can be approximated to energetic efficiency especially towards the limits of survival. Furthermore, fitness at one stage of the life-cycle should correlate with fitness at other stages, especially for development time, survival and longevity; 'good genotypes' under stress should therefore be at a premium. Conservation in the wild depends primarily on adaptation to abiotically changing habitats since towards the limits of survival, genomic variation is rarely restrictive. The balance between energetic costs under variable environments and energy from resources provides a model for interpreting evolutionary stasis, punctuational and gradual change, and specialist diversification. Ultimately, a species should be in an equilibrium between the physiology of an organism and its adaptation to the environment. The primary key to understanding evolutionary change should therefore be ecological, highlighting energy availability in a stressed world; this approach is predictive for various patterns of evolutionary change in the living and fossil biota.     

Public consultation in ethics an experiment in representative ethics

Genome Canada has funded a research project to evaluate the usefulness of different forms of ethical analysis for assessing the moral weight of public opinion in the governance of genomics. This paper will describe a role of public consultation for ethical analysis and a contribution of ethical analysis to public consultation and the governance of genomics/biotechnology. Public consultation increases the robustness of ethical analysis with a more diverse set of moral experiences. Consultation must be carefully and respectfully designed to generate sufficiently diverse and rich accounts of moral experiences. Since dominant groups tend to define ethical or policy issues in a manner that excludes some interests or perspectives, it is important to identify the range of interests that diverse publics hold before defining the issue and scope of the discussion and the premature foreclosure of ethical dialogue. Consequently, a significant contribution of ethical dialogue strengthened by social analysis is to consider the context and non-policy use of power to govern genomics and to sustain social debate on enduring ethical issues.     

Prediction of coordination number and relative solvent accessibility in proteins

Knowing the coordination number and relative solvent accessibility of all the residues in a protein is crucial for deriving constraints useful in modeling protein folding and protein structure and in scoring remote homology searches. We develop ensembles of bidirectional recurrent neural network architectures to improve the state of the art in both contact and accessibility prediction, leveraging a large corpus of curated data together with evolutionary information. The ensembles are used to discriminate between two different states of residue contacts or relative solvent accessibility, higher or lower than a threshold determined by the average value of the residue distribution or the accessibility cutoff. For coordination numbers, the ensemble achieves performances ranging within 70.6-73.9% depending on the radius adopted to discriminate contacts (6A-12A). These performances represent gains of 16-20% over the baseline statistical predictor, always assigning an amino acid to the largest class, and are 4-7% better than any previous method. A combination of different radius predictors further improves performance. For accessibility thresholds in the relevant 15-30% range, the ensemble consistently achieves a performance above 77%, which is 10-16% above the baseline prediction and better than other existing predictors, by up to several percentage points. For both problems, we quantify the improvement due to evolutionary information in the form of PSI-BLAST-generated profiles over BLAST profiles. The prediction programs are implemented in the form of two web servers, CONpro and ACCpro, available at http://promoter.ics.uci.edu/BRNN-PRED/.     

Stem cell colloquy: conclusion

The stem cell data presented and discussed during the symposium raise the hope that important medical progress can be made in several fields: neuro-degenerative diseases, those linked to cellular deficit, some aspects of aging linked to cellular degeneration, and the treatment of cancers that may harm normal tissues at risk of being infiltrated by malignant cells. Three main types of stem cells are available. (i) Those present in normal adult tissue: contrary to what was believed, some data suggest that certain adult stem cells have a great plasticity (they can differentiate into cells different from those in tissues from which they were taken) and can proliferate in vitro without losing their properties. Nevertheless, their use faces several obstacles: in ill or elderly subjects, then these cells can be limited in number or not multiply well in vitro. In this case, auto-grafting of the cells cannot be used. They must be sought in another subject, and allo-grafting causes difficult and sometimes insoluble problems of immunological tolerance. (ii) Embryonic stem cells from surplus human embryos, obtained by in vitro fertilisation, which the parents decide not to use: these cells have a great potential for proliferation and differentiation, but can also encounter problems of immunological intolerance. (iii) Cells obtained from cell nuclear transfer in oocytes: these cells are well tolerated, since they are genetically and immunologically identical to those of the host. All types of stem cells can be obtained with them. However, they do present problems. For obtaining them, female oocytes are needed, which could lead to their commercialization. Moreover, the first steps for obtaining these cells are identical to those used in reproductive cloning. It therefore appears that each type of cell raises difficult scientific and practical problems. More research is needed to overcome these obstacles and to determine which type of stem cell constitutes the best solution for each type of disease and each patient. There are three main ethical problems: (a) to avoid the commercialization of stem cells and oocytes (this can be managed through strict regulations and the supervision of authorized laboratories); (b) to avoid that human embryos be considered as a mere means to an end (they should only be used after obtaining the informed consent of the parents; the conditions of their use must be well defined and research programs must be authorized); (c) to avoid that research on stem cell therapy using cell nuclear replacement opens the way to reproductive cloning (not only should reproductive cloning be firmly forbidden but authorization for cell nuclear transfer should be limited to a small number of laboratories). Overall, it appears that solutions can be found for administrative and ethical problems. Harmonisation of international regulations would be desirable in this respect, in allowing at the same time each country to be responsible for its regulations. A last ethical rule should be implemented, not to give patients and their families false hopes. The scientific and medical problems are many, and the solutions will be long and difficult to find. Regenerative medicine opens important avenues for research, but medical progress will be slow.     

Stem cells and cell therapy. Contribution to the ethical debate

Divergent and sometimes conflicting positions with respect to human stem cells and cell therapy do not merely reflect disagreement among scientists and conflicts of interest. They attest the ethical tension resulting from recent progress in understanding the earliest stages of development of the human being that can be observed in vitro. Can the extremely potent notion of the human person starting with conception apply to the very first stage of artificial in vitro fertilisation and disregard the fact that to be a real substitute for natural conception, implantation in the uterus that enables the oocyte to nest and a new human being to develop must also be included? Several arguments are presented that plead in favour of making a clear distinction between the status of in vitro cells obtained by artificial fertilisation and that of the embryo, which becomes a developing human being from the moment it implants in the endometrium of the uterus. This subject could have remained in the sphere of the individual conscience, but it has now become a theme for social debate! The revision of the French 1994 so-called Bioethics Laws, which was recently approved on first reading on 22 January 2002, authorises research on spare embryos from in vitro fertilisation under certain conditions. However, for the sole reason that there is a risk of opening the door wide to reproductive cloning, which is unanimously rejected and condemned, all research on stem cells deriving from the nuclear transfer of a somatic cell is prohibited, irrespective of the distinction between cloning for therapeutic purposes and reproductive cloning. It is undeniable that if the efficacy of somatic stem cells could be demonstrated, they would offer a far more preferable solution, for several reasons, than those involving stem cells obtained from spare embryos from IVF or nuclear transfer. Nevertheless, how will a comparison of the two methods be possible if one of them is prohibited a priori? At present, many fear that French researchers will be prevented from doing essential research that, even if it has far to go, is indispensable if we wish to attempt to control the failures of natural procreation and open the way towards the new regenerative medicine that so many look forward to.     

Scientists Prefer them Blind: The History of Hypogean Fish Research

The history of hypogean fish research has been strongly influenced by neo-Lamarckism (including orthogenesis) and typological thinking. Only in the last few decades neo-Darwinism has made any inroads in the research approach to this subject. The majority of the most distinguished and productive hypogean fish researchers have used their research subjects to confirm their own views on evolution rather than to use those subjects as a spring of knowledge to enrich mainstream biological thought. Of these views, I found that the most perversive of all is the notion of evolutionary progress that has led many researchers to envision hypogean fishes as prime examples of regressive evolution. I propose that the utilization of hypogean fishes for the study of convergent evolution should catapult these subjects of research into prime objects of evolutionary ideas.     

Some Evolutionary Arguments about what maintains the Pelagic Interval in Reef Fishes

In this paper, we address the question of the nature of evolutionary forces that account for the oceanic planktonic larva period. Putting the emphasis on coral reef fishes, we first present the most common theories and hypotheses, looking at them critically from the standpoint of individual selection and taking into account new data arising from genetic surveys. We concluded that each individual hypothesis based on short term advantages of a larva period cannot convincingly explain by itself the long term maintenance of such a complex life cycle. We then study the impact of the pelagic interval on species dispersal by compiling data sets from the literature. Following simple analysis of this data, we found that duration of the planktonic larva period drives gene flow in the Great Barrier Reef and colonisation throughout the Pacific. In speculating on the real nature of the short term selective forces responsible for the maintenance of the pelagic interval, we acknowledge the fact that long term constraints alone will not withstand erosion if they are not reinforced by some sort of short term mechanism. We tentatively arrive at the conclusion that these short term forces may be different from what could be expected from functional studies of planktonic life.     

文昌鱼特异的基因倍增

进化生物学和发育生物学的结合产生了一门新兴学科——进化发育生物学,近年来该领域研究取得了丰硕的成果。头索动物文昌鱼是现存生物中最近似于脊椎动物直接祖先的生物,在与脊椎动物分化后形态改变很小,其基因组未曾经历大规模的基因组倍增,在一定程度上反映了脊椎动物祖先型基因组的特征,但在漫长的独立进化历程中基因组自身还是经历了一些变化。本文介绍了在几例在文昌鱼支系中独立发生的基因倍增事件(Hox; Evx; HNF-3; Calmodulin-like),有力地揭示了文昌鱼虽然与脊椎动物直接祖先极其接近,但其基因组有其自身特性,不能简单地将之等同于脊椎动物直接祖先。Abstract: The union of the two complementary disciplines, developmental biology and evolutionary biology resulted in a new division of evolutionary developmental biology, namely “Evo-Devo”. Recently, the research on this field has been fruitful in understanding the origin and development of vertebrates. The cephalochordate amphioxus, which remains in relatively invariant morphology since the divergence from the vertebrate lineage, is the closest living relative to vertebrates. The vertebrate-like simple body plan and preduplicative genome provide amphioxus genes the privilege to serve as key landmark to understand morphological evolution. However, the amphioxus genome has not escaped evolution. In this paper several examples of independent gene (Hox; Evx; HNF-3 and Calmodulin-like) duplications in the cephalochordate lineage were summarized. These particularities and oddities remind the fact that amphioxus is not an immediate ancestor of the vertebrates but ‘only’ the closest living relative to the ancestor, with a mix of prototypical and amphioxus-specific features in its genome.     

Pair-housing rather than single-housing for laboratory rhesus macaques

A total of 378 adult and juvenile rhesus macaques of both sexes were transferred from single- to isosexual pair-housing arrangements. The incidence of serious injury resulting from partner incompatibility was 0.8% during the first year after pair formation. It was concluded that pair-housing offers a safe option to address the animals' social needs in compliance with federal rules and professional standards.