Structure conservation in cytochromes P450

The recent availability of crystal structures for several diverse cytochromes P450 (CYPs) offers the possibility to perform an up-to-date comparative analysis to identify the degree of structure conservation among this superfamily of enzymes specially relevant for their involvement in drug metabolism and toxicity. A set of 9 CYPs sharing between 10% and 27% sequence identity was selected, including 7 class I (CYP 101, 107, 108, 119, 121, 51, and 55) and two class II (CYP 102, and 2C5) structures. After obtaining a multiprotein structure superimposition, a structure-based sequence alignment was derived. Mapping the level of three-dimensional structural conservation onto the sequence alignment revealed that over 28% of the alignment positions have the Calpha carbons of their residues within a root-mean-square deviation (RMSD) of 2 A. This degree of structure conservation is found to be generally preserved, even when the structure undergoes dramatic conformational changes. Performing the analysis on 4 members of the CYP2 family (CYP 2B4, 2C5, 2C8, and 2C9), the percentage of alignment positions within 2 A RMSD amounted to 73%, increasing to over 85% when only structures in a closed conformation are considered. The present findings suggest that it should be plausible to derive models of overall good quality for the major CYP2 metabolizing forms (CYP 2A6, 2C19, 2D6, and 2E1), whereas high levels of uncertainty are still likely to be expected in models for the remaining 2 major P450 metabolizing forms (CYP 1A2 and 3A4), with the corresponding implications for their potential applicability in drug design activities.     

Wing morphology of the active flyer Calliphora vicina (Diptera: Calliphoridae) during its invasion of a sub‐Antarctic archipelago where insect flightlessness is the rule

The cosmopolitan blowfly Calliphora vicina became established in the sub‐Antarctic Kerguelen Islands in the late 1970s, following a warming period that allowed its full development. Although temperature and wind may limit flight activity, the fly invaded the archipelago, reaching sites remote from the introduction point. Most native competitors have converged to flightlessness as a response to stringent environmental conditions and therefore the flight strategy of C. vicina might be either a handicap or a competitive advantage under ongoing climate change. Using geometric morphometrics, we investigated whether the wing had changed over time in C. vicina within the archipelago (1998 vs. 2009) and compared its morphology with that of a continental population from a temperate area (1983 vs. 2009). Wing shape plasticity to temperature was also experimentally investigated. We found no clues of relaxed selection on flight morphology in the range invaded. However, rapid changes of wing shape occurred over time in females from the Kerguelen Islands compared with both males and females of the continental population, despite a shorter time‐lag between samples in the former. The thermal reaction norms for wing shape found for C. vicina from Kerguelen were also different from those of the continental population, but it remains unknown whether this resulted from or preceded the introduction. These combined findings are consistent with a fingerprint of local adaptation in the invasive population. However, the adaptive significance of the changes, in terms of their aerodynamic consequences and the future evolution of C. vicina in the Kerguelen Islands, requires further investigation. From an evolutionary standpoint, sustaining flight capability under the novel sub‐Antarctic conditions might be critical to the invasive success of C. vicina as most competitors are flightless.     

In silico characterization of a RNA binding protein of cattle filarial parasite Setaria digitata

Human lymphatic filariasis (HLF) is a neglected tropical disease which threatens nearly 1.4 billion people in 73 countries worldwide. Wuchereria bancrofti is the major causative agent of HLF and it closely resembles cattle filarial parasite Setaria digitata. Due to difficulties in procuring W. bancrofti parasite material, S. digitata cDNA library has been constructed to identify novel drug targets against HLF and many of the cDNA sequences are yet to be assigned structure and function. In this study, a 549 bp long cDNA (sdrbp) has been sequenced and characterized in silico. The shortest ORF of 249 bp from the isolated cDNA encodes a polypeptide of 82 amino acids and shows an amino acid identity of 54% with the RRM domain of human cleavage stimulation factor-64 kDa subunit (CstF-64). Structure of the protein (sdRBP) obtained by homology modelling using RRM of CstF-64 as template adopts classical RRM topology (β1α1β2β3α2β4). sdRBP model built was validated by superimposition tools and Ramachandran plot analysis. CstF-64 plays an important role in pre-mRNA polyadenylation by interacting with specific GU-rich downstream sequence element. Molecular docking studies of sdRBP with different RNA molecules revealed that sdRBP has greater binding affinity to GU-rich RNA and comparable results were obtained upon similar docking of RRM of CstF-64 with the same RNA molecules. Therefore, sdRBP is likely to perform homologous function in S. digitata. This study brings new dimensions to the functional analysis of RNA binding proteins of S. digitata and their evaluation as new drug targets against HLF.     

黑龙江下城子组类三角蚌的复合模化石及其形态和沉积学意义

复合模化石是贝壳被溶蚀后,由于早期成岩压缩作用的影响,原贝壳的内模和外模互相叠加压印而成的化石,其正、负模上均印有原壳的内面和外表的特征。这种石具有形态和沉积学意义。     

Analysing disparity by applying combined morphological and molecular approaches to French and Japanese carabid beetles

The expression of morphological disparity within a clade is related to its history and to the environmental parameters within which it develops. Recent developments in geometric morphometries allow quantitative estimation of morphological disparity, and facilitate comparisons with genetic data intended to provide phylogenetic information. Such comparisons were made between two sets of ground beetle species from regions that differ biogeographically and environmentally: 12 post-glacial reinvading species from NE France; and 15 Japanese species less likely to be affected by the Pleistocene glacial events. Genetic relationships were inferred from mitochondrial DNA (ND5 gene). Morphological divergences among the species were analysed using Procrustes ver. 2.0, based on 64 landmarks (generalized analyses and computation of additive distance trees). The established morphospaces indicate distinct disparity patterns in France and Japan, even though the genetic data show that neither of the two sets arc monophyletic, and that they are in fact intermixed in the same clade. This discrepancy is partly related to the presence of extreme (elongated) morphologies in the Japanese set. But the stronger disparity observed amongjapanese species does not correspond to greater genetic differences. Those extreme morphologies appear to be related to the degree of endemicity of the species. The differences between the French and Japanese morphological patterns are discussed in the context of possible geographic factors and climatic changes during the Pleistocene.     

Turning the tables of sex distinction in craniofacial identification: Why females possess thicker facial soft tissues than males,not vice versa

Males are universally reported to possess larger facial soft‐tissue thickness (FSTT) than females, however, this observation oversimplifies the raw data yielding an underpowered assessment of FSTT sex‐patterning where: differences are small (η² < 5%) and inconsistent (females are routinely larger than males at the cheeks). Here we investigate body‐size normalized data to assess whether more general and improved understanding of FSTT sex‐variation in humans is possible. FSTTs were measured in 52 healthy living Australians aged 18 to 30 years using B‐mode ultrasound. Participants' stature and body mass were also measured. Sex differences were calculated before and after normalization by the aforementioned body‐composition variables. Methods were repeated in three other independent samples to evaluate reproducibility: 100 American Whites and 60 American Blacks measured by B‐mode ultrasound; and 50 Turkish residents measured by regular supine CT. Compared to raw mean differences (F < M, by ?6%), females displayed much thicker FSTTs than males when normalized for body mass (F > M, by +16%). Consequently, while the sexes share similar raw values, females possess much larger FSTTs for their relatively lighter bodies. The relative FSTT difference was 2.7× larger than the raw mean difference. Sex differences in FSTT are of larger magnitude and reversed direction in mass normalized data. Contrary to popular thought, females possess much larger FSTTs than males owing to their generically lighter bodies (?18 kg). These data patterns help explain why the pooling of sex‐categorized FSTT does not jeopardize the sex‐difference—it is encoded more strongly in terms relative to body mass.     

A short survey on protein blocks

Protein structures are classically described in terms of secondary structures. Even if the regular secondary structures have relevant physical meaning, their recognition from atomic coordinates has some important limitations such as uncertainties in the assignment of boundaries of helical and β-strand regions. Further, on an average about 50% of all residues are assigned to an irregular state, i.e., the coil. Thus different research teams have focused on abstracting conformation of protein backbone in the localized short stretches. Using different geometric measures, local stretches in protein structures are clustered in a chosen number of states. A prototype representative of the local structures in each cluster is generally defined. These libraries of local structures prototypes are named as "structural alphabets". We have developed a structural alphabet, named Protein Blocks, not only to approximate the protein structure, but also to predict them from sequence. Since its development, we and other teams have explored numerous new research fields using this structural alphabet. We review here some of the most interesting applications.     

Shape analysis of symmetric structures: quantifying variation among individuals and asymmetry

Abstract.— Morphometric studies often consider parts with internal left-right symmetry, for instance, the vertebrate skull. This type of symmetry is called object symmetry and is distinguished from matching symmetry, in which two separate structures exist as mirror images of each other, one on each body side. We explain a method for partitioning the total shape variation of landmark configurations with object symmetry into components of symmetric variation among individuals and asymmetry. This method is based on the Procrustes superimposition of the original and a reflected copy of each landmark configuration and is compatible with the two-factor ANOVA model customary in studies of fluctuating asymmetry. We show a fully multivariate framework for testing the effects in the two-factor model with MANOVA statistics, which also applies to shapes with matching symmetry. We apply the new methods in a small case study of pharyngeal jaws of the Neotropical cichlid fish Amphilophus citrinellus . The analysis revealed that the symmetric component of variation in the pharyngeal jaws is dominated by the contrast between two alternative trophic morphs in this species and that there is subtle but statistically significant directional asymmetry. Finally, we provide some general recommendations for morphometric studies of symmetric shapes.     

Ontogenetic study of the skull in modern humans and the common chimpanzees: neotenic hypothesis reconsidered with a tridimensional Procrustes analysis

Heterochronic studies compare ontogenetic trajectories of an organ in different species: here, the skulls of common chimpanzees and modern humans. A growth trajectory requires three parameters: size, shape, and ontogenetic age. One of the great advantages of the Procrustes method is the precise definition of size and shape for whole organs such as the skull. The estimated ontogenetic age (dental stages) is added to the plot to give a graphical representation to compare growth trajectories. We used the skulls of 41 Homo sapiens and 50 Pan troglodytes at various stages of growth. The Procrustes superimposition of all specimens was completed by statistical procedures (principal component analysis, multivariate regression, and discriminant function) to calculate separately size-related shape changes (allometry common to chimpanzees and humans), and interspecific shape differences (discriminant function). The results confirm the neotenic theory of the human skull (sensu Gould [1977] Ontogeny and Phylogeny, Cambridge: Harvard University Press; Alberch et al. [1979] Paleobiology 5:296-317), but modify it slightly. Human growth is clearly retarded in terms of both the magnitude of changes (size-shape covariation) and shape alone (size-shape dissociation) with respect to the chimpanzees. At the end of growth, the adult skull in humans reaches an allometric shape (size-related shape) which is equivalent to that of juvenile chimpanzees with no permanent teeth, and a size which is equivalent to that of adult chimpanzees. Our results show that human neoteny involves not only shape retardation (paedomorphosis), but also changes in relative growth velocity. Before the eruption of the first molar, human growth is accelerated, and then strongly decelerated, relative to the growth of the chimpanzee as a reference. This entails a complex process, which explains why these species reach the same overall (i.e., brain + face) size in adult stage. The neotenic traits seem to concern primarily the function of encephalization, but less so other parts of the skull. Our results, based on the discriminant function, reveal that additional structural traits (corresponding to the nonallometric part of the shape which is specific to humans) are rather situated in the other part of the skull. They mainly concern the equilibrium of the head related to bipedalism, and the respiratory and masticatory functions. Thus, the reduced prognathism, the flexed cranial base (forward position of the foramen magnum which is brought closer to the palate), the reduced anterior portion of the face, the reduced glabella, and the prominent nose mainly correspond to functional innovations which have nothing to do with a neotenic process in human evolution. The statistical analysis used here gives us the possibility to point out that some traits, which have been classically described as paedomorphic because they superficially resemble juvenile traits, are in reality independent of growth.