New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria

Deficiencies in two subunits of the succinyl-coenzyme A synthetase (SCS) have been involved in patients with encephalomyopathy and mild methylmalonic aciduria (MMA). In this study, we described three new SUCLG1 patients and performed a meta-analysis of the literature. Our report enlarges the phenotypic spectrum of SUCLG1 mutations and confirms that a characteristic metabolic profile (presence of MMA and C4-DC carnitine in urines) and basal ganglia MRI lesions are the hallmarks of SCS defects. As mitochondrial DNA depletion in muscle is not a constant finding in SUCLG1 patients, this may suggest that diagnosis should not be based on it, but also that alternative physiopathological mechanisms may be considered to explain the combined respiratory chain deficiency observed in SCS patients.     

Principles and levels of laterality in unimanual and bimanual stone handling patterns by Japanese macaques

The preferential use of one hand over the other is considered the primary behavioral expression of structural and functional asymmetry in cerebral structures, which is a decisive factor in human evolution. We present the first analysis of manual laterality in a form of object play—stone handling (SH) behavior—in a free-ranging group of Japanese macaques. Defined as a stone-directed manipulative activity, and comprised of multiple one-handed SH patterns (e.g., grabbing a stone in one hand and cradling it against its chest), as well as coordinated two-handed SH patterns with manual role differentiation (e.g., holding a stone with one hand and rubbing it with the other), SH behavior is a good candidate for the study of hand lateralization. We systematically followed the methodological framework developed by McGrew and Marchant (1997) to measure and analyze the presence, strength, and direction of manual preference in the performance of SH behavior and in various SH patterns, both at the individual and group level. Some individuals showed a significant manual lateral bias on a single SH pattern (hand preference), whereas others showed consistency in laterality across all or most of the SH patterns they performed (hand specialization). At the group level, we found that, although their collective distribution of left versus right remained random, most subjects were either significantly but incompletely lateralized, or completely lateralized within particular SH patterns (pattern specialization), but not across all SH patterns (no handedness for SH behavior as a whole). As predicted by the task-complexity model, hand specialization and handedness were stronger in the coordinated bimanual SH patterns than in the unimanual patterns. We discuss the implications of our findings for the evolution of manual preferences in noninstrumental object manipulation versus stone tool use in nonhuman primates and hominins.     

Activity and Ranging Patterns of <Emphasis Type="Italic">Colobus angolensis ruwenzorii</Emphasis> in Nyungwe Forest,Rwanda: Possible Costs of Large Group Size

With group sizes sometimes >300 individuals, the Angolan black-and-white colobus (Colobus angolensis ruwenzorii) population in Nyungwe Forest, Rwanda is an intriguing exception to the tendency for folivores to live in smaller groups than expected relative to body size. Researchers have hypothesized that the unusually high quality of foliage at Nyungwe allows colobus there to avoid intragroup feeding competition, releasing constraints on the formation of large groups (Fimbel et al., 2001). We collected data on the activity and ranging patterns of a >300-member Nyungwe colobus group and compared our results to those from smaller groups in other black-and-white colobus (Colobus spp.) populations. Colobus at Nyungwe spent far more time feeding and moving (62%) and far less time resting (32%) than black-and-white colobus at any other site. The annual home range of the Nyungwe colobus was also many times larger (95% minimum convex polygon: 20.7 km ² ; 95% fixed kernel: 24.4 km ² ) than those for other populations. We terminated our research after the group engaged in an unprecedented migration among black-and-white colobus by moving 13 km south of their former range. Our results suggest that intragroup scramble competition may be more intense than originally believed within the large colobus groups at Nyungwe and that long periods of resource renewal may be necessary after a large colobus group passes through an area, thereby potentially helping to explain their wide ranging patterns. We discuss the socioecological convergence between the Nyungwe colobus and Chinese snub-nosed monkeys (Rhinopithecus spp.) and suggest directions for future research on the unique black-and-white colobus population at Nyungwe.

Identification of quantitative trait loci influencing aerial morphogenesis in the model legume <Emphasis Type="Italic">Medicago truncatula</Emphasis>

In many legume crops, especially in forage legumes, aerial morphogenesis defined as growth and development of plant organs, is an essential trait as it determines plant and seed biomass as well as forage quality (protein concentration, dry matter digestibility). Medicago truncatula is a model species for legume crops. A set of 29 accessions of M. truncatula was evaluated for aerial morphogenetic traits. A recombinant inbred lines (RILs) mapping population was used for analysing quantitative variation in aerial morphogenetic traits and QTL detection. Genes described to be involved in aerial morphogenetic traits in other species were mapped to analyse co-location between QTLs and genes. A large variation was found for flowering date, morphology and dynamics of branch elongation among the 29 accessions and within the RILs population. Flowering date was negatively correlated to main stem and branch length. QTLs were detected for all traits, and each QTL explained from 5.2 to 59.2% of the phenotypic variation. A QTL explaining a large part of genetic variation for flowering date and branch growth was found on chromosome 7. The other chromosomes were also involved in the variation detected in several traits. Mapping of candidate genes indicates a co-location between a homologue of Constans gene or a flowering locus T (FT) gene and the QTL of flowering date on chromosome 7. Other candidate genes for several QTLs are described. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch

Ficolins are soluble oligomeric proteins with lectin-like activity, assembled from collagen fibers prolonged by fibrinogen-like recognition domains. They act as innate immune sensors by recognizing conserved molecular markers exposed on microbial surfaces and thereby triggering effector mechanisms such as enhanced phagocytosis and inflammation. In humans, L- and H-ficolins have been characterized in plasma, whereas a third species, M-ficolin, is secreted by monocytes and macrophages. To decipher the molecular mechanisms underlying their recognition properties, we previously solved the structures of the recognition domains of L- and H-ficolins, in complex with various model ligands (Garlatti, V., Belloy, N., Martin, L., Lacroix, M., Matsushita, M., Endo, Y., Fujita, T., Fontecilla-Camps, J. C., Arlaud, G. J., Thielens, N. M., and Gaboriaud, C. (2007) EMBO J. 24, 623-633). We now report the ligand-bound crystal structures of the recognition domain of M-ficolin, determined at high resolution (1.75-1.8 A), which provides the first structural insights into its binding properties. Interaction with acetylated carbohydrates differs from the one previously described for L-ficolin. This study also reveals the structural determinants for binding to sialylated compounds, a property restricted to human M-ficolin and its mouse counterpart, ficolin B. Finally, comparison between the ligand-bound structures obtained at neutral pH and nonbinding conformations observed at pH 5.6 reveals how the ligand binding site is dislocated at acidic pH. This means that the binding function of M-ficolin is subject to a pH-sensitive conformational switch. Considering that the homologous ficolin B is found in the lysosomes of activated macrophages (Runza, V. L., Hehlgans, T., Echtenacher, B., Zahringer, U., Schwaeble, W. J., and Mannel, D. N. (2006) J. Endotoxin Res. 12, 120-126), we propose that this switch could play a physiological role in such acidic compartments.     

Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL

Competitive antagonists of the human prolactin (hPRL) receptor are a novel class of molecules of potential therapeutic interest in the context of cancer. We recently developed the pure antagonist Del1-9-G129R-hPRL by deleting the nine N-terminal residues of G129R-hPRL, a first generation partial antagonist. We determined the crystallographic structure of Del1-9-G129R-hPRL, which revealed no major change compared with wild type hPRL, indicating that its pure antagonistic properties are intrinsically due to the mutations. To decipher the molecular bases of pure antagonism, we compared the biological, physicochemical, and structural properties of numerous hPRL variants harboring N-terminal or Gly(129) mutations, alone or combined. The pure versus partial antagonistic properties of the multiple hPRL variants could not be correlated to differences in their affinities toward the hPRL receptor, especially at site 2 as determined by surface plasmon resonance. On the contrary, residual agonism of the hPRL variants was found to be inversely correlated to their thermodynamic stability, which was altered by all the Gly(129) mutations but not by those involving the N terminus. We therefore propose that residual agonism can be abolished either by further disrupting hormone site 2-receptor contacts by N-terminal deletion, as in Del1-9-G129R-hPRL, or by stabilizing hPRL and constraining its intrinsic flexibility, as in G129V-hPRL.     

The human Nup107-160 nuclear pore subcomplex contributes to proper kinetochore functions

We previously demonstrated that a fraction of the human Nup107-160 nuclear pore subcomplex is recruited to kinetochores at the onset of mitosis. However, the molecular determinants for its kinetochore targeting and the functional significance of this localization were not investigated. Here, we show that the Nup107-160 complex interacts with CENP-F, but that CENP-F only moderately contributes to its targeting to kinetochores. In addition, we show that the recruitment of the Nup107-160 complex to kinetochores mainly depends on the Ndc80 complex. We further demonstrate that efficient depletion of the Nup107-160 complex from kinetochores, achieved either by combining siRNAs targeting several of its subunits excluding Seh1, or by depleting Seh1 alone, induces a mitotic delay. Further analysis of Seh1-depleted cells revealed impaired chromosome congression, reduced kinetochore tension and kinetochore-microtubule attachment defects. Finally, we show that the presence of the Nup107-160 complex at kinetochores is required for the recruitment of Crm1 and RanGAP1-RanBP2 to these structures. Together, our data thus provide the first molecular clues underlying the function of the human Nup107-160 complex at kinetochores.