Structural characterization of a ribose-5-phosphate isomerase B from the pathogenic fungus Coccidioides immitis

Background

F-spondin is a multi-domain extracellular matrix (ECM) protein and a contact-repellent molecule that directs axon outgrowth and cell migration during development. The reelin_N domain and the F-spondin domain (FS domain) comprise a proteolytic fragment that interacts with the cell membrane and guides the projection of commissural axons to floor plate. The FS domain is found in F-spondins, mindins, M-spondin and amphiF-spondin.

Results

We present the crystal structure of human F-spondin FS domain at 1.95Å resolution. The structure reveals a Ca²⁺-binding C2 domain variant with an 8-stranded antiparallel β-sandwich fold. Though the primary sequences of the FS domains of F-spondin and mindin are less than 36% identical, their overall structures are very similar. The unique feature of F-spondin FS domain is the presence of three disulfide bonds associated with the N- and C-termini of the domain and a highly conserved N-linked glycosylation site. The integrin-binding motif found in mindin is not conserved in the F-spondin FS domain.

Conclusion

The structure of the F-spondin FS domain completes the structural studies of the multiple-domain ECM molecule. The homology of its core structure to a common Ca²⁺- and lipid-binding C2 domain suggests that the F-spondin FS domain may be responsible for part of the membrane targeting of F-spondin in its regulation of axon development. The structural properties of the FS domain revealed in this study pave the way for further exploration into the functions of F-spondin.     

The tubercles on humpback whales' flippers: application of bio-inspired technology

The humpback whale (Megaptera novaeangliae) is exceptional among the large baleen whales in its ability to undertake aquabatic maneuvers to catch prey. Humpback whales utilize extremely mobile, wing-like flippers for banking and turning. Large rounded tubercles along the leading edge of the flipper are morphological structures that are unique in nature. The tubercles on the leading edge act as passive-flow control devices that improve performance and maneuverability of the flipper. Experimental analysis of finite wing models has demonstrated that the presence of tubercles produces a delay in the angle of attack until stall, thereby increasing maximum lift and decreasing drag. Possible fluid-dynamic mechanisms for improved performance include delay of stall through generation of a vortex and modification of the boundary layer, and increase in effective span by reduction of both spanwise flow and strength of the tip vortex. The tubercles provide a bio-inspired design that has commercial viability for wing-like structures. Control of passive flow has the advantages of eliminating complex, costly, high-maintenance, and heavy control mechanisms, while improving performance for lifting bodies in air and water. The tubercles on the leading edge can be applied to the design of watercraft, aircraft, ventilation fans, and windmills.     

Heat for nothing or activity for free? Evidence and implications of activity-thermoregulatory heat substitution

If heat generated through activity can substitute for heat required for thermoregulation, then activity in cold environments may be energetically free for endotherms. Although the possibility of activity-thermoregulatory heat substitution has been long recognized, its empirical generality and ecological implications remain unclear. We combine a review of the literature and a model of heat exchange to explore the generality of activity-thermoregulatory heat substitution, to assess the extent to which substitution is likely to vary with body size and ambient temperature, and to examine some potential macroecological implications. A majority of the 51 studies we located showed evidence of activity-thermoregulatory heat substitution (35 of 51 studies), with 28 of 32 species examined characterized by substitution in one or more study. Among studies that did detect substitution, the average magnitude of substitution was 57%, but its occurrence and extent varied taxonomically, allometrically, and with ambient temperature. Modeling of heat production and dissipation suggests that large birds and mammals, engaged in intense activity and exposed to relatively warm conditions, have more scope for substitution than do smaller endotherms engaged in less intense activity and experiencing cooler conditions. However, ambient temperature has to be less than the lower critical temperature (the lower bound of the thermal neutral zone) for activity-thermoregulatory heat substitution to occur and this threshold is lower in large endotherms than in small endotherms. Thus, in nature, substitution is most likely to be observed in intermediate-sized birds and mammals experiencing intermediate ambient temperatures. Activity-thermoregulatory heat substitution may be an important determinant of the activity patterns and metabolic ecology of endotherms. For example, a pattern of widely varying field metabolic rates (FMR) at low latitudes that converges to higher and less variable FMR at high latitudes has been interpreted as suggesting that warm environments at low latitudes allow a greater variety of feasible metabolic niches than do cool, high-latitude environments. However, activity-thermoregulatory heat substitution will generate this pattern of latitudinal FMR variation even if endotherms from cold and warm climates are metabolically and behaviorally identical, because the metabolic rates of resting and active animals are more similar in cold than in warm environments. Activity-thermoregulatory heat substitution is an understudied aspect of endotherm thermal biology that is apt to be a major influence on the physiological, behavioral and ecological responses of free-ranging endotherms to variation in temperature.     

Mapping the protein interaction network in methicillin-resistant Staphylococcus aureus

Mortality attributable to infection with methicillin-resistant Staphylococcus aureus (MRSA) has now overtaken the death rate for AIDS in the United States, and advances in research are urgently needed to address this challenge. We report the results of the systematic identification of protein-protein interactions for the hospital-acquired strain MRSA-252. Using a high-throughput pull-down strategy combined with quantitative proteomics to distinguish specific from nonspecific interactors, we identified 13,219 interactions involving 608 MRSA proteins. Consecutive analyses revealed that this protein interaction network (PIN) exhibits scale-free organization with the characteristic presence of highly connected hub proteins. When clinical and experimental antimicrobial targets were queried in the network, they were generally found to occupy peripheral positions in the PIN with relatively few interacting partners. In contrast, the hub proteins identified in this MRSA PIN that are essential for network integrity and stability have largely been overlooked as drug targets. Thus, this empirical MRSA-252 PIN provides a rich source for identifying critical proteins essential for network stability, many of which can be considered as prospective antimicrobial drug targets.     

Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis

Preterm birth is the major cause of neonatal death and serious morbidity. Most preterm births are due to spontaneous onset of labor without a known cause or effective prevention. Both maternal and fetal genomes influence the predisposition to spontaneous preterm birth (SPTB), but the susceptibility loci remain to be defined. We utilized a combination of unique population structures, family-based linkage analysis, and subsequent case-control association to identify a susceptibility haplotype for SPTB. Clinically well-characterized SPTB families from northern Finland, a subisolate founded by a relatively small founder population that has subsequently experienced a number of bottlenecks, were selected for the initial discovery sample. Genome-wide linkage analysis using a high-density single-nucleotide polymorphism (SNP) array in seven large northern Finnish non-consanginous families identified a locus on 15q26.3 (HLOD 4.68). This region contains the IGF1R gene, which encodes the type 1 insulin-like growth factor receptor IGF-1R. Haplotype segregation analysis revealed that a 55 kb 12-SNP core segment within the IGF1R gene was shared identical-by-state (IBS) in five families. A follow-up case-control study in an independent sample representing the more general Finnish population showed an association of a 6-SNP IGF1R haplotype with SPTB in the fetuses, providing further evidence for IGF1R as a SPTB predisposition gene (frequency in cases versus controls 0.11 versus 0.05, P = 0.001, odds ratio 2.3). This study demonstrates the identification of a predisposing, low-frequency haplotype in a multifactorial trait using a well-characterized population and a combination of family and case-control designs. Our findings support the identification of the novel susceptibility gene IGF1R for predisposition by the fetal genome to being born preterm.     

Halogen bond tunability I: the effects of aromatic fluorine substitution on the strengths of halogen-bonding interactions involving chlorine,bromine, and iodine

In the past several years, halogen bonds have been shown to be relevant in crystal engineering and biomedical applications. One of the reasons for the utility of these types of noncovalent interactions in the development of, for example, pharmaceutical ligands is that their strengths and geometric properties are very tunable. That is, substitution of atoms or chemical groups in the vicinity of a halogen can have a very strong effect on the strength of the halogen bond. In this study we investigate halogen-bonding interactions involving aromatically-bound halogens (Cl, Br, and I) and a carbonyl oxygen. The properties of these halogen bonds are modulated by substitution of aromatic hydrogens with fluorines, which are very electronegative. It is found that these types of substitutions have dramatic effects on the strengths of the halogen bonds, leading to interactions that can be up to 100% stronger. Very good correlations are obtained between the interaction energies and the magnitudes of the positive electrostatic potentials (σ-holes) on the halogens. Interestingly, it is seen that the substitution of fluorines in systems containing smaller halogens results in electrostatic potentials resembling those of systems with larger halogens, with correspondingly stronger interaction energies. It is also shown that aromatic fluorine substitutions affect the optimal geometries of the halogen-bonded complexes, often as the result of secondary interactions.     

Evolution of the hymenopteran megaradiation

The Hymenoptera--ants, bees and wasps--represent one of the most successful but least understood insect radiations. We present the first comprehensive molecular study spanning the entire order Hymenoptera. It is based on approximately 7 kb of DNA sequence from 4 gene regions (18S, 28S, COI and EF-1α) for 116 species representing all superfamilies and 23 outgroup taxa from eight orders of Holometabola. Results are drawn from both parsimony and statistical (Bayesian and likelihood) analyses, and from both by-eye and secondary-structure alignments. Our analyses provide the first firm molecular evidence for monophyly of the Vespina (Orussoidea+Apocrita). Within Vespina, our results indicate a sister-group relationship between Ichneumonoidea and Proctotrupomorpha, while the stinging wasps (Aculeata) are monophyletic and nested inside Evaniomorpha. In Proctotrupomorpha, our results provide evidence for a novel core clade of proctotrupoids, and support for the recently proposed Diaprioidea. An unexpected result is the support for monophyly of a clade of wood-boring sawflies (Xiphydrioidea+Siricoidea). As in previous molecular studies, Orussidae remain difficult to place and are either sister group to a monophyletic Apocrita, or the sister group of Stephanidae within Apocrita. Both results support a single origin of parasitism, but the latter would propose a controversial reversal in the evolution of the wasp-waist. Generally our results support earlier hypotheses, primarily based on morphology, for a basal grade of phytophagous families giving rise to a single clade of parasitic Hymenoptera, the Vespina, from which predatory, pollen-feeding, gall-forming and eusocial forms evolved.     

The Syk/CARD9-coupled receptor Dectin-1 is not required for host resistance to Mycobacterium tuberculosis in mice

There is interest in identifying the pattern recognition receptors involved in initiating protective or non-protective host responses to Mycobacterium tuberculosis (Mtb). Here we explored the role of the Syk/CARD9-coupled receptor, Dectin-1, using an aerosol model of Mtb infection in wild-type and Dectin-1 deficient mice. We observed a reduction in pulmonary bacilli burdens in the Dectin-1 deficient animals, but this did not correlate with significant changes in pulmonary pathology, cytokine levels or ability of these animals to survive the infection. Thus Dectin-1 makes a minor contribution to susceptibility to Mtb infections in mice.