A glycosylated complex of gadolinium,a new potential contrast agent for magnetic resonance angiography?

A new low-molecular weight dendrimer-like MRI contrast agent (Gd-D1) has been synthesized and characterized in vitro by proton and oxygen-17 relaxometry. Its pharmacokinetic parameters and biodistribution patterns were evaluated on rats. Its in vitro and in vivo properties, that is, the longitudinal relaxivity (defined as the increase of the water proton longitudinal relaxation rate induced by one millimole per liter of Gd-D1) equal to 5.6s(-1)mM(-1) at 20 MHz and 310 K, the elimination half-time equal to 85 min, and its low accumulation in liver and spleen, underline its potential as a blood-pool MRI contrast agent.     

Chimpanzee violence: femmes fatales

New observations of coalitionary infanticide by female chimpanzees in Uganda shed light on the nature of female competition.     

Free energy of membrane protein unfolding derived from single-molecule force measurements

Mechanical single-molecule techniques offer exciting possibilities to investigate protein folding and stability in native environments at submolecular resolution. By applying a free-energy reconstruction procedure developed by Hummer and Szabo, which is based on a statistical theorem introduced by Jarzynski, we determined the unfolding free energy of the membrane proteins bacteriorhodopsin (BR), halorhodopsin, and the sodium-proton antiporter NhaA. The calculated energies ranged from 290.5 kcal/mol for BR to 485.5 kcal/mol for NhaA. For the remarkably stable BR, the equilibrium unfolding free energy was independent of pulling rate and temperature ranging between 18 and 42 degrees C. Our experiments also revealed heterogeneous energetic properties in individual transmembrane helices. In halorhodopsin, the stabilization of a short helical segment yielded a characteristic signature in the energy profile. In NhaA, a pronounced peak was observed at a functionally important site in the protein. Since a large variety of single- and multispan membrane proteins can be tackled in mechanical unfolding experiments, our approach provides a basis for systematically elucidating energetic properties of membrane proteins with the resolution of individual secondary-structure elements.     

Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ~70% of affected families. We have combined single-nucleotide-polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for approximately 5% of all BBS cases. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.     

A review of the species of Mesopolobus (Chalcidoidea: Pteromalidae) associated with Ceutorhynchus (Coleoptera: Curculionidae) host-species of European origin

Four species of Mesopolobus Westwood were reared as parasitoids of Ceutorhynchinae hosts in Europe during surveys in 2000-2004. An illustrated key is given to differentiate the four species, M. gemellus Baur & Muller sp. n., M. incultus (Walker), M. morys (Walker) and M. trasullus (Walker), plus M. moryoides Gibson, a parasitoid of the cabbage seedpod weevil, Ceutorhynchus obstrictus (Marsham), in North America. Pteromalus clavicornis Walker is recognized as a junior synonym of M. incultus syn. n., and Pteromalus berecynthos Walker (also a junior synonym of M. incultus) is considered a correct original spelling. For Disema pallipes F?rster (a junior synonym of Mesopolobus morys), a lectotype is designated. Mesopolobus morys is for the first time accurately associated with the seed weevil Ceutorhynchus turbatus (Schultze), a potential agent for classical biological control, of hoary cress, Lepidium draba L. (Brassicaceae), in North America. Mesopolobus gemellus is associated with another seed weevil, Ceutorhynchus typhae (=C. floralis) (Herbst), in pods of shepherd's purse, Capsella bursa-pastoris (L.) Medik. (Brassicaceae). Implications of the host-parasitoid associations are discussed relative to the introduction of species to North America for classical biological control of the cabbage seedpod weevil.     

A sensitivity analysis of the volumetric spatial decomposition algorithm

Recently, we proposed a new computational approach for the volumetric spatial decomposition of a three-dimensional bone structure into its basic rod and plate elements. This method was based on an image skeletonization approach, where two model parameters were used to identify an ideal skeleton. The goal of this study was to estimate the sensitivity of local morphometric indices to these two model parameters. Our results showed that the rod derived indices behaved more smoothly than plate derived indices, which suggests that rod derived indices are more trustworthy. The results also demonstrated that it was reasonable to reduce the model to only one parameter by setting the noise parameter n to twice the value of the slenderness parameter s. In conclusion, we found that local morphometric indices are reliable measures showing large differences between samples and thus may shed new light on structural differences of trabecular bone in a local fashion by adequately choosing one single optimization parameter.     

Synthesis of 4-[2-aminoethyl(nitrosamino)]-1-pyridin-3-yl-butan-1-one, a new NNK hapten for the induction of N-nitrosamine-specific antibodies

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most abundant and potent procarcinogens in tobacco smoke. In order to induce a strong and substained antibody response against NNK, we developed a functionalized derivative that closely mimicked its structural features, in particular, the pyridyloxobutyl moiety, the adjacent ketone, and the N-nitrosamino group. This hapten was conjugated via a C 2 linker to the highly immunogenic diphteria toxoid licensed as a vaccine in humans to induce polyclonal and monoclonal antibodies. Two monoclonal antibodies were obtained with Kd values of 45.8 nM (P9D5) and 37.6 nM (P7H3), respectively, for NNK-C 2. Both the monoclonal (P9D5 and P7H3) and polyclonal antibodies reacted strongly with NNK (IC 50 = 80 microM or 160 microM) and NNAL (IC 50 = 29 microM or 93 microM) and to a lesser extent with some of the metabolites of NNK. Interestingly, the mAbs did not react with the metabolites of the detoxification pathways such as NNK-N-Oxide and NNAL-N-Oxide (IC 50 > 512 microM). Therefore, such antibodies detect NNK and NNAL and may have the potential to modulate their redistribution in vivo, perhaps reducing some detrimental effects of smoking.     

Alternative tactics and individual reproductive success in natural associations of the burying beetle, Nicrophorus vespilloides

Alternative reproductive tactics can be maintained through differentevolutionary avenues. They can be genetically or stochasticallydetermined, in which case they must yield equal fitness, ortheir use can be conditional, in which case the fitness payoffof alternatives may differ. We attempted to assess the reproductivesuccess of alternative reproductive tactics employed by wildmale and female burying beetles in natural associations on carcassesplaced in the field. A beetle's reproductive tactic was definedby its potential involvement in care of larvae, and parentagewas assessed using oligolocus DNA fingerprinting of offspringand potential parents. Both in males and in females, alternativetactics yielded significantly different reproductive benefits:subordinate females (brood parasites) and males (satellite males)had considerably lower reproductive success than dominant oruncontested individuals. Joint breeding was too infrequent forstatistical inferences, generating intermediate offspring numbers.About 15% of offspring were sired by males not present on thecarcass, suggesting that mating away from reproductive resourcescan produce reproductive benefits to males. Our results, inconcert with the observation that beetles using one tactic canbe manipulated into employing the alternative, support the notionthat Nicrophorus vespilloides uses alternatives conditionally,opportunistically employing lower-benefit tactics when moreprofitable tactics are not available, or as additional "on-the-side"tactics to bolster reproductive success.     

Detecting molecular interactions that stabilize, activate and guide ligand-binding of the sodium/proton antiporter MjNhaP1 from Methanococcus jannaschii

Integral membrane proteins are involved in virtually every cellular process. Precisely regulating these machineries would allow controlling many human and vertebrate diseases. Embedded into cellular membranes, membrane proteins establish molecular interactions that sensitively react to environmental changes and to molecular compounds, such as ligands or inhibitors. We applied atomic force microscopy (AFM) to image the Na(+)/H(+) antiporter MjNhaP1 from Methanococcus jannaschii, and single-molecule force spectroscopy (SMFS) to probe molecular interactions that drive the protein structure-function relationship. High-resolution AFM topographs showed the dimeric assembly of MjNhaP1 being reconstituted into a lipid bilayer. SMFS of MjNhaP1 unraveled molecular interactions stabilizing individual structural domains. Transmembrane domains exhibited certain probabilities to unfold individually or cooperatively with other domains resulting in different unfolding pathways. Helices VIII and X established pH sensitive interactions altering significantly upon MjNhaP1 activation, while removal of the ligand (Na(+)) destabilized the entire antiporter except helix VIII. It is assumed that Asp234/235 of helix VIII are involved in the ligand-binding site and that helix X plays a functional role in the activation of the transporter.     

Validation of a solid-phase-bound steroid scaffold for the synthesis of novel cyclic peptidosteroids.

The current article reports on the synthesis of a new type of cyclic peptidosteroid, in which a bile-acid-based scaffold was used for the conformational restriction of a loop-like peptide. Convergent coupling of two tetrapeptides to the non-peptidic steroidal entity was carried out once in the classical C-to-N and once in the non-classical N-to-C direction. Peptide backbone cyclisation was then carried out, giving rise to a ring size equivalent to approximately 12 amino acids. This type of construct will be used in the development of a peptide vaccine against measles.