bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in fine-scale movement and foraging patterns of common wombats along a snow-depth gradient
Authors: Matthews Alison
Published: May 2010

Context. Feeding strategies of large herbivores in snow-covered environments can be influenced by snow depth and snow quality. Common wombats, Vombatus ursinus, are large marsupial herbivores that occur in subalpine areas of Australia where they must dig through the snow to reach low vegetation. Deeper snow at higher elevations is considered to limit foraging and constrain their range, although there have been no quantitative studies investigating the influence of snow on their foraging behaviour. Aims. The present study examined how snow influenced the foraging behaviour of common wombats along a snow-depth gradient. Methods. During the 2008 winter season, snow tracks of 17 wombats were located within the subalpine zone, in a study area ranging from 1520 to 1850 m asl, and followed to record attributes of the snow cover and environment in relation to wombat activity. Key results. Wombats selected sites to feed where the snow was shallower, and deeper snow at feeding sites caused changes in foraging behaviour. Foraging occurred along fairly direct routes between burrows; however, as snow depth increased, wombats deviated more from their path to seek out suitable foraging sites. Most foraging occurred in shallow snow in open areas or where the snow had melted around the bases of trees, shrubs or boulders. About half (52%) of the feeding sites necessitated the wombats digging through the snow to reach low vegetation, predominantly the grasses of Poa spp. Digging craters for feeding occurred in snow depths up to 100 cm, although depths less than 35 cm were preferred. Some shrub species, such as dusty daisy bush, Olearia phlogopappa, that protruded from the snow, were also eaten where the snow was deeper. Dietary analysis confirmed that monocots made up the majority of the diet (93.3%), although some individuals consumed up to 26% dicots. Conclusions. The present study demonstrated that wombats can adjust to a snow-covered environment by altering both their foraging patterns and diet as snow depth increases. However, they will be limited where snow depths are consistently greater than 100 cm. Implications. Under future climate-change scenarios of declining snow cover, wombats may be able to forage and inhabit higher altitudes than where they currently occur, and this has implications for the grazing-sensitive alpine ecosystem. Predicting shifts in the range of other herbivores to higher altitudes will require knowledge of their species-specific foraging thresholds in snow, such as presented in this study.
Population and breeding trends of an urban coloniser: the Australian white ibis
Authors: Martin John , French Kris , Major Richard
Published: May 2010

Context. In the Sydney region, the population of Australian white ibis has dramatically increased from rare observations in the 1950s to a breeding season peak of 8900 in 2008, resulting with human–wildlife conflicts. Within natural habitats across the eastern states, the ibis population has declined, yet within urban environments ibis have been lethally managed for over 30 years. However, limited ecological and no regional population data are available for the Sydney region.
Aims. The present study of ibis in the Sydney region aims to (1) establish the abundance of the population during the breeding and non-breeding seasons, (2) determine whether the population is increasing, and (3) identify the importance of different foraging and roosting sites.
Methods. Across the Sydney region, we surveyed 54 discrete sites for 2.5 years. At each site, we recorded the number of adult, juvenile and nestling ibis as well as the number of active nests. The 54 sites were grouped into 15 areas consisting of five landfills and 10 suburbs, which were assessed with ANOVA.
Key results. The ibis population of the Sydney region doubled from a peak of 4200 in 2006 to 8900 in 2008. Seasonal fluctuations saw adults migrating in to the region to breed, and adults and juveniles dispersing following breeding. On average, 44% of the population was located foraging within landfills, whereas 80% of nesting activity occurred within ‘urban-natural’ habitats.
Conclusions. Seasonal fluctuations indicated that the ibis population of Sydney is connected with the broader state and national population. Landfills provided an abundant foraging resource that supported extended breeding, including consistent nesting for a 19-month period.
Implications. The present study indicated that any localised population management has consequences beyond the immediate or regional population and, consequently, regional management plans or actions need to consider the long-term status of the eastern states’ population. Urban conflicts need to be resolved with human education and a conservation agenda, preferably with the provision of refuge habitat where birds are not disturbed.
Primary cilia regulate Gli/Hedgehog activation in pancreas
Authors: Cervantes Sara , Lau Janet , Cano David A. , Borromeo-Austin Cecilia , Hebrok Matthias
Published: May 2010

Previous studies have suggested that defects in pancreatic epithelium caused by activation of the Hedgehog (Hh) signaling pathway are secondary to changes in the differentiation state of the surrounding mesenchyme. However, recent results describe a role of the pathway in pancreatic epithelium, both during development and in adult tissue during neoplastic transformation. To determine the consequences of epithelial Hh activation during pancreas development, we employed a transgenic mouse model in which an activated version of GLI2, a transcriptional mediator of the pathway, is overexpressed specifically in the pancreatic epithelium. Surprisingly, efficient Hh activation was not observed in these transgenic mice, indicating the presence of physiological mechanisms within pancreas epithelium that prevent full Hh activation. Additional studies revealed that primary cilia regulate the level of Hh activation, and that ablation of these cellular organelles is sufficient to cause significant up-regulation of the Hh pathway in pancreata of mice overexpressing GLI2. As a consequence of overt Hh activation, we observe profound morphological changes in both the exocrine and endocrine pancreas. Increased Hh activity also induced the expansion of an undifferentiated cell population expressing progenitor markers. Thus, our findings suggest that Hh signaling plays a critical role in regulating pancreatic epithelial plasticity.
The structural and energetic basis for high selectivity in a high-affinity protein-protein interaction
Authors: Meenan Nicola A. G. , Sharma Amit , Fleishman Sarel J. , MacDonald Colin J. , Morel Bertrand , Boetzel Ruth , Moore Geoffrey R. , Baker David , Kleanthous Colin
Published: May 2010

High-affinity, high-selectivity protein-protein interactions that are critical for cell survival present an evolutionary paradox: How does selectivity evolve when acquired mutations risk a lethal loss of high-affinity binding? A detailed understanding of selectivity in such complexes requires structural information on weak, noncognate complexes which can be difficult to obtain due to their transient and dynamic nature. Using NMR-based docking as a guide, we deployed a disulfide-trapping strategy on a noncognate complex between the colicin E9 endonuclease (E9 DNase) and immunity protein 2 (Im2), which is seven orders of magnitude weaker binding than the cognate femtomolar E9 DNase-Im9 interaction. The 1.77 Å crystal structure of the E9 DNase-Im2 complex reveals an entirely noncovalent interface where the intersubunit disulfide merely supports the crystal lattice. In combination with computational alanine scanning of interfacial residues, the structure reveals that the driving force for binding is so strong that a severely unfavorable specificity contact is tolerated at the interface and as a result the complex becomes weakened through “frustration.” As well as rationalizing past mutational and thermodynamic data, comparing our noncognate structure with previous cognate complexes highlights the importance of loop regions in developing selectivity and accentuates the multiple roles of buried water molecules that stabilize, ameliorate, or aggravate interfacial contacts. The study provides direct support for dual-recognition in colicin DNase-Im protein complexes and shows that weakened noncognate complexes are primed for high-affinity binding, which can be achieved by economical mutation of a limited number of residues at the interface.
Mdm2 facilitates the association of p53 with the proteasome
Authors: Kulikov Roman , Letienne Justine , Kaur Manjit , Grossman Steven R. , Arts Janine , Blattner Christine
Published: May 2010

The ubiquitin ligase Mdm2 targets the p53 tumor suppressor protein for proteasomal degradation. Mutating phosphorylation sites in the central domain of Mdm2 prevents p53 degradation, although it is still ubiquitylated, indicating that Mdm2 has a post-ubiquitylation function for p53 degradation. We show that Mdm2 associates with several subunits of the 19S proteasome regulatory particle in a ubiquitylation-independent manner. Mdm2 furthermore promotes the formation of a ternary complex of itself, p53, and the proteasome. Replacing phosphorylation sites within the central domain with alanines reduced the formation of the ternary complex. The C-terminus of Mdm2 was sufficient for interaction with the proteasome despite an additional proteasome binding site in the Mdm2 N-terminus. In addition to binding to the proteasome, the C-terminus of Mdm2 bound to the central domain, possibly competing with, and therefore blocking, Mdm2/proteasome interaction. We propose that Mdm2 facilitates, or at least enhances, the association of p53 with the proteasome and that phosphorylation of the central domain of Mdm2 regulates this process.
Synaptic cell adhesion molecule SynCAM 1 is a target for polysialylation in postnatal mouse brain
Authors: Galuska Sebastian P. , Rollenhagen Manuela , Kaup Moritz , Eggers Katinka , Oltmann-Norden Imke , Schiff Miriam , Hartmann Maike , Weinhold Birgit , Hildebrandt Herbert , Geyer Rudolf , Mühlenhoff Martina , Geyer Hildegard
Published: May 2010

Among the large set of cell surface glycan structures, the carbohydrate polymer polysialic acid (polySia) plays an important role in vertebrate brain development and synaptic plasticity. The main carrier of polySia in the nervous system is the neural cell adhesion molecule NCAM. As polySia with chain lengths of more than 40 sialic acid residues was still observed in brain of newborn
Ncam
−/−
mice, we performed a glycoproteomics approach to identify the underlying protein scaffolds. Affinity purification of polysialylated molecules from
Ncam
−/−
brain followed by peptide mass fingerprinting led to the identification of the synaptic cell adhesion molecule SynCAM 1 as a so far unknown polySia carrier. SynCAM 1 belongs to the Ig superfamily and is a powerful inducer of synapse formation. Importantly, the appearance of polysialylated SynCAM 1 was not restricted to the
Ncam
−/−
background but was found to the same extent in perinatal brain of WT mice. PolySia was located on N-glycans of the first Ig domain, which is known to be involved in homo- and heterophilic SynCAM 1 interactions. Both polysialyltransferases, ST8SiaII and ST8SiaIV, were able to polysialylate SynCAM 1 in vitro, and polysialylation of SynCAM 1 completely abolished homophilic binding. Analysis of serial sections of perinatal
Ncam
−/−
brain revealed that polySia-SynCAM 1 is expressed exclusively by NG2 cells, a multifunctional glia population that can receive glutamatergic input via unique neuron-NG2 cell synapses. Our findings sug-gest that polySia may act as a dynamic modulator of SynCAM 1 functions during integration of NG2 cells into neural networks.
Kudzu (
Pueraria montana
) invasion doubles emissions of nitric oxide and increases ozone pollution
Authors: Hickman Jonathan E. , Wu Shiliang , Mickley Loretta J. , Lerdau Manuel T.
Published: May 2010

The nitrogen-fixing legume kudzu (
Pueraria montana
) is a widespread invasive plant in the southeastern United States with physiological traits that may lead to important impacts on ecosystems and the atmosphere. Its spread has the potential to raise ozone levels in the region by increasing nitric oxide (NO) emissions from soils as a consequence of increasing nitrogen (N) inputs and cycling in soils. We studied the effects of kudzu invasions on soils and trace N gas emissions at three sites in Madison County, Georgia in 2007 and used the results to model the effects of kudzu invasion on regional air quality. We found that rates of net N mineralization increased by up to 1,000%, and net nitrification increased by up to 500% in invaded soils in Georgia. Nitric oxide emissions from invaded soils were more than 100% higher (2.81 vs. 1.24 ng NO-N cm
−2
h
−1
). We used the GEOS-Chem chemical transport model to evaluate the potential impact of kudzu invasion on regional atmospheric chemistry and air quality. In an extreme scenario, extensive kudzu invasion leads directly to an increase in the number of high ozone events (above 70 ppb) of up to 7 days each summer in some areas, up from 10 to 20 days in a control scenario with no kudzu invasion. These results establish a quantitative link between a biological invasion and ozone formation and suggest that in this extreme scenario, kudzu invasion can overcome some of the air quality benefits of legislative control.
Water clarity, maternal behavior, and physiology combine to eliminate UV radiation risk to amphibians in a montane landscape
Authors: Palen Wendy J. , Schindler Daniel E.
Published: May 2010

Increasing UV-B radiation (UV-B; 290–320 nm) due to stratospheric ozone depletion has been a leading explanation for the decline in amphibians for nearly 2 decades. Yet, the likelihood that UV-B can influence amphibians at the large spatial scales relevant to population declines has not yet been evaluated. A key limitation has been in relating results from individual sites to the effect of UV-B for populations distributed across heterogeneous landscapes. We measured critical embryonic exposures to UV-B for two species of montane amphibians with contrasting physiological sensitivities, long-toed salamander (
Ambystoma macrodactylum
) and Cascades frog (
Rana cascadae
), at field sites spanning a gradient of UV-B attenuation in water. We then used these experimental results to estimate the proportion of embryos exposed to harmful UV-B across a large number of breeding sites. By combining surveys of the incubation timing, incident UV-B, optical transparency of water, and oviposition depth and light exposure of embryos at each site, we present a comprehensive assessment of the risk posed by UV-B for montane amphibians of the Pacific Northwest. We found that only 1.1% of
A. macrodactylum
and no
R. cascadae
embryos across a landscape of breeding sites are exposed to UV-B exceeding lethal levels. These results emphasize that accurately estimating the risk posed by environmental stressors requires placing experimental results in a broader ecological context that accounts for the heterogeneity experienced by populations distributed across natural landscapes.
Evidence that the polymerase of respiratory syncytial virus initiates RNA replication in a nontemplated fashion
Authors: Noton Sarah L. , Cowton Vanessa M. , Zack Chadene R. , McGivern David R. , Fearns Rachel
Published: May 2010

RNA virus polymerases must initiate replicative RNA synthesis with extremely high accuracy to maintain their genome termini and to avoid generating defective genomes. For the single-stranded negative-sense RNA viruses, it is not known how this accuracy is achieved. To investigate this question, mutations were introduced into the 3′ terminal base of a respiratory syncytial virus (RSV) template, and the RNA products were examined to determine the impact of the mutation. To perform the assay, RNA replication was reconstituted using a modified minireplicon system in which replication was limited to a single step. Importantly, this system allowed analysis of RSV RNA generated intracellularly, but from a defined template that was not subject to selection by replication. Sequence analysis of RNA products generated from templates containing 1U-C and 1U-A substitutions showed that, in both cases, replication products were initiated with a nontemplated, WT A residue, rather than a templated G or U residue, indicating that the polymerase selects the terminal NTP independently of the template. Examination of a template in which the position 1 nucleotide was deleted supported these findings. This mutant directed efficient replication at ∼60% of WT levels, and its product was found to be initiated at the WT position (−1 relative to the template) with a WT A residue. These findings show that the RSV replicase selects ATP and initiates at the correct position, independently of the first nucleotide of the template, suggesting a mechanism by which highly accurate replication initiation is achieved.
Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways
Authors: Otsuki Shuhei , Hanson Sarah R. , Miyaki Shigeru , Grogan Shawn P. , Kinoshita Mitsuo , Asahara Hiroshi , Wong Chi-Huey , Lotz Martin K.
Published: May 2010

The balance between anabolic and catabolic signaling pathways is critical in maintaining cartilage homeostasis and its disturbance contributes to joint diseases such as osteoarthritis (OA). A unique mechanism that modulates the activity of cell signaling pathways is controlled by extracellular heparan endosulfatases Sulf-1 and Sulf-2 (Sulfs) that are overexpressed in OA cartilage. This study addressed the role of Sulfs in cartilage homeostasis and in regulating bone morphogenetic protein (BMP)/Smad and fibroblast growth factor (FGF)/Erk signaling in articular cartilage. Spontaneous cartilage degeneration and surgically induced OA were significantly more severe in

Sulf-1
−/−

and

Sulf-2
−/−

mice compared with wild-type mice. MMP-13, ADAMTS-5, and the BMP antagonist noggin were elevated whereas col2a1 and aggrecan were reduced in cartilage and chondrocytes from

Sulf
−/−

mice. Articular cartilage and cultured chondrocytes from

Sulf
−/−

mice showed reduced Smad1 protein expression and Smad1/5 phosphorylation, whereas Erk1/2 phosphorylation was increased. In human chondrocytes, Sulfs siRNA reduced Smad phosphorylation but enhanced FGF-2-induced Erk1/2 signaling. These findings suggest that Sulfs simultaneously enhance BMP but inhibit FGF signaling in chondrocytes and maintain cartilage homeostasis. Approaches to correct abnormal Sulf expression have the potential to protect against cartilage degradation and promote cartilage repair in OA.
Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency
Authors: Fujimoto Kei , Chen Yun , Polonsky Kenneth S. , Dorn Gerald W.
Published: May 2010

Mutations of the pancreatic duodenal homeobox gene-1,
Pdx1
, cause heritable diabetes in humans and mice. A central abnormality with Pdx1 deficiency is increased death of β-cells, leading to decreased β-cell mass. We show that lentiviral suppression of Pdx1 increases death of mouse insulinoma MIN6 β-cells associated with dissipation of the mitochondrial inner membrane electrochemical gradient, Δψ
m
. Preventing mitochondrial permeability transition pore opening with the cyclophilin D inhibitor cyclosporin A restored Δψ
m
and rescued cell viability. Reduced β-cell mass, markers of β-cell apoptosis, necrosis, and decreased proliferation are present in
Pdx1
haploinsufficient mice. Genetic ablation of the
Ppif
gene, encoding cyclophilin D, restored β-cell mass and decreased TUNEL and complement complex labeling without affecting β-cell proliferation. In adult mice maintained on a high-fat diet,
Ppif
ablation normalized fasting glucose and glucose and insulin responses to acute glucose challenge. Thus, cyclophilin D and the mitochondrial permeability transition are critical regulators of β-cell death caused by Pdx1 insufficiency.
Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo
Authors: Rugg-Gunn Peter J. , Cox Brian J. , Ralston Amy , Rossant Janet
Published: May 2010

A unique property of the mammalian embryo is that stem cells can be derived from its early tissue lineages. These lineages will give rise to the fetus as well as essential extraembryonic tissues. Understanding how chromatin regulation participates in establishment of these lineages in the embryo and their derived stem cells provides insight that will critically inform our understanding of embryogenesis and stem cell biology. Here, we compare the genomewide location of active and repressive histone modifications in embryonic stem cells, trophoblast stem cells, and extraembryonic endoderm stem cells from the mouse. Our results show that the active modification H3K4me3 has a similar role in the three stem cell types, but the repressive modification H3K27me3 varies in abundance and genomewide distribution. Thus, alternative mechanisms mediate transcriptional repression in stem cells from the embryo. In addition, using carrier chromatin immunoprecipitation we show that bivalent histone domains seen in embryonic stem cells exist in pluripotent cells of the early embryo. However, the epigenetic status of extraembryonic progenitor cells in the embryo did not entirely reflect the extraembryonic stem cell lines. These studies indicate that histone modification mechanisms may differ between early embryo lineages and emphasize the importance of examining in vivo and in vitro progenitor cells.
The action of cardiolipin on the bacterial translocon
Authors: Gold Vicki A. M. , Robson Alice , Bao Huan , Romantsov Tatyana , Duong Franck , Collinson Ian
Published: May 2010

Cardiolipin is an ever-present component of the energy-conserving inner membranes of bacteria and mitochondria. Its modulation of the structure and dynamism of the bilayer impacts on the activity of their resident proteins, as a number of studies have shown. Here we analyze the consequences cardiolipin has on the conformation, activity, and localization of the protein translocation machinery. Cardiolipin tightly associates with the SecYEG protein channel complex, whereupon it stabilizes the dimer, creates a high-affinity binding surface for the SecA ATPase, and stimulates ATP hydrolysis. In addition to the effects on the structure and function, the subcellular distribution of the complex is modified by the cardiolipin content of the membrane. Together, the results provide rare and comprehensive insights into the action of a phospholipid on an essential transport complex, which appears to be relevant to a broad range of energy-dependent reactions occurring at membranes.
Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal–Hreidarsson syndrome
Authors: Touzot Fabien , Callebaut Isabelle , Soulier Jean , Gaillard Laetitia , Azerrad Chantal , Durandy Anne , Fischer Alain , de Villartay Jean-Pierre , Revy Patrick
Published: May 2010

Telomeres, the protein–DNA complexes at the ends of linear chromosomes, are protected and regulated by the shelterin molecules, the telomerase complex, and other accessory factors, among which is Apollo, a DNA repair factor of the β-lactamase/β-CASP family. Impaired telomere protection in humans causes dyskeratosis congenita and Hoyeraal–Hreidarsson (HH) syndrome, characterized by premature aging, bone marrow failure, and immunodeficiency. We identified a unique
Apollo
splice variant (designated
Apollo
-Δ) in fibroblasts from a patient with HH syndrome.
Apollo
-Δ generates a dominant negative form of Apollo lacking the telomeric repeat-binding factor homology (TRFH)-binding motif (TBM) required for interaction with the shelterin TRF2 at telomeres. Apollo-Δ hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. These results identify Apollo as a crucial actor in telomere maintenance in vivo, independent of its function as a general DNA repair factor.
Processivity of peptidoglycan synthesis provides a built-in mechanism for the robustness of straight-rod cell morphology
Authors: Sliusarenko Oleksii , Cabeen Matthew T. , Wolgemuth Charles W. , Jacobs-Wagner Christine , Emonet Thierry
Published: May 2010

The propagation of cell shape across generations is remarkably robust in most bacteria. Even when deformations are acquired, growing cells progressively recover their original shape once the deforming factors are eliminated. For instance, straight-rod-shaped bacteria grow curved when confined to circular microchambers, but straighten in a growth-dependent fashion when released. Bacterial cell shape is maintained by the peptidoglycan (PG) cell wall, a giant macromolecule of glycan strands that are synthesized by processive enzymes and cross-linked by peptide chains. Changes in cell geometry require modifying the PG and therefore depend directly on the molecular-scale properties of PG structure and synthesis. Using a mathematical model we quantify the straightening of curved
Caulobacter crescentus
cells after disruption of the cell-curving crescentin structure. We observe that cells straighten at a rate that is about half (57%) the cell growth rate. Next we show that in the absence of other effects there exists a mathematical relationship between the rate of cell straightening and the processivity of PG synthesis—the number of subunits incorporated before termination of synthesis. From the measured rate of cell straightening this relationship predicts processivity values that are in good agreement with our estimates from published data. Finally, we consider the possible role of three other mechanisms in cell straightening. We conclude that regardless of the involvement of other factors, intrinsic properties of PG processivity provide a robust mechanism for cell straightening that is hardwired to the cell wall synthesis machinery.
Resistance to extreme strategies, rather than prosocial preferences, can explain human cooperation in public goods games
Authors: Kümmerli Rolf , Burton-Chellew Maxwell N. , Ross-Gillespie Adin , West Stuart A.
Published: May 2010

The results of numerous economic games suggest that humans behave more cooperatively than would be expected if they were maximizing selfish interests. It has been argued that this is because individuals gain satisfaction from the success of others, and that such prosocial preferences require a novel evolutionary explanation. However, in previous games, imperfect behavior would automatically lead to an increase in cooperation, making it impossible to decouple any form of mistake or error from prosocial cooperative decisions. Here we empirically test between these alternatives by decoupling imperfect behavior from prosocial preferences in modified versions of the public goods game, in which individuals would maximize their selfish gain by completely (100%) cooperating. We found that, although this led to higher levels of cooperation, it did not lead to full cooperation, and individuals still perceived their group mates as competitors. This is inconsistent with either selfish or prosocial preferences, suggesting that the most parsimonious explanation is imperfect behavior triggered by psychological drives that can prevent both complete defection and complete cooperation. More generally, our results illustrate the caution that must be exercised when interpreting the evolutionary implications of economic experiments, especially the absolute level of cooperation in a particular treatment.
Structural basis of UGUA recognition by the Nudix protein CFIm25 and implications for a regulatory role in mRNA 3′ processing
Authors: Yang Qin , Gilmartin Gregory M. , Doublié Sylvie
Published: May 2010

Human Cleavage Factor Im (CFIm) is an essential component of the pre-mRNA 3′ processing complex that functions in the regulation of poly(A) site selection through the recognition of UGUA sequences upstream of the poly(A) site. Although the highly conserved 25 kDa subunit (CFIm25) of the CFImcomplex possesses a characteristic α/β/α Nudix fold, CFIm25 has no detectable hydrolase activity. Here we report the crystal structures of the human CFIm25 homodimer in complex with UGUAAA and UUGUAU RNA sequences. CFIm25 is the first Nudix protein to be reported to bind RNA in a sequence-specific manner. The UGUA sequence contributes to binding specificity through an intramolecular G:A Watson–Crick/sugar-edge base interaction, an unusual pairing previously found to be involved in the binding specificity of the SAM-III riboswitch. The structures, together with mutational data, suggest a novel mechanism for the simultaneous sequence-specific recognition of two UGUA elements within the pre-mRNA. Furthermore, the mutually exclusive binding of RNA and the signaling molecule Ap4A (diadenosine tetraphosphate) by CFIm25 suggests a potential role for small molecules in the regulation of mRNA 3′ processing.
Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex.
Authors: Buchwald Gretel , Ebert Judith , Basquin Claire , Sauliere Jerome , Jayachandran Uma , Bono Fulvia , Le Hir Hervé , Conti Elena
Published: May 2010

In mammals, Up-frameshift proteins (UPFs) form a surveillance complex that interacts with the exon junction complex (EJC) to elicit nonsense-mediated mRNA decay (NMD). UPF3b is the component of the surveillance complex that bridges the interaction with the EJC. Here, we report the 3.4 Å resolution crystal structure of a minimal UPF3b-EJC assembly, consisting of the interacting domains of five proteins (UPF3b, MAGO, Y14, eIF4AIII, and Barentsz) together with RNA and adenylyl-imidodiphosphate. Human UPF3b binds with the C-terminal domain stretched over a composite surface formed by eIF4AIII, MAGO, and Y14. Residues that affect NMD when mutated are found at the core interacting surfaces, whereas differences between UPF3b and UPF3a map at peripheral interacting residues. Comparison with the binding mode of the protein PYM underscores how a common molecular surface of MAGO and Y14 recognizes different proteins acting at different times in the same pathway. The binding mode to eIF4AIII identifies a surface hot spot that is used by different DEAD-box proteins to recruit their regulators.
Activation of dormant ovarian follicles to generate mature eggs
Authors: Li Jing , Kawamura Kazuhiro , Cheng Yuan , Liu Shuang , Klein Cynthia , Liu Shu , Duan En-Kui , Hsueh Aaron J. W.
Published: May 2010

Although multiple follicles are present in mammalian ovaries, most of them remain dormant for years or decades. During reproductive life, some follicles are activated for development. Genetically modified mouse models with oocyte-specific deletion of genes in the PTEN-PI3K-Akt-Foxo3 pathway exhibited premature activation of all dormant follicles. Using an inhibitor of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) phosphatase and a PI3K activating peptide, we found that short-term treatment of neonatal mouse ovaries increased nuclear exclusion of Foxo3 in primordial oocytes. After transplantation under kidney capsules of ovariectomized hosts, treated follicles developed to the preovulatory stage with mature eggs displaying normal epigenetic changes of imprinted genes. After in vitro fertilization and embryo transfer, healthy progeny with proven fertility were delivered. Human ovarian cortical fragments from cancer patients were also treated with the PTEN inhibitor. After xeno-transplantation to immune-deficient mice for 6 months, primordial follicles developed to the preovulatory stage with oocytes capable of undergoing nuclear maturation. Major differences between male and female mammals are unlimited number of sperm and paucity of mature oocytes. Thus, short-term in vitro activation of dormant ovarian follicles after stimulation of the PI3K-Akt pathway allows the generation of a large supply of mature female germ cells for future treatment of infertile women with a diminishing ovarian reserve and for cancer patients with cryo-preserved ovaries. Generation of a large number of human oocytes also facilitates future derivation of embryonic stem cells for regenerative medicine.
Biophysical basis for the geometry of conical stromatolites
Authors: Petroff Alexander P. , Sim Min Sub , Maslov Andrey , Krupenin Mikhail , Rothman Daniel H. , Bosak Tanja
Published: May 2010

Stromatolites may be Earth’s oldest macroscopic fossils; however, it remains controversial what, if any, biological processes are recorded in their morphology. Although the biological interpretation of many stromatolite morphologies is confounded by the influence of sedimentation, conical stromatolites form in the absence of sedimentation and are, therefore, considered to be the most robust records of biophysical processes. A qualitative similarity between conical stromatolites and some modern microbial mats suggests a photosynthetic origin for ancient stromatolites. To better understand and interpret ancient fossils, we seek a quantitative relationship between the geometry of conical stromatolites and the biophysical processes that control their growth. We note that all modern conical stromatolites and many that formed in the last 2.8 billion years display a characteristic centimeter-scale spacing between neighboring structures. To understand this prominent—but hitherto uninterpreted—organization, we consider the role of diffusion in mediating competition between stromatolites. Having confirmed this model through laboratory experiments and field observation, we find that organization of a field of stromatolites is set by a diffusive time scale over which individual structures compete for nutrients, thus linking form to physiology. The centimeter-scale spacing between modern and ancient stromatolites corresponds to a rhythmically fluctuating metabolism with a period of approximately 20 hr. The correspondence between the observed spacing and the day length provides quantitative support for the photosynthetic origin of conical stromatolites throughout geologic time.
Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax
Authors: Datta Sandip K. , Sabet Mojgan , Nguyen Kim Phung L. , Valdez Patricia A. , Gonzalez-Navajas Jose M. , Islam Shamima , Mihajlov Ivan , Fierer Joshua , Insel Paul A. , Webster Nicholas J. , Guiney Donald G. , Raz Eyal
Published: May 2010

Cholera toxin (CT) elicits a mucosal immune response in mice when used as a vaccine adjuvant. The mechanisms by which CT exerts its adjuvant effects are incompletely understood. We show that protection against inhalation anthrax by an irradiated spore vaccine depends on CT-mediated induction of IL-17-producing CD4 Th17 cells. Furthermore, IL-17 is involved in the induction of serum and mucosal antibody responses by CT. Th17 cells induced by CT have a unique cytokine profile compared with those induced by IL-6 and TGF-β, and their induction by CT requires cAMP-dependent secretion of IL-1β and β-calcitonin gene-related peptide by dendritic cells. These findings demonstrate that Th17 cells mediate mucosal adjuvant effects of CT and identify previously unexplored pathways involved in Th17 induction that could be targeted for development of unique mucosal adjuvants.
A snapshot of the age distribution of psychological well-being in the United States
Authors: Stone Arthur A. , Schwartz Joseph E. , Broderick Joan E. , Deaton Angus
Published: May 2010

Psychological well-being (WB) includes a person's overall appraisal of his or her life (Global WB) and affective state (Hedonic WB), and it is considered a key aspect of the health of individuals and groups. Several cross-sectional studies have documented a relation between Global WB and age. Little is known, however, about the age distribution of Hedonic WB. It may yield a different view of aging because it is less influenced by the cognitive reconstruction inherent in Global WB measures and because it includes both positive and negative components of WB. In this study we report on both Global and Hedonic WB assessed in a 2008 telephone survey of 340,847 people in the United States. Consistent with prior studies, Global WB and positive Hedonic WB generally had U-shaped age profiles showing increased WB after the age of 50 years. However, negative Hedonic WB variables showed distinctly different and stronger patterns: Stress and Anger steeply declined from the early 20s, Worry was elevated through middle age and then declined, and Sadness was essentially flat. Unlike a prior study, men and women had very similar age profiles of WB. Several measures that could plausibly covary with the age-WB association (e.g., having children at home) did not alter the age-WB patterns. Global and Hedonic WB measures appear to index different aspects of WB over the lifespan, and the postmidlife increase in WB, especially in Hedonic WB, deserves continued exploration.
Dynamical stability of body center cubic iron at the Earth’s core conditions
Authors: Luo Wei , Johansson Börje , Eriksson Olle , Arapan Sergiu , Souvatzis Petros , Katsnelson Mikhail I. , Ahuja Rajeev
Published: May 2010

Here, using self-consistent ab initio lattice dynamical calculations that go beyond the quasiharmonic approximation, we show that the high-pressure high-temperature bcc-Fe phase is dynamically stable. In this treatment the temperature-dependent phonon spectra are derived by exciting all the lattice vibrations, in which the phonon–phonon interactions are considered. The high-pressure and high-temperature bcc-Fe phase shows standard bcc-type phonon dispersion curves except for the transverse branch, which is overdamped along the high symmetry direction Γ-N, at temperatures below 4,500 K. When lowering the temperature down to a critical value T
C
, the lattice instability of the bcc structure is reached. The pressure dependence of this critical temperature is studied at conditions relevant for the Earth’s core.
Arabidopsis thaliana
transcription factors bZIP19 and bZIP23 regulate the adaptation to zinc deficiency
Authors: Assunção Ana G. L. , Herrero Eva , Lin Ya-Fen , Huettel Bruno , Talukdar Sangita , Smaczniak Cezary , Immink Richard G. H. , van Eldik Mandy , Fiers Mark , Schat Henk , Aarts Mark G. M.
Published: May 2010

Zinc is an essential micronutrient for all living organisms. When facing a shortage in zinc supply, plants adapt by enhancing the zinc uptake capacity. The molecular regulators controlling this adaptation are not known. We present the identification of two closely related members of the
Arabidopsis thaliana
basic-region leucine-zipper (
bZIP
) transcription factor gene family,
bZIP19
and
bZIP23
, that regulate the adaptation to low zinc supply. They were identified, in a yeast-one-hybrid screening, to associate to promoter regions of the zinc deficiency-induced
ZIP4
gene of the Zrt- and Irt-related protein (ZIP) family of metal transporters. Although mutation of only one of the
bZIP
genes hardly affects plants, we show that the
bzip19 bzip23
double mutant is hypersensitive to zinc deficiency. Unlike the wild type, the
bzip19 bzip23
mutant is unable to induce the expression of a small set of genes that constitutes the primary response to zinc deficiency, comprising additional ZIP metal transporter genes. This set of target genes is characterized by the presence of one or more copies of a 10-bp imperfect palindrome in their promoter region, to which both bZIP proteins can bind. The bZIP19 and bZIP23 transcription factors, their target genes, and the characteristic
cis
zinc deficiency response elements they can bind to are conserved in higher plants. These findings are a significant step forward to unravel the molecular mechanism of zinc homeostasis in plants, allowing the improvement of zinc bio-fortification to alleviate human nutrition problems and phytoremediation strategies to clean contaminated soils.
Information processing at the
foxa
node of the sea urchin endomesoderm specification network
Authors: de-Leon Smadar Ben-Tabou , Davidson Eric H.
Published: May 2010

The
foxa
regulatory gene is of central importance for endoderm specification across Bilateria, and this gene lies at an essential node of the well-characterized sea urchin endomesoderm gene regulatory network (GRN). Here we experimentally dissect the
cis
-regulatory system that controls the complex pattern of
foxa
expression in these embryos. Four separate
cis
-regulatory modules (CRMs) cooperate to control
foxa
expression in different spatial domains of the endomesoderm, and at different times. A detailed mutational analysis revealed the inputs to each of these
cis
-regulatory modules. The complex and dynamic expression of
foxa
is regulated by a combination of repressors, a permissive switch, and multiple activators. A mathematical kinetic model was applied to study the dynamic response of
foxa cis
-regulatory modules to transient inputs. This study shed light on the mesoderm–endoderm fate decision and provides a functional explanation, in terms of the genomic regulatory code, for the spatial and temporal expression of a key developmental control gene.
Information-theoretic analysis of phenotype changes in early stages of carcinogenesis
Authors: Remacle F. , Kravchenko-Balasha Nataly , Levitzki Alexander , Levine R. D.
Published: May 2010

Cancer is a multistep process characterized by altered signal transduction, cell growth, and metabolism. To identify such processes in early carcinogenesis we use an information theoretic approach to characterize gene expression quantified as mRNA levels in primary keratinocytes (
K
) and human papillomavirus 16 (HPV16)-transformed keratinocytes (HF1 cells) from early (
E
) and late (
L
) passages and from benzo(
a
)pyrene-treated (BP) L cells. Our starting point is that biological signaling processes are subjected to the same quantitative laws as inanimate, nonequilibrium chemical systems. Environmental and genomic constraints thereby limit the maximal thermodynamic entropy that the biological system can reach. The procedure uncovers the changes in gene expression patterns in different networks and defines the significance of each altered network in the establishment of a particular phenotype. The development of transformed HF1 cells is shown to be represented by one major transcription pattern that is important at all times. Two minor transcription patterns are also identified, one that contributes at early times and a distinguishably different pattern that contributes at later times. All three transcription patterns defined by our analysis were validated by gene expression values and biochemical means. The major transcription pattern includes reduced transcripts participating in the apoptotic network and enhanced transcripts participating in cell cycle, glycolysis, and oxidative phosphorylation. The two minor patterns identify genes that are mainly involved in lipid or carbohydrate metabolism.
Aux frontières de la pragmatique et de la linguistique: Les variables de l'information culturelle dans la lexicographie bilingueN
Authors: De Surmont Jean-Nicolas
Published: May 2010

The introduction of cultural information (among others culturems) into the bilingual dictionaries suggests the old debate on the definition of culture, extremely productive word in definitions as much in the field of anthropology than that of sociology. At the borders of these two disciplines are the realia, these cultural realities sometimes named statalisms according to the definition of Jacques Pohl (1984). But the concept of realia is vaster than the referential extent than that of statalism to its creation (that of the administrative and political characteristics). On the basis of the concept of realia, we will try to determine the framework and the implications of them on a lexicographical level. The variation of French will be used as background with the theoretical lighting posed by this text. After this short glance on the theoretical and practical problems posed by the introduction of cultural information, we will formulate some proposals for solutions.N
A Canadian Example of Insanity Defence Reform: Accused Found Not Criminally Responsible Before and After the Winko Decision
Authors: Desmarais SarahL. , Hucker Stephen , Brink Johann , De Freitas Karen
Published: May 2010

This article reports on the effects of legislative reform on mentally disordered accused persons absolutely discharged from Review Boards in three Canadian jurisdictions. The sample included 592 accused randomly selected from all persons absolutely discharged in British Columbia, Ontario, and Quebec. Of these, 291 were absolutely discharged by provincial Review Boards in the three-year period prior to the landmark Winko decision and 301 in the three-year period following the decision. Analyses of information collected from Review Board files revealed few significant post-Winko changes, instead highlighting differences in practice and policy between jurisdictions. The only observed change in characteristics across jurisdictions was an increase in the prevalence of substance abuse disorders following Winko. No significant effects on outcomes were observed. Although the long-term effects of Winko remain to be seen, the effects appear to be minimal to date. Treating the Winko decision as a case example, discussion focuses on how findings of the present study may contribute to our understanding of the impact of policy and legislative reform on mentally disordered accused.
In-Home or Out-of-Home?: Predicting Long-Term Placement Recommendations for Juvenile Offenders
Authors: DeGue Sarah , Scalora Mario , Ullman Daniel , Gallavan Deanna
Published: May 2010

An important role served by mental health professionals in the juvenile court system involves the provision of recommendations regarding the long-term placement of youthful offenders. However, research on the factors used by clinicians in making these decisions is scarce. The present study examines the use of demographic, historical, and clinical variables, as well as an actuarial risk assessment instrument, the Youth Level of Service/Case Management Inventory (YLS/CMI; Hoge & Andrews, 1994, 2002), in the courtordered placement recommendations of 220 juvenile offenders. Univariate analyses revealed strong relationships between factors common in the risk assessment literature and level of placement recommendation. In fact, youth recommended for out-of-home placements scored significantly higher on seven out of eight subscales of the YLS/CMI. Additionally, multivariate analyses found that the strongest predictors of placement recommendation were two YLS/CMI subscales (family circumstances/parenting and attitudes/orientation) and the presence of mood disorder. These findings suggest that clinical decisionmaking regarding placement recommendations incorporates the assessment of a hybrid of risk-related and treatment amenability issues. Implications of these results in regards to clinical decision-making and juvenile justice policy are discussed.