bluuebunny/crossref_metadata_2025 huggingface dataset:
Current selection for lower migratory activity will drive the evolution of residency in a migratory bird population
Authors: Pulido Francisco , Berthold Peter
Published: April 2010

Global warming is impacting biodiversity by altering the distribution, abundance, and phenology of a wide range of animal and plant species. One of the best documented responses to recent climate change is alterations in the migratory behavior of birds, but the mechanisms underlying these phenotypic adjustments are largely unknown. This knowledge is still crucial to predict whether populations of migratory birds will adapt to a rapid increase in temperature. We monitored migratory behavior in a population of blackcaps (Sylvia atricapilla) to test for evolutionary responses to recent climate change. Using a common garden experiment in time and captive breeding we demonstrated a genetic reduction in migratory activity and evolutionary change in phenotypic plasticity of migration onset. An artificial selection experiment further revealed that residency will rapidly evolve in completely migratory bird populations if selection for shorter migration distance persists. Our findings suggest that current alterations of the environment are favoring birds wintering closer to the breeding grounds and that populations of migratory birds have strongly responded to these changes in selection. The reduction of migratory activity is probably an important evolutionary process in the adaptation of migratory birds to climate change, because it reduces migration costs and facilitates the rapid adjustment to the shifts in the timing of food availability during reproduction.
Addition of poly(A) and poly(A)-rich tails during RNA degradation in the cytoplasm of human cells
Authors: Slomovic Shimyn , Fremder Ella , Staals Raymond H. G. , Pruijn Ger J. M. , Schuster Gadi
Published: April 2010

Polyadenylation of RNA is a posttranscriptional modification that can play two somewhat opposite roles: stable polyadenylation of RNA encoded in the nuclear genomes of eukaryote cells contributes to nuclear export, translation initiation, and possibly transcript longevity as well. Conversely, transient polyadenylation targets RNA molecules to rapid exonucleolytic degradation. The latter role has been shown to take place in prokaryotes and organelles, as well as the nucleus of eukaryotic cells. Here we present evidence of hetero- and homopolymeric adenylation of truncated RNA molecules within the cytoplasm of human cells. RNAi-mediated silencing of the major RNA decay machinery of the cell resulted in the accumulation of these polyadenylated RNA fragments, indicating that they are degradation intermediates. Together, these results suggest that a mechanism of RNA decay, involving transient polyadenylation, is present in the cytoplasm of human cells.
High-resolution x-ray diffraction microscopy of specifically labeled yeast cells
Authors: Nelson Johanna , Huang Xiaojing , Steinbrener Jan , Shapiro David , Kirz Janos , Marchesini Stefano , Neiman Aaron M. , Turner Joshua J. , Jacobsen Chris
Published: April 2010

X-ray diffraction microscopy complements other x-ray microscopy methods by being free of lens-imposed radiation dose and resolution limits, and it allows for high-resolution imaging of biological specimens too thick to be viewed by electron microscopy. We report here the highest resolution (11–13 nm) x-ray diffraction micrograph of biological specimens, and a demonstration of molecular-specific gold labeling at different depths within cells via through-focus propagation of the reconstructed wavefield. The lectin concanavalin A conjugated to colloidal gold particles was used to label the α-mannan sugar in the cell wall of the yeast
Saccharomyces cerevisiae
. Cells were plunge-frozen in liquid ethane and freeze-dried, after which they were imaged whole using x-ray diffraction microscopy at 750 eV photon energy.
Inference in particle tracking experiments by passing messages between images
Authors: Chertkov M. , Kroc L. , Krzakala F. , Vergassola M. , Zdeborová L.
Published: April 2010

Methods to extract information from the tracking of mobile objects/particles have broad interest in biological and physical sciences. Techniques based on simple criteria of proximity in time-consecutive snapshots are useful to identify the trajectories of the particles. However, they become problematic as the motility and/or the density of the particles increases due to uncertainties on the trajectories that particles followed during the images’ acquisition time. Here, we report an efficient method for learning parameters of the dynamics of the particles from their positions in time-consecutive images. Our algorithm belongs to the class of message-passing algorithms, known in computer science, information theory, and statistical physics as belief propagation (BP). The algorithm is distributed, thus allowing parallel implementation suitable for computations on multiple machines without significant intermachine overhead. We test our method on the model example of particle tracking in turbulent flows, which is particularly challenging due to the strong transport that those flows produce. Our numerical experiments show that the BP algorithm compares in quality with exact Markov Chain Monte Carlo algorithms, yet BP is far superior in speed. We also suggest and analyze a random distance model that provides theoretical justification for BP accuracy. Methods developed here systematically formulate the problem of particle tracking and provide fast and reliable tools for the model’s extensive range of applications.
Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts
Authors: Bassett J. H. Duncan , Boyde Alan , Howell Peter G. T. , Bassett Richard H. , Galliford Thomas M. , Archanco Marta , Evans Holly , Lawson Michelle A. , Croucher Peter , St. Germain Donald L. , Galton Valerie Anne , Williams Graham R.
Published: April 2010

Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3′-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.
Rapid deglacial and early Holocene expansion of peatlands in Alaska
Authors: Jones Miriam C. , Yu Zicheng
Published: April 2010

Northern peatlands represent one of the largest biospheric carbon (C) reservoirs; however, the role of peatlands in the global carbon cycle remains intensely debated, owing in part to the paucity of detailed regional datasets and the complexity of the role of climate, ecosystem processes, and environmental factors in controlling peatland C dynamics. Here we used detailed C accumulation data from four peatlands and a compilation of peatland initiation ages across Alaska to examine Holocene peatland dynamics and climate sensitivity. We find that 75% of dated peatlands in Alaska initiated before 8,600 years ago and that early Holocene C accumulation rates were four times higher than the rest of the Holocene. Similar rapid peatland expansion occurred in West Siberia during the Holocene thermal maximum (HTM). Our results suggest that high summer temperature and strong seasonality during the HTM in Alaska might have played a major role in causing the highest rates of C accumulation and peatland expansion. The rapid peatland expansion and C accumulation in these vast regions contributed significantly to the peak of atmospheric methane concentrations in the early Holocene. Furthermore, we find that Alaskan peatlands began expanding much earlier than peatlands in other regions, indicating an important contribution of these peatlands to the pre-Holocene increase in atmospheric methane concentrations.
Dissecting comimetic radiations inHeliconiusreveals divergent histories of convergent butterflies
Authors: Quek Swee-Peck , Counterman Brian A. , Albuquerque de Moura Priscila , Cardoso Marcio Z. , Marshall Charles R. , McMillan W. Owen , Kronforst Marcus R.
Published: April 2010

Mimicry amongHeliconiusbutterflies provides a classic example of coevolution but unresolved relationships among mimetic subspecies have prevented examination of codiversification between species. We present amplified fragment length polymorphism and mtDNA datasets for the major comimetic races ofHeliconius eratoandH. melpomene. The AFLP data reveal unprecedented resolution, clustering samples by geography and race in both species. Our results show that, althoughH. eratoandH. melpomeneco-occur, mimic each other, and exhibit parallel shifts in color pattern, they experienced very different modes of diversification and geographic histories. Our results suggest thatH. eratooriginated on the western side of South America whereasH. melpomeneoriginated in the east.H. eratounderwent rapid diversification and expansion with continued gene-flow following diversification, resulting in widely dispersed sister taxa. In contrast,H. melpomeneunderwent a slower pace of diversification with lower levels of gene flow, producing a stepwise directional expansion from west to east. Our results also suggest that each of the three main wing pattern phenotypes originated and/or was lost multiple times in each species. The rayed pattern is likely to be the ancestral phenotype inH. eratowhereas postman or red patch is likely to be ancestral inH. melpomene. Finally,H. cydnoandH. himeraare monophyletic entities clearly nested withinH. melpomeneandH. erato, rather than being their respective sister species. Estimates of mtDNA divergence suggest a minimum age of 2.8 and 2.1 My forH. eratoandH. melpomene, respectively, placing their origins in the late Pliocene.
Actin filament remodeling by actin depolymerization factor/cofilin
Authors: Pfaendtner Jim , De La Cruz Enrique M. , Voth Gregory A.
Published: April 2010

We investigate, using molecular dynamics, how the severing protein, actin depolymerization factor (ADF)/cofilin, modulates the structure, conformational dynamics, and mechanical properties of actin filaments. The actin and cofilactin filament bending stiffness and corresponding persistence lengths obtained from all-atom simulations are comparable to values obtained from analysis of thermal fluctuations in filament shape. Filament flexibility is strongly affected by the nucleotide-linked conformation of the actin subdomain 2 DNase-I binding loop and the filament radial mass density distribution. ADF/cofilin binding between subdomains 1 and 3 of a filament subunit triggers reorganization of subdomain 2 of the neighboring subunit such that the DNase-I binding loop (DB-loop) moves radially away from the filament. Repositioning of the neighboring subunit DB-loop significantly weakens subunit interactions along the long-pitch helix and lowers the filament bending rigidity. Lateral filament contacts between the hydrophobic loop and neighboring short-pitch helix monomers in native filaments are also compromised with cofilin binding. These works provide a molecular interpretation of biochemical solution studies documenting the disruption of filament subunit interactions and also reveal the molecular basis of actin filament allostery and its linkage to ADF/cofilin binding.
Legionella pneumophila
6S RNA optimizes intracellular multiplication
Authors: Faucher Sébastien P. , Friedlander Gilgi , Livny Jonathan , Margalit Hanah , Shuman Howard A.
Published: April 2010

Legionella pneumophila
is a Gram-negative opportunistic human pathogen that infects and multiplies in a broad range of phagocytic protozoan and mammalian phagocytes. Based on the observation that small regulatory RNAs (sRNAs) play an important role in controlling virulence-related genes in several pathogenic bacteria, we attempted to identify sRNAs expressed by
L. pneumophila
. We used computational prediction followed by experimental verification to identify and characterize sRNAs encoded in the
L. pneumophila
genome. A 50-mer probe microarray was constructed to test the expression of predicted sRNAs in bacteria grown under a variety of conditions. This strategy successfully identified 22 expressed RNAs, out of which 6 were confirmed by northern blot and RACE. One of the identified sRNAs is highly expressed in postexponential phase, and computational prediction of its secondary structure reveals a striking similarity to the structure of 6S RNA, a widely distributed prokaryotic sRNA, known to regulate the activity of σ
70
-containing RNA polymerase. A 70-mer probe microarray was used to identify genes affected by
L. pneumophila
6S RNA in stationary phase. The 6S RNA positively regulates expression of genes encoding type IVB secretion system effectors, stress response genes such as
groES
and
recA
, as well as many genes involved in acquisition of nutrients and genes with unknown or hypothetical functions. Deletion of 6S RNA significantly reduced
L. pneumophila
intracellular multiplication in both protist and mammalian host cells, but had no detectable effect on growth in rich media.
SynCAM 1 participates in axo-dendritic contact assembly and shapes neuronal growth cones
Authors: Stagi Massimiliano , Fogel Adam I. , Biederer Thomas
Published: April 2010

Neuronal growth cones are highly motile structures that tip developing neurites and explore their surroundings before axo-dendritic contact and synaptogenesis. However, the membrane proteins organizing these processes remain insufficiently understood. Here we identify that the synaptic cell adhesion molecule 1 (SynCAM 1), an immunoglobulin superfamily member, is already expressed in developing neurons and localizes to their growth cones. Upon interaction of growth cones with target neurites, SynCAM 1 rapidly assembles at these contacts to form stable adhesive clusters. Synaptic markers can also be detected at these sites. Addressing the functions of SynCAM 1 in growth cones preceding contact, we determine that it is required and sufficient to restrict the number of active filopodia. Further, SynCAM 1 negatively regulates the morphological complexity of migrating growth cones. Focal adhesion kinase, a binding partner of SynCAM 1, is implicated in its morphogenetic activities. These results reveal that SynCAM 1 acts in developing neurons to shape migrating growth cones and contributes to the adhesive differentiation of their axo-dendritic contacts.
Dopamine D2 receptor density in the limbic striatum is related to implicit but not explicit movement sequence learning
Authors: Karabanov Anke , Cervenka Simon , de Manzano Örjan , Forssberg Hans , Farde Lars , Ullén Fredrik
Published: April 2010

A large body of literature suggests that motor sequence learning involves dopamine-modulated plastic processes in the basal ganglia. Sequence learning can occur both implicitly, without conscious awareness and intention to learn, and explicitly, i.e., under conscious control. Here, we investigated whether individual differences in implicit and explicit sequence learning of movement sequences in a group of 15 healthy participants are related to dopamine D2 receptor densities in functional subregions of the striatum. Sequence learning was assessed using the serial reaction time task, and measures of implicit and explicit knowledge were estimated using a process dissociation procedure. Correlation analyses were performed between these measures and D2 receptor densities, which had been measured previously with positron emission tomography. Striatal D2 densities were negatively related to measures of sequence learning. In the limbic subregion, D2 densities were specifically related to implicit but not explicit learning. These findings suggest that individual differences in striatal DA function underlie differences in sequence learning ability and support that implicit and explicit sequence learning depend on partly distinct neural circuitry. The findings are also in line with the general view that implicit learning systems are evolutionarily primitive and tend to rely more on phylogenetically old neural circuitry than does explicit learning and cognition.
Dynamic O-GlcNAc cycling at promoters of
Caenorhabditis elegans
genes regulating longevity, stress, and immunity
Authors: Love Dona C. , Ghosh Salil , Mondoux Michelle A. , Fukushige Tetsunari , Wang Peng , Wilson Mark A. , Iser Wendy B. , Wolkow Catherine A. , Krause Michael W. , Hanover John A.
Published: April 2010

Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in
C. elegans
because knockouts of the O-GlcNAc cycling enzymes are viable and fertile. Using anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays on wild-type and mutant strains, we detected over 800 promoters where O-GlcNAc cycling occurs, including microRNA loci and multigene operons. Intriguingly, O-GlcNAc-marked promoters are biased toward genes associated with PIP3 signaling, hexosamine biosynthesis, and lipid/carbohydrate metabolism. These marked genes are linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways in
C. elegans
. Whole-genome transcriptional profiling of the O-GlcNAc cycling mutants confirmed dramatic deregulation of genes in these key pathways. As predicted, the O-GlcNAc cycling mutants show altered lifespan and UV stress susceptibility phenotypes. We propose that O-GlcNAc cycling at promoters participates in a molecular program impacting nutrient-responsive pathways in
C. elegans
, including stress, pathogen response, and adult lifespan. The observed impact of O-GlcNAc cycling on both signaling and transcription in
C. elegans
has important implications for human diseases of aging, including diabetes and neurodegeneration.
Segregation distortion causes large-scale differences between male and female genomes in hybrid ants
Authors: Kulmuni Jonna , Seifert Bernhard , Pamilo Pekka
Published: April 2010

Hybridization in isolated populations can lead either to hybrid breakdown and extinction or in some cases to speciation. The basis of hybrid breakdown lies in genetic incompatibilities between diverged genomes. In social Hymenoptera, the consequences of hybridization can differ from those in other animals because of haplodiploidy and sociality. Selection pressures differ between sexes because males are haploid and females are diploid. Furthermore, sociality and group living may allow survival of hybrid genotypes. We show that hybridization in
Formica
ants has resulted in a stable situation in which the males form two highly divergent gene pools whereas all the females are hybrids. This causes an exceptional situation with large-scale differences between male and female genomes. The genotype differences indicate strong transmission ratio distortion depending on offspring sex, whereby the mother transmits some alleles exclusively to her daughters and other alleles exclusively to her sons. The genetic differences between the sexes and the apparent lack of multilocus hybrid genotypes in males can be explained by recessive incompatibilities which cause the elimination of hybrid males because of their haploid genome. Alternatively, differentiation between sexes could be created by prezygotic segregation into male-forming and female-forming gametes in diploid females. Differentiation between sexes is stable and maintained throughout generations. The present study shows a unique outcome of hybridization and demonstrates that hybridization has the potential of generating evolutionary novelties in animals.
Metamorphic proteins mediate evolutionary transitions of structure
Authors: Yadid Itamar , Kirshenbaum Noam , Sharon Michal , Dym Orly , Tawfik Dan S.
Published: April 2010

The primary sequence of proteins usually dictates a single tertiary and quaternary structure. However, certain proteins undergo reversible backbone rearrangements. Such metamorphic proteins provide a means of facilitating the evolution of new folds and architectures. However, because natural folds emerged at the early stages of evolution, the potential role of metamorphic intermediates in mediating evolutionary transitions of structure remains largely unexplored. We evolved a set of new proteins based on ∼100 amino acid fragments derived from tachylectin-2—a monomeric, 236 amino acids, five-bladed β-propeller. Their structures reveal a unique pentameric assembly and novel β-propeller structures. Although identical in sequence, the oligomeric subunits adopt two, or even three, different structures that together enable the pentameric assembly of two propellers connected via a small linker. Most of the subunits adopt a wild-type-like structure within individual five-bladed propellers. However, the bridging subunits exhibit domain swaps and asymmetric strand exchanges that allow them to complete the two propellers and connect them. Thus, the modular and metamorphic nature of these subunits enabled dramatic changes in tertiary and quaternary structure, while maintaining the lectin function. These oligomers therefore comprise putative intermediates via which β-propellers can evolve from smaller elements. Our data also suggest that the ability of one sequence to equilibrate between different structures can be evolutionary optimized, thus facilitating the emergence of new structures.
Embryonic trafficking of γδ T cells to skin is dependent on E/P selectin ligands and CCR4
Authors: Jiang Xiaodong , Campbell James J. , Kupper Thomas S.
Published: April 2010

Dendritic epidermal T cells (DETC) express an invariant Vγ3/Vδ1 T-cell receptor, appear in fetal epidermis, and form a population of resident epidermal T cells. Their temporal development in the thymus has been studied extensively. However, little is known about the mechanisms involved in the embryonic trafficking of DETC from thymus to epidermis. We demonstrate that DETC in adult skin, as well as the DETC precursors in fetal thymus, express E and P selectin ligands (E- and P-lig). Mice deficient in α1,3 fucosyltransferases IV and VII (FTIV/VII) cannot synthesize the carbohydrate motifs that form key elements of these selectin ligands. The numbers of DETC in the epidermis of FTIV/VII
−/−
mice were dramatically reduced compared with normal mice. However, the development of DETC precursors in fetal thymus was identical in normal and FTIV/VII
−/−
mice, suggesting that the DETC precursors produced in FTIV/VII
−/−
mice could not traffic effectively to skin because they lack E- and P-lig. We tested this hypothesis by daily injection of blocking antibodies against E and P selectin into pregnant mice. Mice born from dams treated with anti-selectin antibodies, but not those born from dams treated with isotype control, had significantly diminished numbers of DETC. To test the role of chemokine receptors in DETC skin homing, we examined skin from CCR4
−/−
and CCR10
−/−
mice, respectively. DETC were significantly reduced in CCR4
−/−
mice but were present at normal levels in CCR10
−/−
mice. Our results present evidence for the crucial role of trafficking molecules in embryonic migration of DETC precursors to skin.
Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration
Authors: Wu Yalin , Yanase Emiko , Feng Xidong , Siegel Marshall M. , Sparrow Janet R.
Published: April 2010

Fluorescent bisretinoids, such as A2E and all-
trans
-retinal dimer, form as a by-product of vitamin A cycling in retina and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin pigments. These pigments are implicated in pathological mechanisms involved in several vision-threatening diseases including age-related macular degeneration. Efforts to understand damaging events initiated by these bisretinoids have revealed that photoexcitation of A2E by wavelengths in the visible spectrum leads to singlet oxygen production and photooxidation of A2E. Here we have employed liquid chromatography coupled to electrospray ionization mass spectrometry together with tandem mass spectrometry (MS/MS), to demonstrate that A2E also undergoes photooxidation-induced degradation and we have elucidated the structures of some of the aldehyde-bearing cleavage products. Studies in which A2E was incubated with a singlet oxygen generator yielded results consistent with a mechanism involving bisretinoid photocleavage at sites of singlet molecular oxygen addition. We provide evidence that one of the products released by A2E photodegradation is methylglyoxal, a low molecular weight reactive dicarbonyl with the capacity to form advanced glycation end products. Methylglyoxal is already known to be generated by carbohydrate and lipid oxidation; this is the first report of its production via bisretinoid photocleavage. It is significant that AGE-modified proteins are detected in deposits (drusen) that accumulate below RPE cells in vivo; drusen have been linked to age-related macular degeneration pathogenesis. Whereas various processes play a role in drusen formation, these findings are indicative of a contribution from lipofuscin photooxidation in RPE.
Neuronal synchrony reveals working memory networks and predicts individual memory capacity
Authors: Palva J. Matias , Monto Simo , Kulashekhar Shrikanth , Palva Satu
Published: April 2010

Visual working memory (VWM) is used to maintain sensory information for cognitive operations, and its deficits are associated with several neuropsychological disorders. VWM is based on sustained neuronal activity in a complex cortical network of frontal, parietal, occipital, and temporal areas. The neuronal mechanisms that coordinate this distributed processing to sustain coherent mental images and the mechanisms that set the behavioral capacity limit have remained unknown. We mapped the anatomical and dynamic structures of network synchrony supporting VWM by using a neuro informatics approach and combined magnetoencephalography and electroencephalography. Interareal phase synchrony was sustained and stable during the VWM retention period among frontoparietal and visual areas in α- (10–13 Hz), β- (18–24 Hz), and γ- (30–40 Hz) frequency bands. Furthermore, synchrony was strengthened with increasing memory load among the frontoparietal regions known to underlie executive and attentional functions during memory maintenance. On the other hand, the subjects’ individual behavioral VWM capacity was predicted by synchrony in a network in which the intraparietal sulcus was the most central hub. These data suggest that interareal phase synchrony in the α-, β-, and γ-frequency bands among frontoparietal and visual regions could be a systems level mechanism for coordinating and regulating the maintenance of neuronal object representations in VWM.
Atmospheric chemistry in volcanic plumes
Authors: von Glasow Roland
Published: April 2010

Recent field observations have shown that the atmospheric plumes of quiescently degassing volcanoes are chemically very active, pointing to the role of chemical cycles involving halogen species and heterogeneous reactions on aerosol particles that have previously been unexplored for this type of volcanic plumes. Key features of these measurements can be reproduced by numerical models such as the one employed in this study. The model shows sustained high levels of reactive bromine in the plume, leading to extensive ozone destruction, that, depending on plume dispersal, can be maintained for several days. The very high concentrations of sulfur dioxide in the volcanic plume reduces the lifetime of the OH radical drastically, so that it is virtually absent in the volcanic plume. This would imply an increased lifetime of methane in volcanic plumes, unless reactive chlorine chemistry in the plume is strong enough to offset the lack of OH chemistry. A further effect of bromine chemistry in addition to ozone destruction shown by the model studies presented here, is the oxidation of mercury. This relates to mercury that has been coemitted with bromine from the volcano but also to background atmospheric mercury. The rapid oxidation of mercury implies a drastically reduced atmospheric lifetime of mercury so that the contribution of volcanic mercury to the atmospheric background might be less than previously thought. However, the implications, especially health and environmental effects due to deposition, might be substantial and warrant further studies, especially field measurements to test this hypothesis.
Collective dynamics underpins Rayleigh behavior in disordered polycrystalline ferroelectrics
Authors: Bintachitt P. , Jesse S. , Damjanovic D. , Han Y. , Reaney I. M. , Trolier-McKinstry S. , Kalinin S. V.
Published: April 2010

Nanoscale and mesoscopic disorder and associated local hysteretic responses underpin the unique properties of spin and cluster glasses, phase-separated oxides, polycrystalline ferroelectrics, and ferromagnets alike. Despite the rich history of the field, the relationship between the statistical descriptors of hysteresis behavior such as Preisach density, and micro and nanostructure has remained elusive. By using polycrystalline ferroelectric capacitors as a model system, we now report quantitative nonlinearity measurements in 0.025–1 μm
3
volumes, approximately 10
6
times smaller than previously possible. We discover that the onset of nonlinear behavior with thickness proceeds through formation and increase of areal density of micron-scale regions with large nonlinear response embedded in a more weakly nonlinear matrix. This observation indicates that large-scale collective domain wall dynamics, as opposed to motion of noninteracting walls, underpins Rayleigh behavior in disordered ferroelectrics. The measurements provide evidence for the existence and extent of the domain avalanches in ferroelectric materials, forcing us to rethink 100-year old paradigms.
Extensive phosphorylation with overlapping specificity by
Mycobacterium tuberculosis
serine/threonine protein kinases
Authors: Prisic Sladjana , Dankwa Selasi , Schwartz Daniel , Chou Michael F. , Locasale Jason W. , Kang Choong-Min , Bemis Guy , Church George M. , Steen Hanno , Husson Robert N.
Published: April 2010

The
Mycobacterium tuberculosis
genome encodes 11 serine/threonine protein kinases (STPKs) that are structurally related to eukaryotic kinases. To gain insight into the role of Ser/Thr phosphorylation in this major global pathogen, we used a phosphoproteomic approach to carry out an extensive analysis of protein phosphorylation in
M. tuberculosis
. We identified more than 500 phosphorylation events in 301 proteins that are involved in a broad range of functions. Bioinformatic analysis of quantitative in vitro kinase assays on peptides containing a subset of these phosphorylation sites revealed a dominant motif shared by six of the
M. tuberculosis
STPKs. Kinase assays on a second set of peptides incorporating targeted substitutions surrounding the phosphoacceptor validated this motif and identified additional residues preferred by individual kinases. Our data provide insight into processes regulated by STPKs in
M. tuberculosis
and create a resource for understanding how specific phosphorylation events modulate protein activity. The results further provide the potential to predict likely cognate STPKs for newly identified phosphoproteins.
Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake
Authors: Olson David P. , Pulinilkunnil Thomas , Cline Gary W. , Shulman Gerald I. , Lowell Bradford B.
Published: April 2010

Deletion of acetyl CoA carboxylase-2 (Acc2) reportedly causes leanness in the setting of hyperphagia. To determine the cellular basis for these effects, we generated a mouse model in which Acc2 can be selectively deleted by the action of Cre recombinase. Deletion of Acc2 from skeletal muscle, the predominant site of Acc2 expression, had no effect on body weight, food intake, or body composition. When Acc2 was inactivated in the germline, Acc2 knockout (Acc2KO) mice displayed no differences in body weight, food intake, body composition, or glucose homeostasis as compared to controls on chow or high fat diet. Total malonyl CoA content and fatty acid oxidation rates in skeletal muscle of Acc2KO mice were unchanged, suggesting metabolic compensation in response to the loss of Acc2. The limited impact of Acc2 deletion on energy balance raises the possibility that selective pharmacological inhibition of Acc2 for the treatment of obesity may be ineffective.
Heterogeneity of pulmonary perfusion as a mechanistic image-based phenotype in emphysema susceptible smokers
Authors: Alford Sara K. , van Beek Edwin J. R. , McLennan Geoffrey , Hoffman Eric A.
Published: April 2010

Recent evidence suggests that endothelial dysfunction and pathology of pulmonary vascular responses may serve as a precursor to smoking-associated emphysema. Although it is known that emphysematous destruction leads to vasculature changes, less is known about early regional vascular dysfunction which may contribute to and precede emphysematous changes. We sought to test the hypothesis, via multidetector row CT (MDCT) perfusion imaging, that smokers showing early signs of emphysema susceptibility have a greater heterogeneity in regional perfusion parameters than emphysema-free smokers and persons who had never smoked (NS). Assuming that all smokers have a consistent inflammatory response, increased perfusion heterogeneity in emphysema-susceptible smokers would be consistent with the notion that these subjects may have the inability to block hypoxic vasoconstriction in patchy, small regions of inflammation. Dynamic ECG-gated MDCT perfusion scans with a central bolus injection of contrast were acquired in 17 NS, 12 smokers with normal CT imaging studies (SNI), and 12 smokers with subtle CT findings of centrilobular emphysema (SCE). All subjects had normal spirometry. Quantitative image analysis determined regional perfusion parameters, pulmonary blood flow (PBF), and mean transit time (MTT). Mean and coefficient of variation were calculated, and statistical differences were assessed with one-way ANOVA. MDCT-based MTT and PBF measurements demonstrate globally increased heterogeneity in SCE subjects compared with NS and SNI subjects but demonstrate similarity between NS and SNI subjects. These findings demonstrate a functional lung-imaging measure that provides a more mechanistically oriented phenotype that differentiates smokers with and without evidence of emphysema susceptibility.
Dynamic sorting of lipids and proteins in membrane tubes with a moving phase boundary
Authors: Heinrich Michael , Tian Aiwei , Esposito Cinzia , Baumgart Tobias
Published: April 2010

Cellular organelle membranes maintain their integrity, global shape, and composition despite vigorous exchange among compartments of lipids and proteins during trafficking and signaling. Organelle homeostasis involves dynamic molecular sorting mechanisms that are far from being understood. In contrast, equilibrium thermodynamics of membrane mixing and sorting, particularly the phase behavior of binary and ternary model membrane mixtures and its coupling to membrane mechanics, is relatively well characterized. Elucidating the continuous turnover of live cell membranes, however, calls for experimental and theoretical membrane models enabling manipulation and investigation of directional mass transport. Here we introduce the phenomenon of curvature-induced domain nucleation and growth in membrane mixtures with fluid phase coexistence. Membrane domains were consistently observed to nucleate precisely at the junction between a strongly curved cylindrical (tube) membrane and a pipette-aspirated giant unilamellar vesicle. This experimental geometry mimics intracellular sorting compartments, because they often show tubular-vesicular membrane regions. Nucleated domains at tube necks were observed to present diffusion barriers to the transport of lipids and proteins. We find that curvature-nucleated domains grow with characteristic parabolic time dependence that is strongly curvature-dependent. We derive an analytical model that reflects the observed growth dynamics. Numerically calculated membrane shapes furthermore allow us to elucidate mechanical details underlying curvature-dependent directed lipid transport. Our observations suggest a novel dynamic membrane sorting principle that may contribute to intracellular protein and lipid sorting and trafficking.
Revelations in our own backyard:
Chandra’s
unique Galactic Center discoveries
Authors: Markoff Sera
Published: April 2010

Before the launch of Chandra, our Galactic Center supermassive black hole, Sgr A*, had never been positively identified outside the radio bands. A great deal has changed in the past decade, starting with the discovery that our own backyard harbors a very weak, yet clearly active, galactic nucleus. I will review how this revelation has been a boon for accretion studies around black holes in general and has helped us place our own Galaxy in context within the active galactic nuclei (AGN) zoology. Chandra’s exquisite resolution has also unveiled entirely new populations of faint sources and transients, as well as regions of extreme gas dynamics and hints of prior, more typical AGN-like activity in our Galactic Center.
Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase
Authors: Mitchell John , Paul Praveen , Chen Han-Jou , Morris Alex , Payling Miles , Falchi Mario , Habgood James , Panoutsou Stefania , Winkler Sabine , Tisato Veronica , Hajitou Amin , Smith Bradley , Vance Caroline , Shaw Christopher , Mazarakis Nicholas D. , de Belleroche Jacqueline
Published: April 2010

We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.
Nuclear phosphoinositide 3-kinase β controls double-strand break DNA repair
Authors: Kumar Amit , Fernandez-Capetillo Oscar , Carrera Ana C.
Published: April 2010

Class I phosphoinositide 3-kinases are enzymes that generate 3-poly-phosphoinositides at the cell membrane following transmembrane receptor stimulation. Expression of the phosphoinositide 3-kinase β (PI3Kβ) isoform, but not its activity, is essential for early embryonic development. Nonetheless, the specific function of PI3Kβ in the cell remains elusive. Double-strand breaks (DSB) are among the most deleterious lesions for genomic integrity; their repair is required for development. We show that PI3Kβ is necessary for DSB sensing, as PI3Kβ regulates binding of the Nbs1 sensor protein to damaged DNA. Indeed, Nbs1 did not bind to DSB in PI3Kβ-deficient cells, which showed a general defect in subsequent ATM and ATR activation, resulting in genomic instability. Inhibition of PI3Kβ also retarded the DNA repair but the defect was less marked than that induced by PI3Kβ deletion, supporting a kinase-independent function for PI3Kβ in DNA repair. These results point at class I PI3Kβ as a critical sensor of genomic integrity.
Evolutionary dynamics of
Clostridium difficile
over short and long time scales
Authors: He Miao , Sebaihia Mohammed , Lawley Trevor D. , Stabler Richard A. , Dawson Lisa F. , Martin Melissa J. , Holt Kathryn E. , Seth-Smith Helena M.B. , Quail Michael A. , Rance Richard , Brooks Karen , Churcher Carol , Harris David , Bentley Stephen D. , Burrows Christine , Clark Louise , Corton Craig , Murray Vicky , Rose Graham , Thurston Scott , van Tonder Andries , Walker Danielle , Wren Brendan W. , Dougan Gordon , Parkhill Julian
Published: April 2010

Clostridium difficile
has rapidly emerged as the leading cause of antibiotic-associated diarrheal disease, with the transcontinental spread of various PCR ribotypes, including 001, 017, 027 and 078. However, the genetic basis for the emergence of
C. difficile
as a human pathogen is unclear. Whole genome sequencing was used to analyze genetic variation and virulence of a diverse collection of thirty
C. difficile
isolates, to determine both macro and microevolution of the species. Horizontal gene transfer and large-scale recombination of core genes has shaped the
C. difficile
genome over both short and long time scales. Phylogenetic analysis demonstrates
C. difficile
is a genetically diverse species, which has evolved within the last 1.1–85 million years. By contrast, the disease-causing isolates have arisen from multiple lineages, suggesting that virulence evolved independently in the highly epidemic lineages.
Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex
Authors: Namekata Kazuhiko , Harada Chikako , Taya Choji , Guo Xiaoli , Kimura Hideo , Parada Luis F. , Harada Takayuki
Published: April 2010

Atypical Rho-guanine nucleotide exchange factors (Rho-GEFs) that contain Dock homology regions (DHR-1 and DHR-2) are expressed in a variety of tissues; however, their functions and mechanisms of action remain unclear. We identify key conserved amino acids in the DHR-2 domain that are critical for the catalytic activity of Dock-GEFs (Dock1–4). We further demonstrate that Dock-GEFs directly associate with WASP family verprolin-homologous (WAVE) proteins through the DHR-1 domain. Brain-derived neurotrophic factor (BDNF)-TrkB signaling recruits the Dock3/WAVE1 complex to the plasma membrane, whereupon Dock3 activates Rac and dissociates from the WAVE complex in a phosphorylation-dependent manner. BDNF induces axonal sprouting through Dock-dependent Rac activation, and adult transgenic mice overexpressing Dock3 exhibit enhanced optic nerve regeneration after injury without affecting WAVE expression levels. Our results highlight a unique mechanism through which Dock-GEFs achieve spatial and temporal restriction of WAVE signaling, and identify Dock-GEF activity as a potential therapeutic target for axonal regeneration.
The serotonin
1A
receptor gene as a genetic and prenatal maternal environmental factor in anxiety
Authors: Gleason G. , Liu B. , Bruening S. , Zupan B. , Auerbach A. , Mark W. , Oh J.-E. , Gal-Toth J. , Lee F. , Toth M.
Published: April 2010

Low serotonin
1A
receptor (5-HT
1A
R) binding is a risk factor for anxiety and depression, and deletion of the

5-HT
1A
R

results in anxiety-like behavior in mice. Here we show that anxiety-like behavior in mice also can be caused, independently of the offspring's own

5-HT
1A
R

genotype, by a receptor deficit in the mother: a nongenetic transmission of a genetic defect. Some of the nongenetically transmitted anxiety manifestations were acquired prenatally and linked to a delay in dentate gyrus maturation in the ventral hippocampus of the offspring. Both the developmental delay and the anxiety-like phenotype were phenocopied by the genetic inactivation of

p16
ink4a

encoding a cyclin-dependent kinase inhibitor implicated in neuronal precursor differentiation. No maternal

5-HT
1A
R

genotype-dependent anxiety developed when the strain background was switched from Swiss Webster to C57BL/6, consistent with the increased resilience of this strain to early adverse environment. Instead, all anxiety manifestations were caused by the offspring's own receptor deficiency, indicating that the genetic and nongenetic effects converge to common anxiety manifestations. We propose that 5-HT
1A
R deficit represents a dual risk for anxiety and that vulnerability to anxiety associated with genetic 5-HT
1A
R deficiency can be transmitted by both genetic and nongenetic mechanisms in a population. Thus, the overall effect of risk alleles can be higher than estimated by traditional genetic assays and may contribute to the relatively high heritability of anxiety and psychiatric disorders in general.
Persistent schema-dependent hippocampal-neocortical connectivity during memory encoding and postencoding rest in humans
Authors: van Kesteren Marlieke T. R. , Fernández Guillén , Norris David G. , Hermans Erno J.
Published: April 2010

The hippocampus is thought to promote gradual incorporation of novel information into long-term memory by binding, reactivating, and strengthening distributed cortical-cortical connections. Recent studies implicate a key role in this process for hippocampally driven crosstalk with the (ventro)medial prefrontal cortex (vmPFC), which is proposed to become a central node in such representational networks over time. The existence of a relevant prior associative network, or schema, may moreover facilitate this process. Thus, hippocampal-vmPFC crosstalk may support integration of new memories, particularly in the absence of a relevant prior schema. To address this issue, we used functional magnetic resonance imaging (fMRI) and prior schema manipulation to track hippocampal-vmPFC connectivity during encoding and postencoding rest. We manipulated prior schema knowledge by exposing 30 participants to the first part of a movie that was temporally scrambled for 15 participants. The next day, participants underwent fMRI while encoding the movie's final 15 min in original order and, subsequently, while resting. Schema knowledge and item recognition performance show that prior schema was successfully and selectively manipulated. Intersubject synchronization (ISS) and interregional partial correlation analyses furthermore show that stronger prior schema was associated with more vmPFC ISS and less hippocampal-vmPFC interregional connectivity during encoding. Notably, this connectivity pattern persisted during postencoding rest. These findings suggest that additional crosstalk between hippocampus and vmPFC is required to compensate for difficulty integrating novel information during encoding and provide tentative support for the notion that functionally relevant hippocampal-neocortical crosstalk persists during off-line periods after learning.