bluuebunny/crossref_metadata_2025 huggingface dataset:
Saltopus, a dinosauriform from the Upper Triassic of Scotland
Authors: Benton Michael J. , Walker Alick D.
Published: May 2011

Saltopus elginensis, reported in 1910 from the yellow sandstones of the Lossiemouth Sandstone Formation (Late Triassic) of Morayshire, NE Scotland, has long been controversial. It was described first as a theropod dinosaur, but others disagreed. Reanalysis of the type, and only, specimen using casts from the natural rock moulds, as well as X-rays and CT scans, has revealed new anatomical data not available to previous researchers. Saltopus was a small, 800–1000 mm-long biped, whose tail made up more than half its length. It is an avemetatarsalian because it has elongated and tightly bunched metatarsals, the tibia is longer than the femur, the calcaneal tuber is rudimentary or absent, and metatarsal II is equal to or longer than metatarsal IV; a unique assemblage of characters diagnosing this clade. Saltopus is a dinosauromorph on the basis of the reduced fingers IV and V, the saddle-shaped dorsal margin of the iliac blade, and the articulation of sacral rib 1 close to the front of the iliac blade. Saltopus is a dinosauriform on the basis of the trochanteric shelf and lesser trochanter on the proximal end of the femur, the waisted sacral ribs, and perhaps the rod-like and straight pubis. However, it lacks all apomorphies of Dinosauria, retaining for example the primitive condition of two sacral vertebrae. Cladistic analyses place Saltopus within Dinosauromorpha and Dinosauriformes, and between the basal dinosauriform Pseudolagosuchus and the derived clade consisting of Silesauridae and Dinosauria, so making it one of a radiation of small pre-dinosaurian bipedal archosaurs in the Triassic found so far in North and South America and in Europe.
New dinosaur species from the Upper Triassic Upper Maleri and Lower Dharmaram formations of Central India
Authors: Novas Fernando E. , Ezcurra Martin D. , Chatterjee Sankar , Kutty T. S.
Published: May 2011

The beginning of dinosaur evolution is currently known based on a handful of highly informative Gondwanan outcrops of Ischigualastian age (late Carnian–early Norian). The richest Triassic dinosaur records of the southern continents are those of South America and South Africa, with taxonomically diverse faunas, whereas faunas from India and central Africa are more poorly known. Here, the known diversity of Gondwanan Triassic dinosaurs is increased with new specimens from central India, which allow a more comprehensive characterisation of these dinosaur assemblages. Five dinosauriform specimens are reported from the probable late Norian–earliest Rhaetian Upper Maleri Formation, including two new sauropodomorph species, the non-plateosaurian Nambalia roychowdhurii and the plateosaurian Jaklapallisaurus asymmetrica, a guaibasaurid and two basal dinosauriforms. The Lower Dharmaram Formation, probably latest Norian–Rhaetian in age, includes basal sauropodomorph and neotheropod remains, providing the second record of a Triassic Gondwanan neotheropod. The currently available evidence suggests that the oldest known Gondwanan dinosaur assemblages (Ischigualastian) were not homogeneous, but more diverse in South America than in India. In addition, the Upper Maleri and Lower Dharmaram dinosaur assemblages resemble purported coeval South American and European beds in the presence of basal sauropodomorphs. Accordingly, the current available evidence of the Triassic beds of the Pranhita–Godavari Basin suggests that dinosaurs increased in diversity and abundance during the late Norian to Rhaetian in this region of Gondwana.
The roles of herbivory and omnivory in early dinosaur evolution
Authors: Barrett Paul M. , Butler Richard J. , Nesbitt Sterling J.
Published: May 2011

Herbivorous and omnivorous dinosaurs were rare during the Carnian stage of the Late Triassic. By contrast, the succeeding Norian stage witnessed the rapid diversification of sauropodomorphs and the rise of the clade to ecological dominance. Ornithischians, by contrast, remained relatively rare components of dinosaur assemblages until much later in the Mesozoic. The causes underlying the differential success of ornithischians and sauropodomorphs remain unclear, but might be related to trophic specialisation. Sauropodomorphs replaced an established herbivore guild consisting of rhynchosaurs, aetosaurs and basal synapsids, but this faunal turnover appears to have been opportunistic and cannot be easily attributed to either competitive interactions or responses to floral change. Consideration of diversity patterns and relative abundance suggests that the ability to eat plants might have been a major factor promoting sauropodomorph success, but that it was less important in the early evolution of Ornithischia. On the basis of current evidence it is difficult to determine the diet of the ancestral dinosaur and scenarios in which omnivory or carnivory represent the basal condition appear equally likely.
Ereigniskorrelierte Potentiale: Ein neuer Zugang zur Erforschung der Objektverarbeitung bei Babys
Authors: Pauen Sabina , Höhl Stefanie
Published: May 2011

Der vorliegende Beitrag gibt einen Überblick über neuere EKP-Studien zur einfachen Objektdiskrimination, zur Objektkategorisierung und zum sozialen Objektlernen bei Babys. Als Vorteile der EKP-Messung gegenüber Blickzeitmessungen erweisen sich dabei vor allem die kurze Darbietungszeit von Reizen und die hohe zeitliche Auflösung der Messungen. Als relevante EKP-Komponenten werden die Negative central component (Nc) sowie die Positive Slow Wave (PSW) identifiziert. In Bestätigung und Erweiterung von Erkenntnissen der Verhaltensforschung konnte mit Hilfe von EKP-Studien festgestellt werden, dass Säuglinge bereits bis vor dem 6. Lebensmonat in der Lage sind, vertraute Objekte wiederzuerkennen, Objekte auf unterschiedlichen Abstraktionsebenen zu kategorisieren und soziale Hinweisreize zu nutzen, um zu entscheiden, welche Objekte besonders interessant sind. Ihre Objektverarbeitung geht damit weit über einfache Wahrnehmungs- und Diskriminationsleistungen hinaus.
Frequency and intensity of extreme drought in the Delaware Basin, 1600–2002
Authors: Kauffman G. J. , Vonck K. J.
Published: May 2011

The frequency and severity of drought in the Delaware Basin between 1600 and 2002 are examined using the Palmer Drought Severity Index (PDSI) estimated from tree ring data and correlated with reconstructed annual low flows. In the Delaware Basin, the most severe drought in nearly a century occurred during 1995–2002 as the Brandywine River, Delaware's largest surface water supply, ran dry at its mouth and declined to the lowest flow on record since 1912. To evaluate the long‐term context of the 1995–2002 droughts given a variable hydroclimate, tree ring and PDSI data were correlated to reconstruct flows along the river to 1600, the beginning of European exploration to the Delaware Bay. Reconstructed PDSI and low flows were fit using general extreme value (GEV) distributions to estimate drought frequency. Some variability is present as reconstructed low flows tend to overestimate recorded streamflow in severe dry years, a finding reported by others. Some uncertainty appears in the correlations as the coefficient of multiple determination (CRSQ) between recorded and estimated PDSI from tree ring data is 0.50–0.54, a level of variance considered to be “quite good,” and the coefficient of determination (r2) between PDSI and low flow is 0.52. Given the uncertainty, PDSI and reconstructed low flow data both agree that the most extreme drought in 400 years occurred during 1635, and the drought of 1995–2000 was historically extreme with differences only in the degree of severity. On the basis of PDSI, the 2002, 1999, and 1995 droughts were the sixth, twelfth, and seventeenth most severe in 400 years with frequencies of once every 50, 33, and 16 years, respectively. Based on low flow, the 2002, 1999, and 1995 droughts were the second, fourth, and ninth most severe since 1600 with frequencies of once every 200, 100, and 50 years, respectively. The record drought of 2002 has a low probability of reoccurring in any given year (2.0% by PDSI and 0.5% by low flow), but droughts nearly as severe have occurred during the 1630s, 1680s, 1820s, 1840s, 1860s, 1930s, 1940s, and 1960s. Increased intensities of drought low flows in Delaware during the late twentieth century through 2002 were coincident with population growth, watershed urbanization, and atmospheric warming although these associations were not correlated and further study is needed. Over 400 years of tree ring, PDSI, and reconstructed streamflow data indicate that the Delaware Basin record drought of 1995–2002 was a historically severe event with important implications for water supply and drought management. Droughts more severe than the record 2002 event have occurred in the past, and droughts may become even more intense should watershed urbanization and atmospheric warming continue in the future.
Modeling the flow of glaciers in steep terrains: The integrated second‐order shallow ice approximation (iSOSIA)
Authors: Egholm David L. , Knudsen Mads F. , Clark Chris D. , Lesemann Jerome E.
Published: May 2011

The rugged topography of mountain ranges represents a special challenge to computational ice sheet models simulating past or present glaciations. In mountainous regions, the topography steers glaciers through relatively narrow and steep valleys, and as a consequence hereof, the flow rate of alpine‐style glaciers varies significantly at length scales comparable to that of the topography. Localized flow rate undulations generate longitudinal and transverse stress gradients within the ice, which, in turn, are of known importance to the flow itself, whether by internal deformation of the ice or by basal sliding, and to the interaction with topography through glacial erosion. Standard models capable of simulating mountain range–scale glaciations build on the so‐called shallow ice approximation, which, among other parameters, neglects the longitudinal and transverse stress gradients, and therefore fails to capture the full effects of the rugged topography and related feedbacks between erosion by glacial sliding and the extent and style of glaciation. Here we present and test a new depth‐integrated model framework which, on the one hand, takes into account the “higher‐order” effects related to steep and rugged bed topography while it still, on the other hand, provides the computational efficiency needed for three‐dimensional simulations of glaciation and landscape evolution in response to, for example, long‐term climate variations. The model framework (integrated second‐order shallow ice approximation (iSOSIA)) is based on depth integration of the second‐order shallow ice approximation. Although depth integration is not guaranteed to maintain so‐called second‐order accuracy, the results of computational benchmark experiments show that iSOSIA, in spite of its efficient depth‐integrated structure, performs well in situations with steep and rapidly undulating bed topography.
Patterns and timing of exhumation and deformation in the Eastern Cordillera of NW Argentina revealed by (U‐Th)/He thermochronology
Authors: Carrapa Barbara , Trimble John D. , Stockli Daniel F.
Published: May 2011

The Eastern Cordillera (EC) and related ranges of Bolivia and Argentina exhibit a wide variety of structural features, both thick and thin skinned, that make this region a prime area to study the evolution of these two contrasting styles. Using a combination of structural, geochronological, and thermochronological techniques, this study investigates how and in what order the various structures of the Argentinean EC from 25 to 26°S have developed during the Cenozoic. New mapping in the Angastaco area preserves one of the thickest Cenozoic stratigraphic sections and records a complex structural evolution during the Neogene, characterized by inversion of Cretaceous Salta Rift structures. Detrital zircon U‐Pb geochronology combined with stratigraphic and structural features typical of synsedimentary deformation constrains the age of orgenic growth in the area to ∼14 Ma. Detrital apatite (U‐Th)/He thermochronology on samples collected across the width of the southernmost EC at this latitude document an eastward younging of ages interpreted as the result of sequential eastward propagation of exhumation (and inferred deformation) from ∼14 to 3 Ma at a rate of ∼8.3 mm/a. Our data, when compared with existing data, show that the Puna Plateau of NW Argentina was exhuming and deforming at the same time as the EC and inter‐Andean regions of Bolivia, suggesting that the deformation front connects along strike despite of the differences in structural style. Whereas the deformation front reached the sub‐Andes of Bolivia by ∼10 Ma, deformation localized in the EC of NW Argentina until ∼4 Ma. Rates of propagation through the whole region seem to be quasi‐uniform regardless of different structural styles.
Gas flow to a barometric pumping well in a multilayer unsaturated zone
Authors: You Kehua , Zhan Hongbin , Li Jian
Published: May 2011

When an open well is installed in an unsaturated zone, gas can flow between the subsurface and the well depending on the gas pressure gradient near the well. This well is called a barometric pumping well (BPW). Quantifying gas flow rate to and from a BPW is indispensable to optimize the passive soil vapor extraction in remediation of volatile organic compounds in the unsaturated zone. This study presents a two‐dimensional (2‐D) semianalytical solution for a multilayer unsaturated zone (ML solution) to determine gas flow rate to and from a BPW. The gas flow rate is approximated by a decomposing method frequently used in previous studies, that is, first solving the one‐dimensional (1‐D) vertical flow equation in response to the surface barometric pressure fluctuations and then superimposing this solution on that of the 1‐D horizontally radial flow equation. The error induced by this approximation is quantified by a 2‐D numerical simulation for the first time in this study. Results show that the maximum error induced is 20% at the peak flow rates. The ML solution is demonstrated to be sufficient for predicting subsurface gas pressure and gas flow rate in a multilayer unsaturated zone by the barometric pumping test at the Hanford site.
Ultrastructural localization of highly variable 185/333 immune response proteins in the coelomocytes of the sea urchin, Heliocidaris erythrogramma
Authors: Dheilly Nolwenn M , Birch Debra , Nair Sham V , Raftos David A
Published: May 2011

The 185/333 proteins of sea urchins represent a family of highly variable immune response molecules with unknown functions. In this study, we show that 185/333 proteins are expressed by three cell types: amoebocytes, colourless spherule cells and gut‐associated amoebocytes. A sub‐population of amoebocytes express 185/333 proteins on the membranes of vesicles emanating from the trans‐Golgi and which later fuse with the plasma membranes of the cells. The previously uncharacterized gut‐associated amoebocytes also show a high level of 185/333 protein expression on their internal vesicles and plasma membranes. Colourless spherule cells contain 185/333 proteins within large spherules (specialized intracellular vesicles). In the presence of bacteria and yeast, the ultrastucture of colourless spherule cells changes and 185/333 proteins disappear. In contrast, 185/333 proteins were not found in the phagosomes of coelomocytes. The 185/333‐positive gut amoebocytes were often associated with anuclear bodies, which appeared to incorporate material of microbial origin that was surrounded by 185/333 proteins. The association between 185/333 proteins on gut amoebocytes and anuclear bodies suggests that these proteins may be involved in the phagocytosis of microbes in the gut epithelium.
Border versus Boundary at La Frontera
Authors: Casey Edward S
Published: May 2011

In this essay I discuss the complex and evolving situation at La Frontera, the US – Mexico border. I do so in light of my current research on the intervention of edges in human experiences. In that research, I distinguish several basic types of edge, such as rims, frames, and margins. Two of these types are of particular relevance to the circumstance at La Frontera: borders and boundaries. I identify certain primary differences between these two kinds of edge in order to illuminate the earlier history of La Frontera as well as what is now happening at this vexed site. I take up issues of mapping the border, the nature of the borderline, borderlands, and especially the presence of the massive wall that has been constructed along considerable portions of La Frontera. Implications for basic issues of being versus becoming in matters of society and space conclude the piece.
Fog-Bound: Aerial Space and the Elemental Entanglements of Body-with-World
Authors: Martin Craig
Published: May 2011

A simple journey through a fog-bound shoreline. This paper reflects on such a journey to investigate the relationship between aerial space and the elemental relational materialism produced by fog. It takes the experience of fog as its conceptual pivot, using this ‘indexing’ of air to argue for a reconsideration of the visual mechanisms of aerial space. As a phenomenon, the presence of fog generates a variety of distillations: tellingly, for this paper, it confiscates the horizon on a temporary basis, forestalling the perception of this visible line or ground of calibration. It is the loss of perceivable distance through the opacity of fog that strands us in the momentary instant of disorientation. The initial experience of disorientation is, however, set within a more complex agenda that acknowledges the connective potential of fog to deepen the relationship between vision, distance, and embodied immersion in aerial space. In particular, I address Casey's work on the incoming power of place and the outgoing function of the body to argue that fog acts as a gathering-force, intensifying the immanent entanglements of body with world.
How social influence can undermine the wisdom of crowd effect
Authors: Lorenz Jan , Rauhut Heiko , Schweitzer Frank , Helbing Dirk
Published: May 2011

Social groups can be remarkably smart and knowledgeable when their averaged judgements are compared with the judgements of individuals. Already Galton [Galton F (1907)
Nature
75:7] found evidence that the median estimate of a group can be more accurate than estimates of experts. This wisdom of crowd effect was recently supported by examples from stock markets, political elections, and quiz shows [Surowiecki J (2004)
The Wisdom of Crowds
]. In contrast, we demonstrate by experimental evidence (
N
= 144) that even mild social influence can undermine the wisdom of crowd effect in simple estimation tasks. In the experiment, subjects could reconsider their response to factual questions after having received average or full information of the responses of other subjects. We compare subjects’ convergence of estimates and improvements in accuracy over five consecutive estimation periods with a control condition, in which no information about others’ responses was provided. Although groups are initially “wise,” knowledge about estimates of others narrows the diversity of opinions to such an extent that it undermines the wisdom of crowd effect in three different ways. The “social influence effect” diminishes the diversity of the crowd without improvements of its collective error. The “range reduction effect” moves the position of the truth to peripheral regions of the range of estimates so that the crowd becomes less reliable in providing expertise for external observers. The “confidence effect” boosts individuals’ confidence after convergence of their estimates despite lack of improved accuracy. Examples of the revealed mechanism range from misled elites to the recent global financial crisis.
Current drivers and future directions of global livestock disease dynamics
Authors: Perry Brian D. , Grace Delia , Sones Keith
Published: May 2011

We review the global dynamics of livestock disease over the last two decades. Our imperfect ability to detect and report disease hinders assessment of trends, but we suggest that, although endemic diseases continue their historic decline in wealthy countries, poor countries experience static or deteriorating animal health and epidemic diseases show both regression and expansion. At a mesolevel, disease is changing in terms of space and host, which is illustrated by bluetongue, Lyme disease, and West Nile virus, and it is also emerging, as illustrated by highly pathogenic avian influenza and others. Major proximate drivers of change in disease dynamics include ecosystem change, ecosystem incursion, and movements of people and animals; underlying these are demographic change and an increasing demand for livestock products. We identify three trajectories of global disease dynamics: (
i
) the worried well in developed countries (demanding less risk while broadening the circle of moral concern), (
ii
) the intensifying and market-orientated systems of many developing countries, where highly complex disease patterns create hot spots for disease shifts, and (
iii
) the neglected cold spots in poor countries, where rapid change in disease dynamics is less likely but smallholders and pastoralists continue to struggle with largely preventable and curable livestock diseases.
Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease
Authors: Cayzac Sebastien , Delcasso Sebastien , Paz Vietminh , Jeantet Yannick , Cho Yoon H.
Published: May 2011

In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre–motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.
Structural topology of phospholamban pentamer in lipid bilayers by a hybrid solution and solid-state NMR method
Authors: Verardi Raffaello , Shi Lei , Traaseth Nathaniel J. , Walsh Naomi , Veglia Gianluigi
Published: May 2011

Phospholamban (PLN) is a type II membrane protein that inhibits the sarcoplasmic reticulum Ca
2+
-ATPase (SERCA), thereby regulating calcium homeostasis in cardiac muscle. In membranes, PLN forms pentamers that have been proposed to function either as a storage for active monomers or as ion channels. Here, we report the T-state structure of pentameric PLN solved by a hybrid solution and solid-state NMR method. In lipid bilayers, PLN adopts a
pinwheel
topology with a narrow hydrophobic pore, which excludes ion transport. In the T state, the cytoplasmic amphipathic helices (domains Ia) are absorbed into the lipid bilayer with the transmembrane domains arranged in a left-handed coiled-coil configuration, crossing the bilayer with a tilt angle of approximately 11° with respect to the membrane normal. The tilt angle difference between the monomer and pentamer is approximately 13°, showing that intramembrane helix–helix association forces dominate over the hydrophobic mismatch, driving the overall topology of the transmembrane assembly. Our data reveal that both topology and function of PLN are shaped by the interactions with lipids, which fine-tune the regulation of SERCA.
Autoregulatory and repressive inputs localize
Hydra Wnt3
to the head organizer
Authors: Nakamura Yukio , Tsiairis Charisios D. , Özbek Suat , Holstein Thomas W.
Published: May 2011

Polarized Wnt signaling along the primary body axis is a conserved property of axial patterning in bilaterians and prebilaterians, and depends on localized sources of Wnt ligands. However, the mechanisms governing the localized
Wnt
expression that emerged early in evolution are poorly understood. Here we find in the cnidarian
Hydra
that two functionally distinct
cis
-regulatory elements control the head organizer-associated
Hydra Wnt3
(
HyWnt3
). An autoregulatory element, which mediates direct inputs of Wnt/β-catenin signaling, highly activates
HyWnt3
transcription in the head region. In contrast, a repressor element is necessary and sufficient to restrict the activity of the autoregulatory element, thereby allowing the organizer-specific expression. Our results reveal that a combination of autoregulation and repression is crucial for establishing a Wnt-expressing organizing center in a basal metazoan. We suggest that this transcriptional control is an evolutionarily old strategy in the formation of Wnt signaling centers and metazoan axial patterning.
Direct development of neurons within foregut endoderm of sea urchin embryos
Authors: Wei Zheng , Angerer Robert C. , Angerer Lynne M.
Published: May 2011

Although it is well established that neural cells are ectodermal derivatives in bilaterian animals, here we report the surprising discovery that some of the pharyngeal neurons of sea urchin embryos develop de novo from the endoderm. The appearance of these neurons is independent of mouth formation, in which the stomodeal ectoderm joins the foregut. The neurons do not derive from migration of ectoderm cells to the foregut, as shown by lineage tracing with the photoactivatable protein KikGR. Their specification and development depend on expression of Nkx3-2, which in turn depends on Six3, both of which are expressed in the foregut lineage. SoxB1, which is closely related to the vertebrate Sox factors that support a neural precursor state, is also expressed in the foregut throughout gastrulation, suggesting that this region of the fully formed archenteron retains an unexpected pluripotency. Together, these results lead to the unexpected conclusion that, within a cell lineage already specified to be endoderm by a well-established gene regulatory network [Peter IS, Davidson EH (2010)
Dev Biol
340:188–199], there also operates a Six3/Nkx3-2–dependent pathway required for the de novo specification of some of the neurons in the pharynx. As a result, neuroendoderm precursors form in the foregut aided by retention of a SoxB1-dependent pluripotent state.
Clay mineral continental amplifier for marine carbon sequestration in a greenhouse ocean
Authors: Kennedy Martin J. , Wagner Thomas
Published: May 2011

The majority of carbon sequestration at the Earth’s surface occurs in marine continental margin settings within fine-grained sediments whose mineral properties are a function of continental climatic conditions. We report very high mineral surface area (MSA) values of 300 and 570 m
2
 g in Late Cretaceous black shales from Ocean Drilling Program site 959 of the Deep Ivorian Basin that vary on subcentennial time scales corresponding with abrupt increases from approximately 3 to approximately 18% total organic carbon (TOC). The observed MSA changes with TOC across multiple scales of variability and on a sample-by-sample basis (centimeter scale), provides a rigorous test of a hypothesized influence on organic carbon burial by detrital clay mineral controlled MSA. Changes in TOC also correspond with geochemical and sedimentological evidence for water column anoxia. Bioturbated intervals show a lower organic carbon loading on mineral surface area of 0.1 mg-OC m
-2
when compared to 0.4 mg-OC m
-2
for laminated and sulfidic sediments. Although either anoxia or mineral surface protection may be capable of producing TOC of < 5%, when brought together they produced the very high TOC (10–18%) apparent in these sediments. This nonlinear response in carbon burial resulted from minor precession-driven changes of continental climate influencing clay mineral properties and runoff from the African continent. This study identifies a previously unrecognized land–sea connection among continental weathering, clay mineral production, and anoxia and a nonlinear effect on marine carbon sequestration during the Coniacian-Santonian Oceanic Anoxic Event 3 in the tropical eastern Atlantic.
Human Mu Opioid Receptor (
OPRM1
A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers
Authors: Ray Riju , Ruparel Kosha , Newberg Andrew , Wileyto E. Paul , Loughead James W. , Divgi Chaitanya , Blendy Julie A. , Logan Jean , Zubieta Jon-Kar , Lerman Caryn
Published: May 2011

Evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (
OPRM1
A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of
OPRM1
A118G genotype on MOR binding potential (BP
ND
or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [
11
C]carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type
OPRM1
A allele exhibited significantly higher levels of MOR BP
ND
than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BP
ND
difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.
T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters
Authors: Manz Boryana N. , Jackson Bryan L. , Petit Rebecca S. , Dustin Michael L. , Groves Jay
Published: May 2011

T cells react to extremely small numbers of activating agonist peptides. Spatial organization of T-cell receptors (TCR) and their peptide-major histocompatibility complex (pMHC) ligands into microclusters is correlated with T-cell activation. Here we have designed an experimental strategy that enables control over the number of agonist peptides per TCR cluster, without altering the total number engaged by the cell. Supported membranes, partitioned with grids of barriers to lateral mobility, provide an effective way of limiting the total number of pMHC ligands that may be assembled within a single TCR cluster. Observations directly reveal that restriction of pMHC content within individual TCR clusters can decrease T-cell sensitivity for triggering initial calcium flux at fixed total pMHC density. Further analysis suggests that triggering thresholds are determined by the number of activating ligands available to individual TCR clusters, not by the total number encountered by the cell. Results from a series of experiments in which the overall agonist density and the maximum number of agonist per TCR cluster are independently varied in primary T cells indicate that the most probable minimal triggering unit for calcium signaling is at least four pMHC in a single cluster for this system. This threshold is unchanged by inclusion of coagonist pMHC, but costimulation of CD28 by CD80 can modulate the threshold lower.
Hyperspectral imaging of cuttlefish camouflage indicates good color match in the eyes of fish predators
Authors: Chiao Chuan-Chin , Wickiser J. Kenneth , Allen Justine J. , Genter Brock , Hanlon Roger T.
Published: May 2011

Camouflage is a widespread phenomenon throughout nature and an important antipredator tactic in natural selection. Many visual predators have keen color perception, and thus camouflage patterns should provide some degree of color matching in addition to other visual factors such as pattern, contrast, and texture. Quantifying camouflage effectiveness in the eyes of the predator is a challenge from the perspectives of both biology and optical imaging technology. Here we take advantage of hyperspectral imaging (HSI), which records full-spectrum light data, to simultaneously visualize color match and pattern match in the spectral and the spatial domains, respectively. Cuttlefish can dynamically camouflage themselves on any natural substrate and, despite their colorblindness, produce body patterns that appear to have high-fidelity color matches to the substrate when viewed directly by humans or with RGB images. Live camouflaged cuttlefish on natural backgrounds were imaged using HSI, and subsequent spectral analysis revealed that most reflectance spectra of individual cuttlefish and substrates were similar, rendering the color match possible. Modeling color vision of potential di- and trichromatic fish predators of cuttlefish corroborated the spectral match analysis and demonstrated that camouflaged cuttlefish show good color match as well as pattern match in the eyes of fish predators. These findings (
i
) indicate the strong potential of HSI technology to enhance studies of biological coloration and (
ii
) provide supporting evidence that cuttlefish can produce color-coordinated camouflage on natural substrates despite lacking color vision.
In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract
Authors: Fuhrmann Gregor , Leroux Jean-Christophe
Published: May 2011

Exogenous enzymes are administered orally to treat several diseases, such as pancreatic insufficiency and lactose intolerance. Due to the proteinaceous nature of enzymes, they are subject to inactivation and/or digestion in the gastrointestinal (GI) tract. Here we describe a convenient fluorescence-based assay to monitor the activity of therapeutic enzymes in real time in vivo in the GI tract. To establish the proof of principle, the assay was applied to proline-specific endopeptidases (PEPs), a group of enzymes recently proposed as adjuvant therapy for celiac disease (a highly prevalent immunogenetic enteropathy). A short PEP-specific peptide sequence which is part of larger immunotoxic sequences of gluten was labeled with a fluorescent dye and a corresponding quencher. Upon enzymatic cleavage, the fluorescence emission was dequenched and detected with an in vivo imaging system. PEPs originating from
Flavobacterium meningosepticum
(FM) and
Myxococcus xanthus
(MX) were evaluated after oral administration in rats. While MX PEP could not cleave the peptide in the stomach, FM PEP showed significant gastric activity reaching 40–60% of the maximal in vivo signal intensity. However, both enzymes produced comparable fluorescence signals in the small intestine. Coadministration of an antacid drug significantly enhanced MX PEP’s gastric activity due to increased pH and/or inhibition of stomach proteases. With this simple procedure, differences in the in vivo performance of PEPs, which could not be identified under in vitro conditions, were detected. This imaging assay could be used to study other oral enzymes in vivo and therefore be instrumental in improving their therapeutic efficiency.
Two-phase dynamics of p53 in the DNA damage response
Authors: Zhang Xiao-Peng , Liu Feng , Wang Wei
Published: May 2011

The tumor suppressor p53 mainly induces cell cycle arrest/DNA repair or apoptosis in the DNA damage response. How to choose between these two outcomes is not fully understood. We proposed a four-module model of the p53 signaling network and associated the network dynamics with cellular outcomes after ionizing radiation. We found that the cellular response is mediated by both the level and posttranslational modifications of p53 and that p53 is activated in a progressive manner. First, p53 is partially activated by primary modifications such as phosphorylation at Ser-15/20 to induce cell cycle arrest, with its level varying in a series of pulses. If the damage cannot be fixed after a critical number of p53 pulses, then p53 is fully activated by further modifications such as phosphorylation at Ser-46 to trigger apoptosis, with its concentration switching to rather high levels. Thus, p53 undergoes a two-phase response in irreparably damaged cells. Such combinations of pulsatile and switch-like behaviors of p53 may represent a flexible and efficient control mode, avoiding the premature apoptosis and promoting the execution of apoptosis. In our model, p53 pulses are recurrently driven by ataxia telangiectasia mutated (ATM) pulses triggered by DNA damage. The p53-Mdm2 and ATM-p53-Wip1 negative feedback loops are responsible for p53 pulses, whereas the switching behavior occurs when the p53-PTEN-Akt-Mdm2 positive feedback loop becomes dominant. Our results suggest that a sequential predominance of distinct feedback loops may elicit multiple-phase dynamical behaviors. This work provides a new mechanism for p53 dynamics and cell fate decision.
KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP
2
) sensitivity of I

Ks

to modulate channel activity
Authors: Li Yang , Zaydman Mark A. , Wu Dick , Shi Jingyi , Guan Michael , Virgin-Downey Brett , Cui Jianmin
Published: May 2011

Phosphatidylinositol 4,5-bisphosphate (PIP
2
) is necessary for the function of various ion channels. The potassium channel, I

Ks

, is important for cardiac repolarization and requires PIP
2
to activate. Here we show that the auxiliary subunit of I

Ks

, KCNE1, increases PIP
2
sensitivity 100-fold over channels formed by the pore-forming KCNQ1 subunits alone, which effectively amplifies current because native PIP
2
levels in the membrane are insufficient to activate all KCNQ1 channels. A juxtamembranous site in the KCNE1 C terminus is a key structural determinant of PIP
2
sensitivity. Long QT syndrome associated mutations of this site lower PIP
2
affinity, resulting in reduced current. Application of exogenous PIP
2
to these mutants restores wild-type channel activity. These results reveal a vital role of PIP
2
for KCNE1 modulation of I

Ks

channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.
Continuous polo-like kinase 1 activity regulates diffusion to maintain centrosome self-organization during mitosis
Authors: Mahen Robert , Jeyasekharan Anand D. , Barry Nicholas P. , Venkitaraman Ashok R.
Published: May 2011

Whether mitotic structures like the centrosome can self-organize from the regulated mobility of their dynamic protein components remains unclear. Here, we combine fluorescence spectroscopy and chemical genetics to study in living cells the diffusion of polo-like kinase 1 (PLK1), an enzyme critical for centrosome maturation at the onset of mitosis. The cytoplasmic diffusion of a functional EGFP-PLK1 fusion correlates inversely with known changes in its enzymatic activity during the cell cycle. Specific EGFP-PLK1 inhibition using chemical genetics enhances mobility, as do point mutations inactivating the polo-box or kinase domains responsible for substrate recognition and catalysis. Spatial mapping of EGFP-PLK1 diffusion across living cells, using raster image correlation spectroscopy and line scanning, detects regions of low mobility in centrosomes. These regions exhibit characteristics of increased transient recursive EGFP-PLK1 binding, distinct from the diffusion of stable EGFP-PLK1–containing complexes in the cytoplasm. Chemical genetic suppression of mitotic EGFP-PLK1 activity, even after centrosome maturation, causes defects in centrosome structure, which recover when activity is restored. Our findings imply that continuous PLK1 activity during mitosis maintains centrosome self-organization by a mechanism dependent on its reaction and diffusion, suggesting a model for the formation of stable mitotic structures using dynamic protein kinases.
Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators
Authors: Owens Philip , Pickup Michael W. , Novitskiy Sergey V. , Chytil Anna , Gorska Agnieszka E. , Aakre Mary E. , West James , Moses Harold L.
Published: May 2011

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induce growth inhibition in carcinoma cells as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers and may have tumor suppressive and promoting effects. We sought to determine whether disruption of the BMP receptor 2 (BMPR2) would alter mammary tumor progression in mice that express the Polyoma middle T antigen. Mice expressing Polyoma middle T antigen under the mouse mammary tumor virus promoter were combined with mice that have doxycycline-inducible expression of a dominant-negative (DN) BMPR2. We did not observe any differences in tumor latency. However, mice expressing the BMPR2-DN had a fivefold increase in lung metastases. We characterized several cell autonomous changes and found that BMPR2-DN–expressing tumor cells had higher rates of proliferation. We also identified unique changes in inflammatory cells and secreted chemokines/cytokines that accompanied BMPR2-DN–expressing tumors. By immunohistochemistry, it was found that BMPR2-DN primary tumors and metastases had an altered reactive stroma, indicating specific changes in the tumor microenvironment. Among the changes we discovered were increased myeloid derived suppressor cells and the chemokine CCL9. BMP was shown to directly regulate CCL9 expression. We conclude that BMPR2 has tumor-suppressive function in mammary epithelia and microenvironment and that disruption can accelerate mammary carcinoma metastases.
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling
Authors: Dávalos Alberto , Goedeke Leigh , Smibert Peter , Ramírez Cristina M. , Warrier Nikhil P. , Andreo Ursula , Cirera-Salinas Daniel , Rayner Katey , Suresh Uthra , Pastor-Pareja José Carlos , Esplugues Enric , Fisher Edward A. , Penalva Luiz O. F. , Moore Kathryn J. , Suárez Yajaira , Lai Eric C. , Fernández-Hernando Carlos
Published: May 2011

Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs
hsa-miR-33a
and
hsa-miR-33b
are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine
O
-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.
Isocyanic acid in the atmosphere and its possible link to smoke-related health effects
Authors: Roberts James M. , Veres Patrick R. , Cochran Anthony K. , Warneke Carsten , Burling Ian R. , Yokelson Robert J. , Lerner Brian , Gilman Jessica B. , Kuster William C. , Fall Ray , de Gouw Joost
Published: May 2011

We measured isocyanic acid (HNCO) in laboratory biomass fires at levels up to 600 parts per billion by volume (ppbv), demonstrating that it has a significant source from pyrolysis/combustion of biomass. We also measured HNCO at mixing ratios up to 200 pptv (parts-per-trillion by volume) in ambient air in urban Los Angeles, CA, and in Boulder, CO, during the recent 2010 Fourmile Canyon fire. Further, our measurements of aqueous solubility show that HNCO is highly soluble, as it dissociates at physiological pH. Exposure levels > 1 ppbv provide a direct source of isocyanic acid and cyanate ion (NCO
-
) to humans at levels that have recognized health effects: atherosclerosis, cataracts, and rheumatoid arthritis, through the mechanism of protein carbamylation. In addition to the wildland fire and urban sources, we observed HNCO in tobacco smoke, HNCO has been reported from the low-temperature combustion of coal, and as a by-product of urea-selective catalytic reduction (SCR) systems that are being phased-in to control on-road diesel NO

x

emissions in the United States and the European Union. Given the current levels of exposure in populations that burn biomass or use tobacco, the expected growth in biomass burning emissions with warmer, drier regional climates, and planned increase in diesel SCR controls, it is imperative that we understand the extent and effects of this HNCO exposure.
Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance
Authors: St. John Ashley L. , Rathore Abhay P. S. , Yap Han , Ng Mah-Lee , Metcalfe Dean D. , Vasudevan Subhash G. , Abraham Soman N.
Published: May 2011

A wealth of evidence supports the essential contributions of mast cells (MCs) to immune defense against bacteria and parasites; however, the role of MCs in viral infections has not been defined. We now report that rodent, monkey, and human MCs are able to detect dengue virus (DENV), a lymphotropic, enveloped, single-stranded, positive-sense RNA virus that results in MC activation and degranulation. We observe that the response of MCs to DENV also involves the activation of antiviral intracellular host response pathways, melanoma differentiation-associated gene 5 (MDA5) and retinoic acid inducible gene 1 (RIG-I), and the de novo transcription of cytokines, including TNF-α and IFN-α, and chemokines, such as CCL5, CXCL12, and CX3CL1. This multifaceted response of MCs to DENV is consequential to the containment of DENV in vivo because, after s.c. infection, MC-deficient mice show increased viral burden within draining lymph nodes, which are known to be targeted organs during DENV spread, compared with MC-sufficient mice. This containment of DENV is linked to the MC-driven recruitment of natural killer and natural killer T cells into the infected skin. These findings support expanding the defined role of immunosurveillance by MCs to include viral pathogens.
NF-κB dysregulation in microRNA-146a–deficient mice drives the development of myeloid malignancies
Authors: Zhao Jimmy L. , Rao Dinesh S. , Boldin Mark P. , Taganov Konstantin D. , O'Connell Ryan M. , Baltimore David
Published: May 2011

MicroRNA miR-146a has been implicated as a negative feedback regulator of NF-κB activation. Knockout of the
miR-146a
gene in C57BL/6 mice leads to histologically and immunophenotypically defined myeloid sarcomas and some lymphomas. The sarcomas are transplantable to immunologically compromised hosts, showing that they are true malignancies. The animals also exhibit chronic myeloproliferation in their bone marrow. Spleen and marrow cells show increased transcription of NF-κB–regulated genes and tumors have higher nuclear p65. Genetic ablation of NF-κB p50 suppresses the myeloproliferation, showing that dysregulation of NF-κB is responsible for the myeloproliferative disease.