bluuebunny/crossref_metadata_2025 huggingface dataset:
Science in support of the
Deepwater Horizon
response
Authors: Lubchenco Jane , McNutt Marcia K. , Dreyfus Gabrielle , Murawski Steven A. , Kennedy David M. , Anastas Paul T. , Chu Steven , Hunter Tom
Published: December 2012

This introduction to the Special Feature presents the context for science during the
Deepwater Horizon
oil spill response, summarizes how scientific knowledge was integrated across disciplines and statutory responsibilities, identifies areas where scientific information was accurate and where it was not, and considers lessons learned and recommendations for future research and response. Scientific information was integrated within and across federal and state agencies, with input from nongovernmental scientists, across a diverse portfolio of needs—stopping the flow of oil, estimating the amount of oil, capturing and recovering the oil, tracking and forecasting surface oil, protecting coastal and oceanic wildlife and habitat, managing fisheries, and protecting the safety of seafood. Disciplines involved included atmospheric, oceanographic, biogeochemical, ecological, health, biological, and chemical sciences, physics, geology, and mechanical and chemical engineering. Platforms ranged from satellites and planes to ships, buoys, gliders, and remotely operated vehicles to laboratories and computer simulations. The unprecedented response effort depended directly on intense and extensive scientific and engineering data, information, and advice. Many valuable lessons were learned that should be applied to future events.
A conserved molecular basis for photoperiod adaptation in two temperate legumes
Authors: Weller James L. , Liew Lim Chee , Hecht Valérie F. G. , Rajandran Vinodan , Laurie Rebecca E. , Ridge Stephen , Wenden Bénédicte , Vander Schoor Jacqueline K. , Jaminon Odile , Blassiau Christelle , Dalmais Marion , Rameau Catherine , Bendahmane Abdelhafid , Macknight Richard C. , Lejeune-Hénaut Isabelle
Published: December 2012

Legumes were among the first plant species to be domesticated, and accompanied cereals in expansion of agriculture from the Fertile Crescent into diverse environments across the Mediterranean basin, Europe, Central Asia, and the Indian subcontinent. Although several recent studies have outlined the molecular basis for domestication and eco-geographic adaptation in the two main cereals from this region, wheat and barley, similar questions remain largely unexplored in their legume counterparts. Here we identify two major loci controlling differences in photoperiod response between wild and domesticated pea, and show that one of these,
HIGH RESPONSE TO PHOTOPERIOD
(
HR
), is an ortholog of
EARLY FLOWERING 3
(
ELF3
), a gene involved in circadian clock function. We found that a significant proportion of flowering time variation in global pea germplasm is controlled by
HR
, with a single, widespread functional variant conferring altered circadian rhythms and the reduced photoperiod response associated with the spring habit. We also present evidence that
ELF3
has a similar role in lentil, another major legume crop, with a distinct functional variant contributing to reduced photoperiod response in cultivars widely deployed in short-season environments. Our results identify the factor likely to have permitted the successful prehistoric expansion of legume cultivation to Northern Europe, and define a conserved genetic basis for major adaptive changes in flowering phenology and growth habit in an important crop group.
Motor transport of self-assembled cargos in crowded environments
Authors: Conway Leslie , Wood Derek , Tüzel Erkan , Ross Jennifer L.
Published: December 2012

Intracellular transport of cargo particles is performed by multiple motors working in concert. However, the mechanism of motor association to cargos is unknown. It is also unknown how long individual motors stay attached, how many are active, and how multimotor cargos would navigate a densely crowded filament with many other motors. Prior theoretical and experimental biophysical model systems of intracellular cargo have assumed fixed teams of motors transporting along bare microtubules or microtubules with fixed obstacles. Here, we investigate a regime of cargos transporting along microtubules crowded with free motors. Furthermore, we use cargos that are able to associate or dissociate motors as it translocates. We perform in vitro motility reconstitution experiments with high-resolution particle tracking. Our model system consists of a quantum dot cargo attached to kinesin motors, and additional free kinesin motors that act as traffic along the microtubule. Although high densities of kinesin motors hinder forward motion, resulting in a lower velocity, the ability to associate motors appears to enhance the run length and attachment time of the quantum dot, improving overall cargo transport. These results suggest that cargos that can associate new motors as they transport could overcome traffic jams.
Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice
Authors: Sadakata Tetsushi , Shinoda Yo , Oka Megumi , Sekine Yukiko , Sato Yumi , Saruta Chihiro , Miwa Hideki , Tanaka Mika , Itohara Shigeyoshi , Furuichi Teiichi
Published: December 2012

Ca
2
+
-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Here, we generated
Caps2
-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in social- and anxiety-related behaviors. Together, these findings represent a unique mouse model of a molecular mechanism linking BDNF-mediated coordination of brain development to autism-related behaviors and patient genotype.
Full dynamics of a red blood cell in shear flow
Authors: Dupire Jules , Socol Marius , Viallat Annie
Published: December 2012

At the cellular scale, blood fluidity and mass transport depend on the dynamics of red blood cells in blood flow, specifically on their deformation and orientation. These dynamics are governed by cellular rheological properties, such as internal viscosity and cytoskeleton elasticity. In diseases in which cell rheology is altered genetically or by parasitic invasion or by changes in the microenvironment, blood flow may be severely impaired. The nonlinear interplay between cell rheology and flow may generate complex dynamics, which remain largely unexplored experimentally. Under simple shear flow, only two motions, “tumbling” and “tank-treading,” have been described experimentally and relate to cell mechanics. Here, we elucidate the full dynamics of red blood cells in shear flow by coupling two videomicroscopy approaches providing multidirectional pictures of cells, and we analyze the mechanical origin of the observed dynamics. We show that contrary to common belief, when red blood cells flip into the flow, their orientation is determined by the shear rate. We discuss the “rolling” motion, similar to a rolling wheel. This motion, which permits the cells to avoid energetically costly deformations, is a true signature of the cytoskeleton elasticity. We highlight a hysteresis cycle and two transient dynamics driven by the shear rate: an intermittent regime during the “tank-treading-to-flipping” transition and a Frisbee-like “spinning” regime during the “rolling-to-tank-treading” transition. Finally, we reveal that the biconcave red cell shape is highly stable under moderate shear stresses, and we interpret this result in terms of stress-free shape and elastic buckling.
Eight pairs of descending visual neurons in the dragonfly give wing motor centers accurate population vector of prey direction
Authors: Gonzalez-Bellido Paloma T. , Peng Hanchuan , Yang Jinzhu , Georgopoulos Apostolos P. , Olberg Robert M.
Published: December 2012

Intercepting a moving object requires prediction of its future location. This complex task has been solved by dragonflies, who intercept their prey in midair with a 95% success rate. In this study, we show that a group of 16 neurons, called target-selective descending neurons (TSDNs), code a population vector that reflects the direction of the target with high accuracy and reliability across 360°. The TSDN spatial (receptive field) and temporal (latency) properties matched the area of the retina where the prey is focused and the reaction time, respectively, during predatory flights. The directional tuning curves and morphological traits (3D tracings) for each TSDN type were consistent among animals, but spike rates were not. Our results emphasize that a successful neural circuit for target tracking and interception can be achieved with few neurons and that in dragonflies this information is relayed from the brain to the wing motor centers in population vector form.
Complete fiber structures of complex trimeric autotransporter adhesins conserved in enterobacteria
Authors: Hartmann Marcus D. , Grin Iwan , Dunin-Horkawicz Stanislaw , Deiss Silvia , Linke Dirk , Lupas Andrei N. , Hernandez Alvarez Birte
Published: December 2012

Trimeric autotransporter adhesins (TAAs) are modular, highly repetitive surface proteins that mediate adhesion to host cells in a broad range of Gram-negative pathogens. Although their sizes may differ by more than one order of magnitude, they all follow the same basic head-stalk-anchor architecture, where the head mediates adhesion and autoagglutination, the stalk projects the head from the bacterial surface, and the anchor provides the export function and attaches the adhesin to the bacterial outer membrane after export is complete. In complex adhesins, head and stalk domains may alternate several times before the anchor is reached. Despite extensive sequence divergence, the structures of TAA domains are highly constrained, due to the tight interleaving of their constituent polypeptide chains. We have therefore taken a “domain dictionary” approach to characterize representatives for each domain type by X-ray crystallography and use these structures to reconstruct complete TAA fibers. With SadA from
Salmonella enterica
, EhaG from enteropathogenic
Escherichia coli
(EHEC), and UpaG from uropathogenic
E. coli
(UPEC), we present three representative structures of a complex adhesin that occur in a conserved genomic context in Enterobacteria and is essential in the infection process of uropathogenic
E. coli
. Our work proves the applicability of the dictionary approach to understanding the structure of a class of proteins that are otherwise poorly tractable by high-resolution methods and provides a basis for the rapid and detailed annotation of newly identified TAAs.
How nature can exploit nonspecific catalytic and carbohydrate binding modules to create enzymatic specificity
Authors: Cuskin Fiona , Flint James E. , Gloster Tracey M. , Morland Carl , Baslé Arnaud , Henrissat Bernard , Coutinho Pedro M. , Strazzulli Andrea , Solovyova Alexandra S. , Davies Gideon J. , Gilbert Harry J.
Published: December 2012

Noncatalytic carbohydrate binding modules (CBMs) are components of glycoside hydrolases that attack generally inaccessible substrates. CBMs mediate a two- to fivefold elevation in the activity of endo-acting enzymes, likely through increasing the concentration of the appended enzymes in the vicinity of the substrate. The function of CBMs appended to exo-acting glycoside hydrolases is unclear because their typical endo-binding mode would not fulfill a targeting role. Here we show that the
Bacillus subtilis
exo-acting β-fructosidase SacC, which specifically hydrolyses levan, contains the founding member of CBM family 66 (CBM66). The SacC-derived CBM66 (
Bs
CBM66) targets the terminal fructosides of the major fructans found in nature. The crystal structure of
Bs
CBM66 in complex with ligands reveals extensive interactions with the terminal fructose moiety (Fru-3) of levantriose but only limited hydrophobic contacts with Fru-2, explaining why the CBM displays broad specificity. Removal of
Bs
CBM66 from SacC results in a ∼100-fold reduction in activity against levan. The truncated enzyme functions as a nonspecific β-fructosidase displaying similar activity against β-2,1– and β-2,6–linked fructans and their respective fructooligosaccharides. Conversely, appending
Bs
CBM66 to BT3082, a nonspecific β-fructosidase from
Bacteroides thetaiotaomicron
, confers exolevanase activity on the enzyme. We propose that
Bs
CBM66 confers specificity for levan, a branched fructan, through an “avidity” mechanism in which the CBM and the catalytic module target the termini of different branches of the same polysaccharide molecule. This report identifies a unique mechanism by which CBMs modulate enzyme function, and shows how specificity can be tailored by integrating nonspecific catalytic and binding modules into a single enzyme.
Dendritic upconverting nanoparticles enable in vivo multiphoton microscopy with low-power continuous wave sources
Authors: Esipova Tatiana V. , Ye Xingchen , Collins Joshua E. , Sakadžić Sava , Mandeville Emiri T. , Murray Christopher B. , Vinogradov Sergei A.
Published: December 2012

We report a group of optical imaging probes, comprising upconverting lanthanide nanoparticles (UCNPs) and polyanionic dendrimers. Dendrimers with rigid cores and multiple carboxylate groups at the periphery are able to tightly bind to surfaces of UCNPs pretreated with NOBF
4
, yielding stable, water-soluble, biocompatible nanomaterials. Unlike conventional linear polymers, dendrimers adhere to UCNPs by donating only a fraction of their peripheral groups to the UCNP–surface interactions. The remaining termini make up an interface between the nanoparticle and the aqueous phase, enhancing solubility and offering multiple possibilities for subsequent modification. Using optical probes as dendrimer cores makes it possible to couple the UCNPs signal to analyte-sensitive detection via UCNP-to-chromophore excitation energy transfer (EET). As an example, we demonstrate that UCNPs modified with porphyrin–dendrimers can operate as upconverting ratiometric pH nanosensors. Dendritic UCNPs possess excellent photostability, solubility, and biocompatibility, which make them directly suitable for in vivo imaging. Polyglutamic dendritic UCNPs injected in the blood of a mouse allowed mapping of the cortical vasculature down to 400 μm under the tissue surface, thus demonstrating feasibility of in vivo high-resolution two-photon microscopy with continuous wave (CW) excitation sources. Dendrimerization as a method of solubilization of UCNPs opens up numerous possibilities for use of these unique agents in biological imaging and sensing.
F-actin buckling coordinates contractility and severing in a biomimetic actomyosin cortex
Authors: Murrell Michael P. , Gardel Margaret L.
Published: December 2012

Here we develop a minimal model of the cell actomyosin cortex by forming a quasi-2D cross-linked filamentous actin (F-actin) network adhered to a model cell membrane and contracted by myosin thick filaments. Myosin motors generate both compressive and tensile stresses on F-actin and consequently induce large bending fluctuations, which reduces their effective persistence length to <1 μm. Over a large range of conditions, we show the extent of network contraction corresponds exactly to the extent of individual F-actin shortening via buckling. This demonstrates an essential role of buckling in breaking the symmetry between tensile and compressive stresses to facilitate mesoscale network contraction of up to 80% strain. Portions of buckled F-actin with a radius of curvature ∼300 nm are prone to severing and thus compressive stresses mechanically coordinate contractility with F-actin severing, the initial step of F-actin turnover. Finally, the F-actin curvature acquired by myosin-induced stresses can be further constrained by adhesion of the network to a membrane, accelerating filament severing but inhibiting the long-range transmission of the stresses necessary for network contractility. Thus, the extent of membrane adhesion can regulate the coupling between network contraction and F-actin severing. These data demonstrate the essential role of the nonlinear response of F-actin to compressive stresses in potentiating both myosin-mediated contractility and filament severing. This may serve as a general mechanism to mechanically coordinate contractility and cortical dynamics across diverse actomyosin assemblies in smooth muscle and nonmuscle cells.
Sex-specific mating pheromones in the nematode
Panagrellus redivivus
Authors: Choe Andrea , Chuman Tatsuji , von Reuss Stephan H. , Dossey Aaron T. , Yim Joshua J. , Ajredini Ramadan , Kolawa Adam A. , Kaplan Fatma , Alborn Hans T. , Teal Peter E. A. , Schroeder Frank C. , Sternberg Paul W. , Edison Arthur S.
Published: December 2012

Nematodes use an extensive chemical language based on glycosides of the dideoxysugar ascarylose for developmental regulation (dauer formation), male sex attraction, aggregation, and dispersal. However, no examples of a female- or hermaphrodite-specific sex attractant have been identified to date. In this study, we investigated the pheromone system of the gonochoristic sour paste nematode
Panagrellus redivivus
, which produces sex-specific attractants of the opposite sex. Activity-guided fractionation of the
P. redivivus
exometabolome revealed that males are strongly attracted to ascr#1 (also known as daumone), an ascaroside previously identified from
Caenorhabditis elegans
hermaphrodites. Female
P. redivivus
are repelled by high concentrations of ascr#1 but are specifically attracted to a previously unknown ascaroside that we named dhas#18, a dihydroxy derivative of the known ascr#18 and an ascaroside that features extensive functionalization of the lipid-derived side chain. Targeted profiling of the
P. redivivus
exometabolome revealed several additional ascarosides that did not induce strong chemotaxis. We show that
P. redivivus
females, but not males, produce the male-attracting ascr#1, whereas males, but not females, produce the female-attracting dhas#18. These results show that ascaroside biosynthesis in
P. redivivus
is highly sex-specific. Furthermore, the extensive side chain functionalization in dhas#18, which is reminiscent of polyketide-derived natural products, indicates unanticipated biosynthetic capabilities in nematodes.
Out-of-register β-sheets suggest a pathway to toxic amyloid aggregates
Authors: Liu Cong , Zhao Minglei , Jiang Lin , Cheng Pin-Nan , Park Jiyong , Sawaya Michael R. , Pensalfini Anna , Gou Dawei , Berk Arnold J. , Glabe Charles G. , Nowick James , Eisenberg David
Published: December 2012

Although aberrant protein aggregation has been conclusively linked to dozens of devastating amyloid diseases, scientists remain puzzled about the molecular features that render amyloid fibrils or small oligomers toxic. Here, we report a previously unobserved type of amyloid fibril that tests as cytotoxic: one in which the strands of the contributing β-sheets are out of register. In all amyloid fibrils previously characterized at the molecular level, only in-register β-sheets have been observed, in which each strand makes its full complement of hydrogen bonds with the strands above and below it in the fibril. In out-of-register sheets, strands are sheared relative to one another, leaving dangling hydrogen bonds. Based on this finding, we designed out-of-register β-sheet amyloid mimics, which form both cylindrin-like oligomers and fibrils, and these mimics are cytotoxic. Structural and energetic considerations suggest that out-of-register fibrils can readily convert to toxic cylindrins. We propose that out-of-register β-sheets and their related cylindrins are part of a toxic amyloid pathway, which is distinct from the more energetically favored in-register amyloid pathway.
Reconstructing constructional semantics
Authors: Barðdal Jóhanna , Smitherman Thomas , Bjarnadóttir Valgerður , Danesi Serena , Jenset Gard B. , McGillivray Barbara
Published: December 2012

As the historical linguistic community is well aware, reconstructing semantics is a notoriously difficult undertaking. Such reconstruction has so far mostly been carried out on lexical items, like words and morphemes, and has not been conducted for larger and more complex linguistic units, which intuitively seems to be a more intricate task, especially given the lack of methodological criteria and guidelines within the field. This follows directly from the fact that most current theoretical frameworks are not construction-based, that is, they do not assume that constructions are form-meaning correspondences. In order to meet this challenge, we present an attempt at reconstructing constructional semantics, and more precisely the semantics of the Dative Subject Construction for an earlier stage of Indo-European. For this purpose we employ lexical semantic verb classes in combination with the semantic map model (Barðdal 2007, Barðdal, Kristoffersen & Sveen 2011), showing how incredibly stable semantic fields may remain across long time spans, and how reconstructing such semantic fields may be accomplished.
Cognitive explanations, distributional evidence, and diachrony
Authors: Cristofaro Sonia
Published: December 2012

Cognitively oriented approaches to the study of language standardly use synchronic distributional evidence to make assumptions both about the psychological mechanisms that lead speakers to create particular constructions, and about the components of a speaker’s mental representation of their language. Yet, as synchronic distributional patterns are a result of speciﬁc diachronic processes, any assumption about the psychological mechanisms or types of mental representation underlying particular patterns should take into account the diachronic processes that give rise to these patterns. Based on evidence from different languages and language families, the paper discusses several diachronic processes pertaining to the development of various types of alignment systems and prototype effects in dependent clauses. It is shown that these processes provide no evidence for a number of assumptions about psychological mechanisms and a speaker’s mental representation that have been made on synchronic grounds in order to account for the relevant distributional patterns. It follows that this type of assumptions cannot be inferred directly from synchronic distributional patterns, and should be investigated independently of these patterns.
Influence of Sex and Reproductive Status on Seasonal Movement of Lake Sturgeon in Namakan Reservoir, Minnesota–Ontario
Authors: Shaw Stephanie L. , Chipps Steven R. , Windels Steve K. , Webb Molly A. H. , McLeod Darryl T.
Published: December 2012

We evaluated the influence of sex and reproductive condition on seasonal distribution and movement patterns of Lake Sturgeon Acipenser fulvescens in Namakan Reservoir, Minnesota–Ontario. Blood samples were collected from 133 Lake Sturgeon prior to spawning and plasma concentrations of testosterone and estradiol‐17ß were analyzed using radioimmunoassay. Steroid concentrations were used to determine sex and the reproductive stage of each sturgeon. A subset of 60 adults were implanted with acoustic transmitters prior to spawning in 2007 and 2008. Movement was monitored using an array of 15 stationary receivers covering U.S. and Canadian waters of Namakan Reservoir and its tributaries. Of the monitored sturgeon, there was no significant difference in the minimum distance traveled between sexes or among seasons. Site residency did not differ between sexes but differed significantly among seasons, and Lake Sturgeon of both sexes had higher residency during winter (mean = 24 d). Five females implanted with transmitters were characterized as presumed reproductive and 14 as nonreproductive based on plasma steroid concentrations. In general, movement patterns (i.e., migration) of presumed reproductive females corresponded positively with availability of spawning habitat in tributaries. Moreover, presumed reproductive females traveled greater distances than nonreproductive females, particularly during prespawn, spawning, and fall time periods. Distance traveled by presumed reproductive females was highest in the fall compared with other seasons and may be linked to increased energy requirements during late oogenesis before spawning in spring. Combining movement data with information on Lake Sturgeon reproductive status and habitat suitability provided a robust approach for understanding their seasonal migration patterns and identifying spawning locations.
Use of Dual-Frequency Identification Sonar to Monitor Adult River Herring in a Small Coastal Stream
Authors: Magowan Kevin , Reitsma Joshua , Murphy Diane
Published: December 2012

A standard dual-frequency identification sonar (DIDSON) was deployed in the Herring River, Harwich, Massachusetts, for 3 d in late April 2011 to capture video-like images of migrating adult river herring (alewife Alosa pseudoharengus and blueback herring Alosa aestivalis). Images recorded 24 h a day were used to manually count and assign species based on DIDSON images of fish size, shape, and behavior. From these counts, the run size was estimated to be 1,976–2,059 individuals during the study. At first, river herring often hesitated to swim through the sample area where the weirs and DIDSON were deployed; however, they eventually did pass, often multiple times. This unique hesitation behavior complicated counting efforts, though it was beneficial to discerning species using DIDSON images. In addition, extremely shallow water upstream of the study site, lack of tree cover, and a high threat of avian predation likely contributed to river herring milling activity at the study site. By providing many clear images of river herring, DIDSON proved to be an effective type of sonar with which to monitor and count river herring continuously in a small coastal stream.

Received January 19, 2012; accepted July 30, 2012
Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression
Authors: Ricke Robin M. , Jeganathan Karthik B. , Malureanu Liviu , Harrison Andrew M. , van Deursen Jan M.
Published: December 2012

The mitotic checkpoint protein Bub1 is essential for embryogenesis and survival of proliferating cells, and bidirectional deviations from its normal level of expression cause chromosome missegregation, aneuploidy, and cancer predisposition in mice. To provide insight into the physiological significance of this critical mitotic regulator at a modular level, we generated Bub1 mutant mice that lack kinase activity using a knockin gene-targeting approach that preserves normal protein abundance. In this paper, we uncover that Bub1 kinase activity integrates attachment error correction and mitotic checkpoint signaling by controlling the localization and activity of Aurora B kinase through phosphorylation of histone H2A at threonine 121. Strikingly, despite substantial chromosome segregation errors and aneuploidization, mice deficient for Bub1 kinase activity do not exhibit increased susceptibility to spontaneous or carcinogen-induced tumorigenesis. These findings provide a unique example of a modular mitotic activity orchestrating two distinct networks that safeguard against whole chromosome instability and reveal the differential importance of distinct aneuploidy-causing Bub1 defects in tumor suppression.
KIF14 negatively regulates Rap1a–Radil signaling during breast cancer progression
Authors: Ahmed Syed M. , Thériault Brigitte L. , Uppalapati Maruti , Chiu Catherine W.N. , Gallie Brenda L. , Sidhu Sachdev S. , Angers Stéphane
Published: December 2012

The small GTPase Rap1 regulates inside-out integrin activation and thereby influences cell adhesion, migration, and polarity. Several Rap1 effectors have been described to mediate the cellular effects of Rap1 in a context-dependent manner. Radil is emerging as an important Rap effector implicated in cell spreading and migration, but the molecular mechanisms underlying its functions are unclear. We report here that the kinesin KIF14 associates with the PDZ domain of Radil and negatively regulates Rap1-mediated inside-out integrin activation by tethering Radil on microtubules. The depletion of KIF14 led to increased cell spreading, altered focal adhesion dynamics, and inhibition of cell migration and invasion. We also show that Radil is important for breast cancer cell proliferation and for metastasis in mice. Our findings provide evidence that the concurrent up-regulation of Rap1 activity and increased KIF14 levels in several cancers is needed to reach optimal levels of Rap1–Radil signaling, integrin activation, and cell–matrix adhesiveness required for tumor progression.
Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells
Authors: Nishida Atsushi , Nagahama Kiyotaka , Imaeda Hirotsugu , Ogawa Atsuhiro , Lau Cindy W. , Kobayashi Taku , Hisamatsu Tadakazu , Preffer Frederic I. , Mizoguchi Emiko , Ikeuchi Hiroki , Hibi Toshifumi , Fukuda Minoru , Andoh Akira , Blumberg Richard S. , Mizoguchi Atsushi
Published: December 2012

Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1–expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell–mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.
Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease
Authors: Yao Jiaqi , Ho Daniel , Calingasan Noel Y. , Pipalia Nina H. , Lin Michael T. , Beal M. Flint
Published: December 2012

There is extensive evidence that cholesterol and membrane lipids play a key role in Alzheimer disease (AD) pathogenesis. Cyclodextrins (CD) are cyclic oligosaccharide compounds widely used to bind cholesterol. Because CD exerts significant beneficial effects in Niemann-Pick type C disease, which shares neuropathological features with AD, we examined the effects of hydroxypropyl-β-CD (HP-β-CD) in cell and mouse models of AD. Cell membrane cholesterol accumulation was detected in N2a cells overexpressing Swedish mutant APP (SwN2a), and the level of membrane cholesterol was reduced by HP-β-CD treatment. HP-β-CD dramatically lowered the levels of Aβ42 in SwN2a cells, and the effects were persistent for 24 h after withdrawal. 4 mo of subcutaneous HP-β-CD administration significantly improved spatial learning and memory deficits in Tg19959 mice, diminished Aβ plaque deposition, and reduced tau immunoreactive dystrophic neurites. HP-β-CD lowered levels of Aβ42 in part by reducing β cleavage of the APP protein, and it also up-regulated the expression of genes involved in cholesterol transport and Aβ clearance. This is the first study to show neuroprotective effects of HP-β-CD in a transgenic mouse model of AD, both by reducing Aβ production and enhancing clearance mechanisms, which suggests a novel therapeutic strategy for AD.
The First Billion Years project: proto-galaxies reionizing the Universe
Authors: Paardekooper Jan-Pieter , Khochfar Sadegh , Dalla Claudio Vecchia
Published: December 2012

The contribution of stars in galaxies to cosmic reionization depends on the star formation history in the Universe, the abundance of galaxies during reionization, the escape fraction of ionizing photons and the clumping factor of the intergalactic medium. We compute the star formation rate and clumping factor during reionization in a cosmological volume using a high-resolution hydrodynamical simulation. We post-process the output with detailed radiative transfer simulations to compute the escape fraction of ionizing photons. Together, this gives us the opportunity to assess the contribution of galaxies to reionization self-consistently. The strong mass and redshift dependence of the escape fraction indicates that reionization occurred between z = 15 and 10 and was mainly driven by proto-galaxies forming in dark matter haloes with masses between 107 and 108 M⊙. More massive galaxies that are rare at these redshifts and have significantly lower escape fractions contribute less photons to the reionization process than the more-abundant low-mass galaxies. Star formation in the low-mass haloes is suppressed by radiative feedback from reionization, therefore these proto-galaxies only contribute when the part of the Universe they live in is still neutral. After z ∼ 10, massive galaxies become more abundant and provide most of the ionizing photons. In addition, we find that Population III stars are too short-lived and not frequent enough to have a major contribution to reionization. Although the stellar component of the proto-galaxies that produce the bulk of ionizing photons during reionization is too faint to be detected by the James Webb Space Telescope (JWST), these sources are brightest in the Hα and Lyα recombination lines, which will likely be detected by JWST in deep surveys.
Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations
Authors: Robberecht Caroline , Voet Thierry , Esteki Masoud Zamani , Nowakowska Beata A. , Vermeesch Joris R.
Published: December 2012

Large-scale analysis of balanced chromosomal translocation breakpoints has shown nonhomologous end joining and microhomology-mediated repair to be the main drivers of interchromosomal structural aberrations. Breakpoint sequences of de novo unbalanced translocations have not yet been investigated systematically. We analyzed 12 de novo unbalanced translocations and mapped the breakpoints in nine. Surprisingly, in contrast to balanced translocations, we identify nonallelic homologous recombination (NAHR) between (retro)transposable elements and especially long interspersed elements (LINEs) as the main mutational mechanism. This finding shows yet another involvement of (retro)transposons in genomic rearrangements and exposes a profoundly different mutational mechanism compared with balanced chromosomal translocations. Furthermore, we show the existence of compound maternal/paternal derivative chromosomes, reinforcing the hypothesis that human cleavage stage embryogenesis is a cradle of chromosomal rearrangements.
Gene Regulation of Carbon Fixation, Storage, and Utilization in the DiatomPhaeodactylum tricornutumAcclimated to Light/Dark Cycles
Authors: Chauton Matilde Skogen , Winge Per , Brembu Tore , Vadstein Olav , Bones Atle M.
Published: December 2012

The regulation of carbon metabolism in the diatom Phaeodactylum tricornutum at the cell, metabolite, and gene expression levels in exponential fed-batch cultures is reported. Transcriptional profiles and cell chemistry sampled simultaneously at all time points provide a comprehensive data set on carbon incorporation, fate, and regulation. An increase in Nile Red fluorescence (a proxy for cellular neutral lipids) was observed throughout the light period, and water-soluble glucans increased rapidly in the light period. A near-linear decline in both glucans and lipids was observed during the dark period, and transcription profile data indicated that this decline was associated with the onset of mitosis. More than 4,500 transcripts that were differentially regulated during the light/dark cycle are identified, many of which were associated with carbohydrate and lipid metabolism. Genes not previously described in algae and their regulation in response to light were integrated in this analysis together with proposed roles in metabolic processes. Some very fast light-responding genes in, for example, fatty acid biosynthesis were identified and allocated to biosynthetic processes. Transcripts and cell chemistry data reflect the link between light energy availability and light energy-consuming metabolic processes. Our data confirm the spatial localization of processes in carbon metabolism to either plastids or mitochondria or to glycolysis/gluconeogenesis, which are localized to the cytosol, chloroplast, and mitochondria. Localization and diel expression pattern may be of help to determine the roles of different isoenzymes and the mining of genes involved in light responses and circadian rhythms.
Direct Interaction between a Precursor Mature Domain and Transport Component Tha4 during Twin Arginine Transport of Chloroplasts
Authors: Pal Debjani , Fite Kristen , Dabney-Smith Carole
Published: December 2012

Proteins destined for the thylakoid lumen of chloroplasts must cross three membranes en route. The chloroplast twin arginine translocation (cpTat) system facilitates the transport of about one-half of all proteins that cross the thylakoid membrane in chloroplasts. Known mechanistic features of the cpTat system are drastically different from other known translocation systems, notably in its formation of a transient complex to transport fully folded proteins utilizing only the protonmotive force generated during photosynthesis for energy. However, key details, such as the structure and composition of the translocation pore, are still unknown. One of the three transmembrane cpTat components, Tha4, is thought to function as the pore by forming an oligomer. Yet, little is known about the topology of Tha4 in thylakoid, and little work has been done to detect precursor-Tha4 interactions, which are expected if Tha4 is the pore. Here, we present evidence of the interaction of the precursor with Tha4 under conditions leading to transport, using cysteine substitutions on the precursor and Tha4 and disulfide bond formation in pea (Pisum sativum). The mature domain of a transport-competent precursor interacts with the amphipathic helix and amino terminus of functional Tha4 under conditions leading to transport. Detergent solubilization of thylakoids post cross linking and blue-native polyacrylamide gel electrophoresis analysis shows that Tha4 is found in a complex containing precursor and Hcf106 (i.e. the cpTat translocase). Affinity precipitation of the cross-linked complex via Tha4 clearly demonstrates that the interaction is with full-length precursor. How these data suggest a role for Tha4 in cpTat transport is discussed.
High Light Acclimation in the Secondary Plastids Containing Diatom Phaeodactylum tricornutum is Triggered by the Redox State of the Plastoquinone Pool
Authors: Lepetit Bernard , Sturm Sabine , Rogato Alessandra , Gruber Ansgar , Sachse Matthias , Falciatore Angela , Kroth Peter G. , Lavaud Johann
Published: December 2012

In diatoms, the process of energy-dependent chlorophyll fluorescence quenching (qE) has an important role in photoprotection. Three components are essential for qE: (1) the light-dependent generation of a transthylakoidal proton gradient; (2) the deepoxidation of the xanthophyll diadinoxanthin (Dd) into diatoxanthin (Dt); and (3) specific nucleus-encoded antenna proteins, called Light Harvesting Complex Protein X (LHCX). We used the model diatom Phaeodactylum tricornutum to investigate the concerted light acclimation response of the qE key components LHCX, proton gradient, and xanthophyll cycle pigments (Dd+Dt) and to identify the intracellular light-responsive trigger. At high-light exposure, the up-regulation of three of the LHCX genes and the de novo synthesis of Dd+Dt led to a pronounced rise of qE. By inhibiting either the conversion of Dd to Dt or the translation of LHCX genes, qE amplification was abolished and the diatom cells suffered from stronger photoinhibition. Artificial modification of the redox state of the plastoquinone (PQ) pool via 3-(3,4-dichlorophenyl)-1,1-dimethylurea and 5-dibromo-6-isopropyl-3-methyl-1,4-benzoquinone resulted in a disturbance of Dd+Dt synthesis in an opposite way. Moreover, we could increase the transcription of two of the four LHCX genes under low-light conditions by reducing the PQ pool using 5-dibromo-6-isopropyl-3-methyl-1,4-benzoquinone. Altogether, our results underline the central role of the redox state of the PQ pool in the light acclimation of diatoms. Additionally, they emphasize strong evidence for the existence of a plastid-to-nucleus retrograde signaling mechanism in an organism with plastids that derived from secondary endosymbiosis.
Foxes are now widespread in Tasmania: DNA detection defines the distribution of this rare but invasive carnivore
Authors: Sarre Stephen D. , MacDonald Anna J. , Barclay Candida , Saunders Glen R. , Ramsey David S. L.
Published: December 2012

Invasive vertebrate species are a world‐wide threat to biodiversity and agricultural production. The presence of foxes, one of the most damaging invasive vertebrates introduced to Australia, has now been confirmed in the island state of Tasmania, placing at risk many species of native vertebrates and substantial agricultural industry.

Effective eradication of such a rare but elusive carnivore requires robust strategies informed by novel but systematic detection.

We combine DNA detection approaches for trace samples with systematic stratified and opportunistic surveys of carnivore scats to estimate the current distribution of foxes in Tasmania. We use that DNA evidence and other hard evidence provided by carcasses and other material to build a predictive model of fox habitat suitability for all of Tasmania.

We demonstrate that this destructive species is widespread in northern and eastern Tasmania but has not yet reached the limits of its range. The widespread nature of this distribution reveals that targeting fox activity hotspots only for eradication is unlikely to be successful and that a strategic and statewide approach is required. Our habitat suitability model can provide a basis for prioritizing areas for fox management.

Synthesis and applications. Our approach highlights the importance of early and pre‐emptive surveys of recently established, and therefore rare, invasive species and the necessity of providing a sound and defensible approach to determining the distribution of the invasive species. This approach provides a template for the systematic detection of rare cryptic carnivores.
Confirmatory Factor Analysis of the Pain Care Quality Surveys (PainCQ©)
Authors: Pett Marjorie A. , Beck Susan L. , Guo Jia‐Wen , Towsley Gail L. , Brant Jeannine M. , Lavoie Smith Ellen M. , Berry Patricia H. , Donaldson Gary W.
Published: December 2012

Objective

To examine the reliability and validity and to decrease the battery of items in the Pain Care Quality (PainCQ©) Surveys.

Data Sources/Study Setting

Patient‐reported data were collected prospectively from 337 hospitalized adult patients with pain on medical/surgical oncology units in four hospitals in three states.

Study Design

This methodological study used a cross‐sectional survey design. Each consenting patient completed two PainCQ© Surveys, the Brief Pain Inventory‐Short Form, and demographic questions. Clinical data were extracted from the medical record.

Data Collection/Extraction Methods

All data were double entered into a Microsoft Access database, cleaned, and then extracted into SPSS, AMOS, and Mplus for analysis.

Principal Findings

Confirmatory factor analysis using Structural Equation Modeling supported the initial factor structure. Modification indices guided decisions that resulted in a superior, parsimonious model for the PainCQ‐Interdisciplinary Care Survey (six items, two subscales) and the PainCQ‐Nursing Care Survey (14 items, three subscales). Cronbach's alpha coefficients all exceeded .80.

Conclusions

Cumulative evidence supports the reliability and validity of the companion PainCQ© Surveys in hospitalized patients with pain in the oncology setting. The tools may be relevant in both clinical research and quality improvement. Future research is recommended in other populations, settings, and with more diverse groups.
How Does Drug Treatment for Diabetes Compare between Medicare Advantage Prescription Drug Plans (MAPDs) and Stand‐Alone Prescription Drug Plans (PDPs)?
Authors: Erten Mujde Z. , Stuart Bruce , Davidoff Amy J. , Shoemaker J. Samantha , Bryant‐Comstock Lynda , Shenolikar Rahul
Published: December 2012

Objective

To compare the use of guideline‐recommended prescription medications for diabetes among Medicare beneficiaries enrolled in stand‐alone prescription drug plans (PDPs) with Medicare Advantage prescription drug plans (MAPDs) in the presence of potential selection bias.

Data Sources/Study Setting

Centers for Medicare and Medicaid Services' Chronic Condition Data Warehouse (2006, 2007).

Study Design

Retrospective cross‐sectional comparison of drug use and proportion of days covered (PDC) for oral‐antidiabetics, ACE‐inhibitors/ARBs, and antihyperlipidemics among PDP and MAPD enrollees with diabetes. We estimated “naïve” regression models assuming exogenous plan choice and two‐stage residual inclusion (2SRI) models to study endogeneity in choice of Part D plan type.

Data Collection/Extraction Methods

We identified 111,290 diabetics based on ICD‐9 codes in Medicare claims from a random 5 percent sample of Medicare beneficiaries in 2005 excluding dual eligibles.

Principal Findings

The naïve regression models indicated lower probability of drug use for oral‐antidiabetics (−4 percent; p < .001) and ACE‐inhibitors/ARBS (−2 percent; p = .004) among PDP enrollees, but their PDC was higher (3–5 percent) for all drug classes (p < .001). 2SRI models produced no significant differences in any‐use equations, but significantly higher PDC values for PDP enrollees for oral‐antidiabetics and ACE‐inhibitors/ARBs.

Conclusions

We found similar overall use of recommended drugs in diabetes treatment and no consistent evidence of favorable or adverse selection into PDPs and MAPDs.
The Physiology of Sexual Violence, Genito‐anal Injury and HIV: Opportunities for Improving Risk Estimation
Authors: Klot Jennifer F.
Published: December 2012

Increased understanding about the relative contribution of genito‐anal injury to HIV transmission may improve epidemic model estimates of the distribution of risk among and across different subpopulations. Better understanding about the distribution of HIV among subpopulations that are at highest risk of sexual violence can also improve the design and prioritization of combination prevention interventions that are most likely to reduce the risk of sexual violence and its potential contribution to HIV transmission. The effective incorporation of physiological and social variables into epidemic modelling will likely require new research approaches that can help communicate the level of risk associated with different types of ‘heterosexual’ transmission. Reference models that reflect the potential impact of sexual violence and genital injury can help direct attention toward key variables and uncertainties. For further research that clarifies these relationships will require multidisciplinary collaboration among groups with expertize in epidemiology, social science, public health, and clinical and basic science.