bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Simulated Viewpoint Jitter on Visually Induced Postural Sway
Authors: Palmisano Stephen , Pinniger Gavin J , Ash April , Steele Julie R
Published: March 2009

In this study we examined the effects of simulated horizontal and vertical viewpoint jitter on the vection and postural sway induced by radial patterns of optic flow. During each trial, observers were exposed sequentially to 20 s periods of radially expanding flow, radially contracting flow, and static visual scenes. For half the trials, simulated viewpoint jitter was added to the radially expanding/contracting optic flow patterns. In experiment 1, we found that, while this jitter increased the backward postural sway induced by radial expansion, it actually decreased forward postural sway induced by radial contraction. However, in experiment 2 we found that jitter increased both the forward and backward vection induced by radially expanding and contracting flow patterns. We conclude that the processes involved in postural control are more sensitive to the sensory conflicts generated by viewpoint jitter than those involved in the perception of self-motion, and that the observed asymmetries in forward and backward sway are ecological in origin.
Hollow-using vertebrate fauna of Tasmania: distribution, hollow requirements and conservation status
Authors: Koch Amelia J. , Munks Sarah A. , Woehler Eric J.
Published: March 2009

In Tasmania, a considerable proportion of the forested landscape is available for land clearance and production forestry, which has and will continue to result in a decline in hollow availability unless managed appropriately. All hollow-using species are listed as having priority status under the Tasmanian Regional Forest Agreement. To ensure the habitat for hollow-using fauna is managed effectively, we first have to understand the requirements of the species involved. This paper is a review of the distribution, hollow requirements and conservation status of the five species of arboreal marsupials, eight species of bats and 29 bird species that use hollows in Tasmania. The number of species that use hollows is lower than in many other areas of Australia, but these species represent a large proportion of the vertebrate fauna of Tasmania. Three of these species and nine subspecies are endemic to Tasmania and seven are exotic. Four bird species are listed as Threatened at the state and/or national level. Twenty-five of Tasmania’s hollow-using species are capable of using small hollows, 14 can use medium-sized hollows and three bird species are limited to using large hollows. Current records indicate that the highest diversity of hollow-using species is associated with dry forest areas.
Aerodynamic cleanliness in bats
Authors: Bullen R. D. , McKenzie N. L.
Published: March 2009

In this paper we examine morphometric attributes of the airframes of 24 species of bat from Western Australia. In particular, we consider anatomical features of the ear, head, body and tail related to lift and drag optimisation as well as airflow separation control. We provide an assessment of the relative cleanliness of the species and a range of lift and drag coefficient values for use in metabolic power output modelling. The species assessed have aerodynamic cleanliness optimisations that are appropriate to the range of Reynolds’ numbers in which bats fly. Head/body relative cleanliness was consistent with, and functionally appropriate to, aspects of species foraging niche such as foraging strategy. Cleanliness of face and fineness ratio of head and body were found to be related to minimum foraging drag. Blending of the wing and body, the presence of a wing/body fillet and the texture of the pelage were found to be important. The aerodynamic optimisation of ears and tail membrane were found to correlate with foraging strategy. The interceptors had optimisations for minimum drag generation consistent with their higher foraging flight speed. Rather than being optimised for minimum drag, the air-superiority bats’ tails and ears were consistent with their highly agile but slower-foraging flight speeds. Surface bats were characterised by the absence of optimisations for low drag. The frugivore plus the nectarivore and the carnivore studied appear to be discrete optimisations.
Interspecific variation in relative brain size is not correlated with intensity of sexual selection in waterfowl (Anseriformes)
Authors: Guay P.-J. , Iwaniuk A. N.
Published: March 2009

The role of sexual selection in shaping the brain is poorly understood. Although numerous studies have investigated the role of natural selection, relatively few have focussed on the role of sexual selection. Two important factors influencing the intensity of sexual selection are sperm competition and pair bonding and three different hypotheses have been proposed to explain how they could influence relative brain size. (1) The ‘extra-pair mating’ hypothesis predicts that sexual dimorphism in brain size will increase with sperm competition intensity. (2) The ‘Machiavellian intelligence’ hypothesis predicts that brain size will be larger in species with intense sperm competition. (3) The ‘relationship intelligence’ hypothesis predicts that species forming long-term pair bonds will have larger brains. We investigated sexual dimorphism in brain size and tested these three hypotheses in waterfowl by studying correlations between relative brain volume and three measures of sperm competition (testicular mass, phallus length and mating strategy) and pair-bond duration using the modern phylogenetic comparative approach. We found no evidence of sexual dimorphism in brain size in waterfowl after controlling for body mass and found no support for any of the three hypotheses. This suggests that brain size may not be sexually selected in waterfowl, despite evidence of sexual selection pressures on other morphological characters.
Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy
Authors: Lu Timothy K. , Collins James J.
Published: March 2009

Antimicrobial drug development is increasingly lagging behind the evolution of antibiotic resistance, and as a result, there is a pressing need for new antibacterial therapies that can be readily designed and implemented. In this work, we engineered bacteriophage to overexpress proteins and attack gene networks that are not directly targeted by antibiotics. We show that suppressing the SOS network in
Escherichia coli
with engineered bacteriophage enhances killing by quinolones by several orders of magnitude in vitro and significantly increases survival of infected mice in vivo. In addition, we demonstrate that engineered bacteriophage can enhance the killing of antibiotic-resistant bacteria, persister cells, and biofilm cells, reduce the number of antibiotic-resistant bacteria that arise from an antibiotic-treated population, and act as a strong adjuvant for other bactericidal antibiotics (e.g., aminoglycosides and β-lactams). Furthermore, we show that engineering bacteriophage to target non-SOS gene networks and to overexpress multiple factors also can produce effective antibiotic adjuvants. This work establishes a synthetic biology platform for the rapid translation and integration of identified targets into effective antibiotic adjuvants.
Shape separation of gold nanorods using centrifugation
Authors: Sharma Vivek , Park Kyoungweon , Srinivasarao Mohan
Published: March 2009

We demonstrate the use of centrifugation for efficient separation of colloidal gold nanorods from a mixture of nanorods and nanospheres. We elucidate the hydrodynamic behavior of nanoparticles of various shapes and illustrate that the shape-dependent drag causes particles to have shape-dependent sedimentation behavior. During centrifugation, nanoparticles undergo Brownian motion under an external field and move with different sedimentation velocities dictated by their Svedberg coefficients. This effects a separation of particles of different shape and size. Our theoretical analysis and experiments demonstrate the viability of using centrifugation to shape-separate a mixture of colloidal particles.
Nitrous oxide emission by aquatic macrofauna
Authors: Stief Peter , Poulsen Morten , Nielsen Lars Peter , Brix Hans , Schramm Andreas
Published: March 2009

A large variety of aquatic animals was found to emit the potent greenhouse gas nitrous oxide when nitrate was present in the environment. The emission was ascribed to denitrification by ingested bacteria in the anoxic animal gut, and the exceptionally high N2O-to-N2production ratio suggested delayed induction of the last step of denitrification. Filter- and deposit-feeding animal species showed the highest rates of nitrous oxide emission and predators the lowest, probably reflecting the different amounts of denitrifying bacteria in the diet. We estimate that nitrous oxide emission by aquatic animals is quantitatively important in nitrate-rich aquatic environments like freshwater, coastal marine, and deep-sea ecosystems. The contribution of this source to overall nitrous oxide emission from aquatic environments might further increase because of the projected increase of nitrate availability in tropical regions and the numeric dominance of filter- and deposit-feeders in eutrophic ecosystems.
A FERM domain autoregulates
Drosophila
myosin 7a activity
Authors: Yang Yi , Baboolal Thomas G. , Siththanandan Verl , Chen Michael , Walker Matthew L. , Knight Peter J. , Peckham Michelle , Sellers James R.
Published: March 2009

Full-length
Drosophila
myosin 7a (myosin 7a-FL) has a complex tail containing a short predicted coiled coil followed by a MyTH4-FERM domain, an SH3 domain, and a C-terminal MyTH4-FERM domain. Myosin 7a-FL expressed in Sf9 cells is monomeric despite the predicted coiled coil. We showed previously that Subfragment-1 (S1) from this myosin has MgATPase of
V
max
≈ 1s
−1
and
K
ATPase
≈ 1 μM actin. We find that myosin 7a-FL has
V
max
similar to S1 but
K
ATPase
≈ 30 μM. Thus, at low actin concentrations (5 μM), the MgATPase of S1 is fully activated, whereas that of myosin 7a-FL is low, suggesting that the tail regulates activity. Electron microscopy of myosin 7a-FL with ATP shows the tail is tightly bent back against the motor domain. Myosin 7a-FL extends at either high ionic strength or without ATP, revealing the motor domain, lever, and tail. A series of C-terminal truncations show that deletion of 99 aa (the MyTH7 subdomain of the C-terminal FERM domain) is sufficient to abolish bending, and the
K
ATPase
is then similar to S1. This region is highly conserved in myosin 7a. We found that a double mutation in it, R2140A-K2143A, abolishes bending and reduces
K
ATPase
to S1 levels. In addition, the expressed C-terminal FERM domain binds actin with
K
d
≈ 30 μM regardless of ATP, similar to the
K
ATPase
value for myosin 7a-FL. We propose that at low cellular actin concentrations, myosin 7a-FL is bent and inactive, but at high actin concentrations, it is unfolded and active because the C-terminal FERM domain binds to actin.
Decentralization for cost-effective conservation
Authors: Somanathan E. , Prabhakar R. , Mehta Bhupendra Singh
Published: March 2009

Since 1930, areas of state-managed forest in the central Himalayas of India have increasingly been devolved to management by local communities. This article studies the long-run effects of the devolution on the cost of forest management and on forest conservation. Village council-management costs an order of magnitude less per unit area and does no worse, and possibly better, at conservation than state management. Geographic proximity and historical and ecological information are used to separate the effects of management from those of possible confounding factors.
The N-end rule pathway promotes seed germination and establishment through removal of ABA sensitivity in
Arabidopsis
Authors: Holman Tara J. , Jones Peter D. , Russell Laurel , Medhurst Anne , Úbeda Tomás Susana , Talloji Prabhavathi , Marquez Julietta , Schmuths Heike , Tung Swee-Ang , Taylor Ian , Footitt Steven , Bachmair Andreas , Theodoulou Frederica L. , Holdsworth Michael J.
Published: March 2009

The N-end rule pathway targets protein degradation through the identity of the amino-terminal residue of specific protein substrates. Two components of this pathway in
Arabidopsis thaliana
, PROTEOLYSIS6 (PRT6) and arginyl-tRNA:protein arginyltransferase (ATE), were shown to regulate seed after-ripening, seedling sugar sensitivity, seedling lipid breakdown, and abscisic acid (ABA) sensitivity of germination. Sensitivity of
prt6
mutant seeds to ABA inhibition of endosperm rupture reduced with after-ripening time, suggesting that seeds display a previously undescribed window of sensitivity to ABA. Reduced root growth of
prt6
alleles and the
ate1 ate2
double mutant was rescued by exogenous sucrose, and the breakdown of lipid bodies and seed-derived triacylglycerol was impaired in mutant seedlings, implicating the N-end rule pathway in control of seed oil mobilization. Epistasis analysis indicated that PRT6 control of germination and establishment, as exemplified by ABA and sugar sensitivity, as well as storage oil mobilization, occurs at least in part via transcription factors ABI3 and ABI5. The N-end rule pathway of protein turnover is therefore postulated to inactivate as-yet unidentified key component(s) of ABA signaling to influence the seed-to-seedling transition.
Telomerase insufficiency in rheumatoid arthritis
Authors: Fujii Hiroshi , Shao Lan , Colmegna Inés , Goronzy Jörg J. , Weyand Cornelia M.
Published: March 2009

In rheumatoid arthritis (RA), chronically stimulated T lymphocytes sustain tissue-destructive joint inflammation. Both naïve and memory T cells in RA are prematurely aged with accelerated loss of telomeres suggesting excessive proliferative pressure or inadequate telomeric maintenance. Upon stimulation, RA naïve CD4 T cells are defective in up-regulating telomerase activity (P< 0.0001) due to insufficient induction of the telomerase component human telomerase reverse transcriptase (hTERT); T cell activation and cell cycle progression are intact. Telomerase insufficiency does not affect memory T cells or CD34 hematopoietic stem cells and is present in untreated patients and independent from disease activity. Knockdown of hTERT in primary human T cells increases apoptotic propensity (P= 0.00005) and limits clonal burst (P= 0.0001) revealing a direct involvement of telomerase in T cell fate decisions. Naïve RA CD4 T cells stimulated through the T cell receptor are highly susceptible to apoptosis, expanding to smaller clonal size. Overexpression of ectopic hTERT in naïve RA T cells conveys apoptotic resistance (P= 0.008) and restores proliferative expansion (P< 0.0001). Telomerase insufficiency in RA results in excessive T cell loss, undermining homeostatic control of the naive T cell compartment and setting the stage for lymphopenia-induced T cell repertoire remodeling. Restoring defective telomerase activity emerges as a therapeutic target in resetting immune abnormalities in RA.
Bowl-shaped oligomeric structures on membranes as DegP's new functional forms in protein quality control
Authors: Shen Qing-Tao , Bai Xiao-Chen , Chang Lei-Fu , Wu Yi , Wang Hong-Wei , Sui Sen-Fang
Published: March 2009

In the periplasm of
Escherichia coli
, DegP (also known as HtrA), which has both chaperone-like and proteolytic activities, prevents the accumulation of toxic misfolded and unfolded polypeptides. In solution, upon binding to denatured proteins, DegP forms large cage-like structures. Here, we show that DegP forms a range of bowl-shaped structures, independent of substrate proteins, each with a 4-, 5-, or 6-fold symmetry and all with a DegP trimer as the structural unit, on lipid membranes. These membrane-bound DegP assemblies have the capacity to recruit and process substrates in the bowl chamber, and they exhibit higher proteolytic and lower chaperone-like activities than DegP in solution. Our findings imply that DegP might regulate its dual roles during protein quality control, depending on its assembly state in the narrow bacterial envelope.
Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening
Authors: Gerber Anthony N. , Masuno Kiriko , Diamond Marc I.
Published: March 2009

Glucocorticoids are widely used to suppress inflammation and treat various immune-mediated diseases. Some glucocorticoid receptor (GR)-regulated genes mediate the therapeutic response, whereas others cause debilitating side effects. To discover selective modulators of the GR response, we developed a high-throughput, multiplexed system to monitor regulation of 4 promoters simultaneously. An initial screen of 1,040 natural products and Food and Drug Administration-approved drugs identified modulators that caused GR to regulate only a subset of its target promoters. Some compounds selectively inhibited GR-mediated gene activation without altering the repression of cytokine expression by GR. This approach will facilitate identification of genes and small molecules that augment beneficial effects of GR and diminish deleterious ones. Our results have important implications for the development of GR modulators and the identification of cross-talk pathways that control selective GR gene regulation.
Revising the nitrogen cycle in the Peruvian oxygen minimum zone
Authors: Lam Phyllis , Lavik Gaute , Jensen Marlene M. , van de Vossenberg Jack , Schmid Markus , Woebken Dagmar , Gutiérrez Dimitri , Amann Rudolf , Jetten Mike S. M. , Kuypers Marcel M. M.
Published: March 2009

The oxygen minimum zone (OMZ) of the Eastern Tropical South Pacific (ETSP) is 1 of the 3 major regions in the world where oceanic nitrogen is lost in the pelagic realm. The recent identification of anammox, instead of denitrification, as the likely prevalent pathway for nitrogen loss in this OMZ raises strong questions about our understanding of nitrogen cycling and organic matter remineralization in these waters. Without detectable denitrification, it is unclear how NH
4
+
is remineralized from organic matter and sustains anammox or how secondary NO
2
−
maxima arise within the OMZ. Here we show that in the ETSP-OMZ, anammox obtains 67% or more of NO
2
−
from nitrate reduction, and 33% or less from aerobic ammonia oxidation, based on stable-isotope pairing experiments corroborated by functional gene expression analyses. Dissimilatory nitrate reduction to ammonium was detected in an open-ocean setting. It occurred throughout the OMZ and could satisfy a substantial part of the NH
4
+
requirement for anammox. The remaining NH
4
+
came from remineralization via nitrate reduction and probably from microaerobic respiration. Altogether, deep-sea NO
3
−
accounted for only ≈50% of the nitrogen loss in the ETSP, rather than 100% as commonly assumed. Because oceanic OMZs seem to be expanding because of global climate change, it is increasingly imperative to incorporate the correct nitrogen-loss pathways in global biogeochemical models to predict more accurately how the nitrogen cycle in our future ocean may respond.
Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B
Authors: Montes Tamara , Tortajada Agustín , Morgan B. Paul , Rodríguez de Córdoba Santiago , Harris Claire L.
Published: March 2009

Mutations and polymorphisms in complement genes have been linked with numerous rare and prevalent disorders, implicating dysregulation of complement in pathogenesis. The 3 common alleles of factor B (fB) encode Arg (

fB
32R

), Gln (

fB
32Q

), or Trp (

fB
32W

) at position 32 in the Ba domain. The

fB
32Q

allele is protective for age-related macular degeneration, the commonest cause of blindness in developed countries. Factor B variants were purified from plasma of homozygous individuals and were tested in hemolysis assays. The protective variant fB
32Q
had decreased activity compared with fB
32R
. Biacore comparison revealed markedly different proenzyme formation; fB
32R
bound C3b with 4-fold higher affinity, and formation of activated convertase was enhanced. Binding and functional differences were confirmed with recombinant fB
32R
and fB
32Q
; an intermediate affinity was revealed for fB
32W
. To confirm contribution of Ba to binding, affinity of Ba for C3b was determined. Ba-fB
32R
had 3-fold higher affinity compared with Ba-fB
32Q
. We demonstrate that the disease-protective effect of fB
32Q
is consequent on decreased potential to form convertase and amplify complement activation. Knowledge of the functional consequences of polymorphisms in complement activators and regulators will aid disease prediction and inform targeting of diagnostics and therapeutics.
A macaque model of HIV-1 infection
Authors: Hatziioannou Theodora , Ambrose Zandrea , Chung Nancy P. Y. , Piatak Michael , Yuan Fang , Trubey Charles M. , Coalter Vicky , Kiser Rebecca , Schneider Doug , Smedley Jeremy , Pung Rhonda , Gathuka Mercy , Estes Jacob D. , Veazey Ronald S. , KewalRamani Vineet N. , Lifson Jeffrey D. , Bieniasz Paul D.
Published: March 2009

The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate
TRIM5
and
APOBEC3
antiretroviral genes, we constructed simian-tropic (st)HIV-1 strains that differ from HIV-1 only in the
vif
gene. We demonstrate that such minimally modified stHIV-1 strains are capable of high levels of replication in vitro in pig-tailed macaque (
Macaca nemestrina
) lymphocytes. Importantly, infection of pig-tailed macaques with stHIV-1 results in acute viremia, approaching the levels observed in HIV-1-infected humans, and an ensuing persistent infection for several months. stHIV-1 replication was controlled thereafter, at least in part, by CD8+ T cells. We demonstrate the potential utility of this HIV-1-based animal model in a chemoprophylaxis experiment, by showing that a commonly used HIV-1 therapeutic regimen can provide apparently sterilizing protection from infection following a rigorous high-dose stHIV-1 challenge.
Instant immunity through chemically programmable vaccination and covalent self-assembly
Authors: Popkov Mikhail , Gonzalez Beatriz , Sinha Subhash C. , Barbas Carlos F.
Published: March 2009

The ability to instantly create a state of immunity as achieved in the passive transfer of hyperimmune globulin has had a tremendous impact on public health. Unlike passive immunization, active immunization, which is the foundation of vaccinology, is an anticipatory strategy with inherent limitations. Here we show that elements of active and passive immunization can be combined to create an effective chemistry-driven approach to vaccinology. Reactive immunization was used to create a reservoir of covalent polyclonal antibodies in 3 mouse strains that were subsequently engrafted with syngeneic CT26 colon or B16F10 melanoma tumors. Upon administration of designed integrin α
v
β
3
and α
v
β
5
adapter ligands, the induced covalent polyclonal antibodies self-assembled with the adapter ligands and the animals mounted an instant, chemically programmed, polyclonal response against the implanted tumors. Significant therapeutic responses were observed without recourse to adjuvant therapy. The chemically programmed immune responses were driven by antibody-dependent cellular cytotoxicity and complement-directed cytotoxicity. We suggest that this type of chemistry-driven approach to vaccinology is underexplored and may provide routes to vaccines to protect against diseases that have proven intractable to biology-driven vaccine approaches.
Identifying the proteins to which small-molecule probes and drugs bind in cells
Authors: Ong Shao-En , Schenone Monica , Margolin Adam A. , Li Xiaoyu , Do Kathy , Doud Mary K. , Mani D. R. , Kuai Letian , Wang Xiang , Wood John L. , Tolliday Nicola J. , Koehler Angela N. , Marcaurelle Lisa A. , Golub Todd R. , Gould Robert J. , Schreiber Stuart L. , Carr Steven A.
Published: March 2009

Most small-molecule probes and drugs alter cell circuitry by interacting with 1 or more proteins. A complete understanding of the interacting proteins and their associated protein complexes, whether the compounds are discovered by cell-based phenotypic or target-based screens, is extremely rare. Such a capability is expected to be highly illuminating—providing strong clues to the mechanisms used by small-molecules to achieve their recognized actions
and
suggesting potential unrecognized actions. We describe a powerful method combining quantitative proteomics (SILAC) with affinity enrichment to provide unbiased, robust and comprehensive identification of the proteins that bind to small-molecule probes and drugs. The method is scalable and general, requiring little optimization across different compound classes, and has already had a transformative effect on our studies of small-molecule probes. Here, we describe in full detail the application of the method to identify targets of kinase inhibitors and immunophilin binders.
The atypical kinase Cdk5 is activated by insulin, regulates the association between GLUT4 and E-Syt1, and modulates glucose transport in 3T3-L1 adipocytes
Authors: Lalioti Vasiliki , Muruais Gemma , Dinarina Ana , van Damme Josef , Vandekerckhove Joel , Sandoval Ignacio V.
Published: March 2009

Here, we report that Cdk5 activation is stimulated by insulin and plays a key role in the regulation of GLUT4-mediated glucose uptake in 3T3-L1 adipocytes. Insulin activation of Cdk5 requires PI3K signaling. Insulin-activated Cdk5 phosphorylates E-Syt1, a 5 C2-domain protein-related to the synaptotagmins that is induced during adipocyte differentiation. Phosphorylated E-Syt1 associates with GLUT4, an event inhibited by the Cdks inhibitor roscovitine. Cdk5 silencing inhibits glucose uptake by 3T3-L1 adipocytes. These studies elucidate a previously unknown activity of Cdk5 and demonstrate the involvement of this kinase in the regulation of insulin-dependent glucose uptake in adipocytes.
Epigenetic regulation of genetic integrity is reprogrammed during cloning
Authors: Murphey Patricia , Yamazaki Yukiko , McMahan C. Alex , Walter Christi A. , Yanagimachi Ryuzo , McCarrey John R.
Published: March 2009

Cloning by somatic cell nuclear transfer (SCNT) circumvents processes that normally function during gametogenesis to prepare the gamete genomes to support development of new progeny following fertilization. One such process is enhanced maintenance of genetic integrity in germ cells, such that germ cells typically carry fewer spontaneously acquired mutations than somatic cells in the same individual. Thus, embryos produced from somatic cells by SCNT could directly inherit more mutations than naturally conceived embryos. Alternatively, they could inherit epigenetic programming that predisposes more rapid accumulation of
de novo
mutations during development. We used a transgenic mouse system to test these possibilities by producing cloned midgestation mouse fetuses from three different donor somatic cell types carrying significantly different initial frequencies of spontaneous mutations. We found that on an individual locus basis, mutations acquired spontaneously in a population of donor somatic cells are not likely to be propagated to cloned embryos by SCNT. In addition, we found that the rate of accumulation of spontaneous mutations was similar in fetuses produced by either natural conception or cloning, indicating that cloned fetuses do not acquire mutations more rapidly than naturally conceived fetuses. These results represent the first direct demonstration that the process of cloning by SCNT does not lead to an increase in the frequency of point mutations. These results also demonstrate that epigenetic mechanisms normally contribute to the regulation of genetic integrity in a tissue-specific manner, and that these mechanisms are subject to reprogramming during cloning.
EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes
Authors: Sutter Carrie Hayes , Yin Hong , Li Yunbo , Mammen Jennifer S. , Bodreddigari Sridevi , Stevens Gaylene , Cole Judith A. , Sutter Thomas R.
Published: March 2009

Dioxin is an extremely potent carcinogen. In highly exposed people, the most commonly observed toxicity is chloracne, a pathological response of the skin. Most of the effects of dioxin are attributed to its activation of the aryl hydrocarbon receptor (AHR), a transcription factor that binds to theAhreceptor nuclear translocator (ARNT) to regulate the transcription of numerous genes, includingCYP1A1andCYP1B1. In cultures of normal human epidermal keratinocytes dioxin accelerates cell differentiation, as measured by the formation of cornified envelopes. We show that this acceleration is mediated by the AHR; also, that dioxin increases the expression of several genes known to be regulated by ARNT, which have critical roles in the cornification and epidermal barrier function of the skin. Importantly, we demonstrate that all of these responses are opposed by ligand-activation of the EGF receptor (R), an important regulator of keratinocyte cell fate. In theCYP1A1enhancer, EGFR activation prevents recruitment of the p300 coactivator, although not affecting the binding of the AHR or ARNT. The total cellular level of p300 protein does not decrease, and overexpression of p300 relieves EGFR-mediated repression of transcription, indicating that p300 is a critical target for the repression of the AHR complex by EGFR signaling. These results provide a mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin is able to disrupt epidermal homeostasis and identify EGFR signaling as a regulator of the AHR. This signaling may modulate the incidence and severity of chloracne and be of therapeutic relevance to human poisonings by dioxin.
Cortical network functional connectivity in the descent to sleep
Authors: Larson-Prior Linda J. , Zempel John M. , Nolan Tracy S. , Prior Fred W. , Snyder Abraham Z. , Raichle Marcus E.
Published: March 2009

Descent into sleep is accompanied by disengagement of the conscious brain from the external world. It follows that this process should be associated with reduced neural activity in regions of the brain known to mediate interaction with the environment. We examined blood oxygen dependent (BOLD) signal functional connectivity using conventional seed-based analyses in 3 primary sensory and 3 association networks as normal young adults transitioned from wakefulness to light sleep while lying immobile in the bore of a magnetic resonance imaging scanner. Functional connectivity was maintained in each network throughout all examined states of arousal. Indeed, correlations within the dorsal attention network modestly but significantly increased during light sleep compared to wakefulness. Moreover, our data suggest that neuronally mediated BOLD signal variance generally increases in light sleep. These results do not support the view that ongoing BOLD fluctuations primarily reflect unconstrained cognition. Rather, accumulating evidence supports the hypothesis that spontaneous BOLD fluctuations reflect processes that maintain the integrity of functional systems in the brain.
Lexical coherence in short-term memory: Strategic reconstruction or “semantic glue”?
Authors: Jefferies Elizabeth , Frankish Clive , Noble Katie
Published: March 2009

This study explores the foundation of lexical/semantic phoneme binding effects in verbal short-term memory (STM). The immediate serial recall of pure lists of words and nonwords was compared with the recall of mixed lists that had either a predictable, alternating structure (e.g., wnwnwn) or an unpredictable structure (i.e., the serial positions of the words/nonwords could not be known in advance). The study provides evidence for two separate mechanisms by which long-term linguistic knowledge contributes to STM. First, there was evidence for automatic lexical/semantic binding effects that were independent of knowledge of lexical status. The nonwords in both types of mixed list damaged word recall and encouraged the phonological elements of words to migrate. In both alternating and unpredictable mixed lists, the phonemes of words were more likely than the phonemes of nonwords to be recalled together as a coherent item, suggesting that lexical/semantic knowledge encourages the phonological elements of words to emerge together in immediate serial recall, even when lexical status is unknown. Secondly, there was evidence for “strategic redintegration”, which was dependent on prior knowledge of the lexical status of the items in mixed lists. When participants recalled items that they knew to be words in advance, they were able to use this knowledge to constrain their responses so that they were more likely to be lexically appropriate. These findings motivate modifications to current theories of the interaction between linguistic knowledge and verbal short-term memory.
The speed of free will
Authors: Horowitz Todd S. , Wolfe Jeremy M. , Alvarez George A. , Cohen Michael A. , Kuzmova Yoana I.
Published: March 2009

Do voluntary and task-driven shifts of attention have the same time course? In order to measure the time needed to voluntarily shift attention, we devised several novel visual search tasks that elicited multiple sequential attentional shifts. Participants could only respond correctly if they attended to the right place at the right time. In control conditions, search tasks were similar but participants were not required to shift attention in any order. Across five experiments, voluntary shifts of attention required 200–300 ms. Control conditions yielded estimates of 35–100 ms for task-driven shifts. We suggest that the slower speed of voluntary shifts reflects the “clock speed of free will”. Wishing to attend to something takes more time than shifting attention in response to sensory input.
A Notch updated
Authors: Tien An-Chi , Rajan Akhila , Bellen Hugo J.
Published: March 2009

Cell–cell signaling mediated by the Notch receptor is iteratively involved in numerous developmental contexts, and its dysregulation has been associated with inherited genetic disorders and cancers. The core components of the signaling pathway have been identified for some time, but the study of the modulation of the pathway in different cellular contexts has revealed many layers of regulation. These include complex sugar modifications in the extracellular domain as well as transit of Notch through defined cellular compartments, including specific endosomes.
Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming
Authors: Deák Ferenc , Xu Yi , Chang Wen-Pin , Dulubova Irina , Khvotchev Mikhail , Liu Xinran , Südhof Thomas C. , Rizo Josep
Published: March 2009

Munc18-1 and soluble NSF attachment protein receptors (SNAREs) are critical for synaptic vesicle fusion. Munc18-1 binds to the SNARE syntaxin-1 folded into a closed conformation and to SNARE complexes containing open syntaxin-1. Understanding which steps in fusion depend on the latter interaction and whether Munc18-1 competes with other factors such as complexins for SNARE complex binding is critical to elucidate the mechanisms involved. In this study, we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice. We describe point mutations in Munc18-1 that preserve tight binding to closed syntaxin-1 but markedly disrupt Munc18-1 binding to SNARE complexes containing open syntaxin-1. Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca2+-triggered fusion of primed vesicles. We also find that Munc18-1 and complexin-1 bind simultaneously to SNARE complexes. These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1–SNARE–complexin macromolecular assembly that is poised for Ca2+ triggering of fusion.
Methylation of H3 K4 and K79 is not strictly dependent on H2B K123 ubiquitylation
Authors: Foster Elinor R. , Downs Jessica A.
Published: March 2009

Covalent modifications of histone proteins have profound consequences on chromatin structure and function. Specific modification patterns constitute a code read by effector proteins. Studies from yeast found that H3 trimethylation at K4 and K79 is dependent on ubiquitylation of H2B K123, which is termed a “trans-tail pathway.” In this study, we show that a strain unable to be ubiquitylated on H2B (K123R) is still proficient for H3 trimethylation at both K4 and K79, indicating that H3 methylation status is not solely dependent on H2B ubiquitylation. However, additional mutations in H2B result in loss of H3 methylation when combined with htb1-K123R. Consistent with this, we find that the original strain used to identify the trans-tail pathway has a genomic mutation that, when combined with H2B K123R, results in defective H3 methylation. Finally, we show that strains lacking the ubiquitin ligase Bre1 are defective for H3 methylation, suggesting that there is an additional Bre1 substrate that in combination with H2B K123 facilitates H3 methylation.
Relationship between onset thresholds, trigger types and rotation shear for the m/n = 2/1 neoclassical tearing mode in a high-β spherical torus
Authors: Gerhardt S.P. , Brennan D.P. , Buttery R. , La Haye R.J. , Sabbagh S. , Strait E. , Bell M. , Bell R. , Fredrickson E. , Gates D. , LeBlanc B. , Menard J. , Stutman D. , Tritz K. , Yuh H.
Published: March 2009

The onset conditions for the m/n = 2/1 neoclassical tearing mode are studied in terms of neoclassical drive, triggering instabilities, and toroidal rotation or rotation shear, in the spherical torus NSTX (Ono M. et al
2000 Nucl. Fusion
40 557). There are three typical onset conditions for these modes, given in order of increasing neoclassical drive required for mode onset: triggering by energetic particle modes, triggering by edge localized modes and cases where the modes appear to grow without a trigger. In all cases, the required drive increases with toroidal rotation shear, implying a stabilizing effect from the shear.
Multivariate analysis of variance test for gene set analysis
Authors: Tsai Chen-An , Chen James J.
Published: March 2009

Motivation: Gene class testing (GCT) or gene set analysis (GSA) is a statistical approach to determine whether some functionally predefined sets of genes express differently under different experimental conditions. Shortcomings of the Fisher's exact test for the overrepresentation analysis are illustrated by an example. Most alternative GSA methods are developed for data collected from two experimental conditions, and most is based on a univariate gene-by-gene test statistic or assume independence among genes in the gene set. A multivariate analysis of variance (MANOVA) approach is proposed for studies with two or more experimental conditions.

Results: When the number of genes in the gene set is greater than the number of samples, the sample covariance matrix is singular and ill-condition. The use of standard multivariate methods can result in biases in the analysis. The proposed MANOVA test uses a shrinkage covariance matrix estimator for the sample covariance matrix. The MANOVA test and six other GSA published methods, principal component analysis, SAM-GS, analysis of covariance, Global, GSEA and MaxMean, are evaluated using simulation. The MANOVA test appears to perform the best in terms of control of type I error and power under the models considered in the simulation. Several publicly available microarray datasets under two and three experimental conditions are analyzed for illustrations of GSA. Most methods, except for GSEA and MaxMean, generally are comparable in terms of power of identification of significant gene sets.

Availability: A free R-code to perform MANOVA test is available at http://mail.cmu.edu.tw/~catsai/research.htm

Contact:  jamesj.chen@fda.hhs.gov; catsai@mail.cmu.edu.tw

Supplementary information:  Supplementary data are available at Bioinformatics online.
Laryngeal Mask Airway Is Associated with an Increased Incidence of Adverse Respiratory Events in Children with Recent Upper Respiratory Tract Infections
Authors: von Ungern-Sternberg Britta S. , Boda Krisztina , Schwab Craig , Sims Craig , Johnson Chris , Habre Walid
Published: March 2009

Background

The laryngeal mask airway (LMA) has been advocated as an alternative technique to tracheal intubation for airway management of children with recent upper respiratory tract infections (URIs). The authors determined the occurrence of adverse respiratory events and identified the associated risk factors to assess the safety of LMA in children.

Methods

During a period of 5 months, parents of children scheduled to undergo general anesthesia with an LMA were asked to fill out a questionnaire regarding their child's medical history and potential symptoms of URI. In addition, all episodes of adverse respiratory events in the perioperative period (laryngospasm, bronchospasm, coughing, airway obstruction, and oxygen desaturation) as well as details of anesthesia management were recorded.

Results

Among the 831 children included in the study, 27% presented with a history of a recent URI within the last 2 weeks before anesthesia. The presence of a recent URI doubled the incidence of laryngospasm (odds ratio, 2.6; 95% confidence interval, 1.3-5.0), coughing (odds ratio, 2.7; 95% confidence interval, 1.7-4.3), and oxygen desaturation (odds ratio, 1.9; 95% confidence interval, 1.2-2.8). This incidence was even higher in young children; in those undergoing ear, nose, and throat surgery; and when there were multiple attempts to insert the LMA.

Conclusion

An LMA used in children with recent URIs was associated with a higher incidence of laryngospasm, cough, and oxygen desaturation compared with healthy children. However, the overall incidence of adverse respiratory events was low, suggesting that if anesthesiologists allow at least a 2-week interval after a URI, they can safely proceed with anesthesia using an LMA.
Effect of Equiosmolar Solutions of Mannitol versus Hypertonic Saline on Intraoperative Brain Relaxation and Electrolyte Balance
Authors: Rozet Irene , Tontisirin Nuj , Muangman Saipin , Vavilala Monica S. , Souter Michael J. , Lee Lorri A. , Kincaid M Sean , Britz Gavin W. , Lam Arthur M.
Published: March 2009

Background

The purpose of the study was to compare the effect of equiosmolar solutions of mannitol and hypertonic saline (HS) on brain relaxation and electrolyte balance.

Methods

After institutional review board approval and informed consent, patients with American Society of Anesthesiologists physical status II-IV, scheduled to undergo craniotomy for various brain pathologies, were enrolled into this prospective, randomized, double-blind study. Patients received 5 ml/kg 20% mannitol (n = 20) or 3% HS (n = 20). Partial pressure of carbon dioxide in arterial blood was maintained at 35-40 mmHg, and central venous pressure was maintained at 5 mmHg or greater. Hemodynamic variables, fluid balance, blood gases, electrolytes, lactate, and osmolality (blood, cerebrospinal fluid, urine) were measured at 0, 15, 30, and 60 min and 6 h after infusion; arteriovenous difference of oxygen, glucose, and lactate were calculated. The surgeon assessed brain relaxation on a four-point scale (1 = relaxed, 2 = satisfactory, 3 = firm, 4 = bulging). Appropriate statistical tests were used for comparison; P < 0.05 was considered significant.

Results

There was no difference in brain relaxation (mannitol = 2, HS = 2 points; P = 0.8) or cerebral arteriovenous oxygen and lactate difference between HS and mannitol groups. Urine output with mannitol was higher than with HS (P < 0.03) and was associated with higher blood lactate over time (P < 0.001, compared with HS). Cerebrospinal fluid osmolality increased at 6 h in both groups (P < 0.05, compared with baseline). HS caused an increase in sodium in cerebrospinal fluid over time (P < 0.001, compared with mannitol).

Conclusion

Mannitol and HS cause an increase in cerebrospinal fluid osmolality, and are associated with similar brain relaxation scores and arteriovenous oxygen and lactate difference during craniotomy.
Adenosine A1but Not A2aReceptor Agonist Reduces Hyperalgesia Caused by a Surgical Incision in Rats
Authors: Zahn Peter K. , Straub Heidrun , Wenk Manuel , Pogatzki-Zahn Esther M.
Published: March 2009

Background

Activation of A1 adenosine receptors (A1Rs) causes antinociception after nerve injury and inflammation. However, the role of A2a adenosine receptors (A2aRs) for pain processing is less clear. In the current study, the authors investigated the role of spinal adenosine A1Rs and A2aRs for the maintenance of mechanical hyperalgesia in an animal model for postoperative pain.

Methods

Rats with intrathecal catheters were anesthetized and underwent plantar incision. Spontaneous pain behavior and withdrawal threshold to punctuate stimulation were measured before and after administration of intrathecal R-phenylisopropyl-adenosine (R-PIA; A1R agonist), 2-w p-2-carbonyl-ethyl-phenylethylaminox-5X-N-ethylcarboxami-doadenosine (CGS21680; A2aR agonist), or vehicle. In separate groups of animals, the effects of pertussis toxin, forskolin, glibenclamide, 4-aminopyridine, tetraethylammonium, apamin, charybdotoxin, or margatoxin on R-PIA-induced antinociception were examined.

Results

Intrathecal administration of 5 nmol R-PIA but not 10 nmol CGS21680 decreased nonevoked spontaneous pain behavior. Furthermore, intrathecal administration of R-PIA but not of CGS21680 increased withdrawal thresholds after incision. Pretreatment with pertussis toxin and administration of forskolin, glibenclamide, 4-aminopyridine, and tetraethylammonium inhibited R-PIA-induced antinociception. In addition, intrathecal administration of apamin, charybdotoxin, or margatoxin did not modify mechanical hypoalgesia mediated by R-PIA.

Conclusions

Spinal A1Rs but not A2aRs play an important role in the maintenance of nonevoked and evoked pain behaviors after an incision. Furthermore, A1R-induced spinal antinociception is mediated by interactions with pertussis toxin-sensitive G proteins. In addition, the opening of adenosine triphosphate-sensitive K channels but not of calcium-activated potassium channels and voltage-gated Kv1.3 or Kv1.6 channels contribute to the antinociceptive effect of A1R agonists.