bluuebunny/crossref_metadata_2025 huggingface dataset:
Different ENSO teleconnections and their effects on the stratospheric polar vortex
Authors: Garfinkel C. I. , Hartmann D. L.
Published: September 2008

Reanalysis data are used to study the El Niño–Southern Oscillation (ENSO) signal in the troposphere and stratosphere during the late fall to midwinter period. Warm ENSO events have extratropical tropospheric teleconnections that increase the wave 1 eddies and reduce the wave 2 eddies, as compared to cold ENSO. The increase in wave 1 overwhelms the decrease in wave 2, so the net effect is a weakened vortex. This modification in tropospheric wave forcing is induced by a deepening of the wintertime Aleutian low via the Pacific–North America pattern (PNA). Model results are also used to verify that the PNA is the primary mechanism through which ENSO modulates the vortex. During easterly Quasi‐Biennial Oscillation (EQBO), warm ENSO does not show a PNA response in the observational record. Consequently, the polar vortex does not show a strong response to the different phases of ENSO under EQBO, nor to the different phases of QBO under WENSO. It is not clear whether the lack of a PNA response to warm ENSO during EQBO is a real physical phenomenon or a feature of the limited data record we have.
Dating late Quaternary planktonic foraminifer Neogloboquadrina pachyderma from the Arctic Ocean using amino acid racemization
Authors: Kaufman Darrell S. , Polyak Leonid , Adler Ruth , Channell James E. T. , Xuan Chuang
Published: September 2008

The long‐term rate of racemization for amino acids preserved in planktonic foraminifera was determined by using independently dated sediment cores from the Arctic Ocean. The racemization rates for aspartic acid (Asp) and glutamic acid (Glu) in the common taxon, Neogloboquadrina pachyderma, were calibrated for the last 150 ka using 14C ages and the emerging Quaternary chronostratigraphy of Arctic Ocean sediments. An analysis of errors indicates realistic age uncertainties of about ±12% for Asp and ±17% for Glu. Fifty individual tests are sufficient to analyze multiple subsamples, identify outliers, and derive robust sample mean values. The new age equation can be applied to verify and refine age models for sediment cores elsewhere in the Arctic Ocean, a critical region for understanding the dynamics of global climate change.
Central muscarinic receptor subtypes involved in pilocarpine‐induced salivation, hypertension and water intake
Authors: Borella T L , De Luca L A , Colombari D S A , Menani J V
Published: September 2008

Background and purpose:

Recent evidence has suggested that pilocarpine (ACh receptor agonist) injected peripherally may act centrally producing salivation and hypertension. In this study, we investigated the effects of specific M1(pirenzepine), M2/M4(methoctramine), M1/M3(4‐DAMP) and M4(tropicamide) muscarinic receptor subtype antagonists injected into the lateral cerebral ventricle (LV) on salivation, water intake and pressor responses to peripheral pilocarpine.

Experimental approach:

Male Holtzman rats with stainless steel cannulae implanted in the LV were used. Salivation was measured in rats anaesthetized with ketamine (100 mg per kg body weight) and arterial pressure was recorded in unanaesthetized rats.

Key results:

Salivation induced by i.p. pilocarpine (4 μmol per kg body weight) was reduced only by 4‐DAMP (25–250 nmol) injected into the LV, not by pirenzepine, methoctramine or tropicamide at the dose of 500 nmol. Pirenzepine (0.1 and 1 nmol) and 4‐DAMP (5 and 10 nmol) injected into the LV reduced i.p. pilocarpine‐induced water intake, whereas metoctramine (50 nmol) produced nonspecific effects on ingestive behaviours. Injection of pirenzepine (100 nmol) or 4‐DAMP (25 and 50 nmol) into the LV reduced i.v. pilocarpine‐induced pressor responses. Tropicamide (500 nmol) injected into the LV had no effect on pilocarpine‐induced salivation, pressor responses or water intake.

Conclusions and implications:

The results suggest that central M3receptors are involved in peripheral pilocarpine‐induced salivation and M1receptors in water intake and pressor responses. The involvement of M3receptors in water intake and pressor responses is not clear because 4‐DAMP blocks both M1and M3receptors.

British Journal of Pharmacology(2008)155, 1256–1263; doi:10.1038/bjp.2008.355; published online 29 September 2008
Reflections on Phonological Working Memory, Letter Knowledge, and Phonological Awareness: A Reply to Hartmann (2008)
Authors: Rvachew Susan , Grawburg Meghann
Published: September 2008

Purpose

S. Rvachew and M. Grawburg (2006) found that speech perception and vocabulary skills jointly predicted the phonological awareness skills of children with a speech sound disorder. E. Hartmann (2008) suggested that the Rvachew and Grawburg model would be improved by the addition of phonological working memory. Hartmann further suggested that the link between phoneme awareness and letter knowledge should be modeled as a reciprocal relationship. In this letter, Rvachew and Grawburg respond to Hartmann’s suggestions for modification of the model.

Method

The literature on the role of phonological working memory in the development of vocabulary knowledge and phonological awareness was reviewed. Data presented previously by Rvachew and Grawburg (2006) and Rvachew (2006) were reanalyzed.

Results

The reanalysis of previously reported longitudinal data revealed that the relationship between letter knowledge and specific aspects of phonological awareness was not reciprocal for kindergarten-age children with a speech sound disorder.

Conclusions

Phonological working memory, if measured so that relative performance levels do not reflect differences in articulatory accuracy, may not alter the model because of its close correspondence with speech perception skills. However, further study of the hypothesized causal relationships modeled by Rvachew and Grawburg (2006) would be valuable, especially if experimental research designs were used.
Three-dimensional finite element thermal analysis of dental tissues irradiated with Er,Cr:YSGG laser
Authors: Ana Patricia Aparecida , Velloso Walter F. , Zezell Denise Maria
Published: September 2008

In the present study, a finite element model of a half-sectioned molar tooth was developed in order to understand the thermal behavior of dental hard tissues (both enamel and dentin) under laser irradiation. The model was validated by comparing it with an in vitro experiment where a sound molar tooth was irradiated by an Er,Cr:YSGG pulsed laser. The numerical tooth model was conceived to simulate the in vitro experiment, reproducing the dimensions and physical conditions of the typical molar sound tooth, considering laser energy absorption and calculating the heat transfer through the dental tissues in three dimensions. The numerical assay considered the same three laser energy densities at the same wavelength (2.79μm) used in the experiment. A thermographic camera was used to perform the in vitro experiment, in which an Er,Cr:YSGG laser (2.79μm) was used to irradiate tooth samples and the infrared images obtained were stored and analyzed. The temperature increments in both the finite element model and the in vitro experiment were compared. The distribution of temperature inside the tooth versus time plotted for two critical points showed a relatively good agreement between the results of the experiment and model. The three dimensional model allows one to understand how the heat propagates through the dentin and enamel and to relate the amount of energy applied, width of the laser pulses, and temperature inside the tooth.
Influence of combined deformation and heat treatment on the superconducting properties of a niobium-titanium alloy
Authors: Beloshenko V. A. , Matrosov N. I. , Chishko V. V. , Mironova O. N. , Medvedskaya É. A. , Gajda D. , Zaleski A. J. , Dyakonov V. P. , Puźniak R. , Szymczak H.
Published: September 2008

The influence of combined deformation, including equal-channel multiangle pressing (ECMAP), and heat treatment on the critical current density of a superconducting wire made from the alloy Nb+60at.% Ti is investigated. It is found that the combined deformation, including ECMAP, can increase the critical current density by up to two times. The relationship between the character of the structural inhomogeneities and the pinning force is estimated. The pinning efficiency is linked to the nanostructural state of the alloy.
The controlled relaminarization of low velocity ratio elevated jets-in-crossflow
Authors: Watson G. M. G. , Sigurdson L. W.
Published: September 2008

The controlled suppression of instabilities, or “relaminarization,” in low velocity ratio and Reynolds number elevated jets-in-crossflow (JICFs) is discussed for jet-to-crossflow velocity ratios (R) less than 1.5 and jet Reynolds numbers (Red) less than 2000. The principal control method is via a synthetic jet from an annular slit coaxially surrounding the jet flow. Effects of forcing the JICF jet shear layer are studied using photographs obtained by smoke flow visualization, single point hot-wire measurements, and field measurements using a form of image correlation velocimetry on the smoke images. The unforced JICF is unstable in two R regimes separated by a window of stability centered around the velocity ratio R=1.13. In the lower unstable regime where there is formation of strong jet shear layer instabilities, the synthetic jet can suppress them. A mechanism for the suppression phenomenon is proposed. The synthetic jet reduces the local Reynolds number of a wakelike profile on the upstream side of the JICF between the free stream and jet flow below critical values for growth of an unstable flow structure. The control mechanism has many similarities to base bleed suppression of von Kármán vortex shedding in supercritical bluff bodies. A continuous stream from the same annular slit does indeed have a similar suppression effect to synthetic jet forcing.
Computational exploration of polymer nanocomposite mechanical property modification via cross-linking topology
Authors: Lacevic Naida , Gee Richard H. , Saab Andrew , Maxwell Robert
Published: September 2008

Molecular dynamics simulations have been performed in order to study the effects of nanoscale filler cross-linking topologies and loading levels on the mechanical properties of a model elastomeric nanocomposite. The model system considered here is constructed from octafunctional polyhedral oligomeric silsesquioxane (POSS) dispersed in a poly(dimethylsiloxane) (PDMS) matrix. Shear moduli, G, have been computed for pure and for filled and unfilled PDMS as a function of cross-linking density, POSS fill loading level, and polymer network topology. The results reported here show that G increases as the cross-linking (covalent bonds formed between the POSS and the PDMS network) density increases. Further, G is found to have a strong dependence on cross-linking topology. The increase in shear modulus, G, for POSS filled PDMS is significantly higher than that for unfilled PDMS cross-linked with standard molecular species, suggesting an enhanced reinforcement mechanism for POSS. In contrast, in blended systems (POSS/PDMS mixture with no cross-linking) G was not observed to significantly increase with POSS loading. Finally, we find intriguing differences in the structural arrangement of bond strains between the cross-linked and the blended systems. In the unfilled PDMS the distribution of highly strained bonds appears to be random, while in the POSS filled system, the strained bonds form a netlike distribution that spans the network. Such a distribution may form a structural network “holding” the composite together and resulting in increases in G compared to an unfilled, cross-linked system. These results are of importance for engineering of new POSS-based multifunctional materials with tailor-made mechanical properties.
Self-consistent generalized Kohn-Sham local hybrid functionals of screened exchange: Combining local and range-separated hybridization
Authors: Janesko Benjamin G. , Krukau Aliaksandr V. , Scuseria Gustavo E.
Published: September 2008

We present local hybrid functionals that incorporate a position-dependent admixture of short-range (screened) nonlocal exact [Hartree-Fock-type (HF)] exchange. We test two limiting cases: screened local hybrids with no long-range HF exchange and long-range-corrected local hybrids with 100% long-range HF exchange. Long-range-corrected local hybrids provide the exact asymptotic exchange-correlation potential in finite systems, while screened local hybrids avoid the problems inherent to long-range HF exchange in metals and small-bandgap systems. We treat these functionals self-consistently using the nonlocal exchange potential constructed from Kohn-Sham orbital derivatives. Generalized Kohn-Sham calculations with screened and long-range-corrected local hybrids can provide accurate molecular thermochemistry and kinetics, comparable to existing local hybrids of full-range exchange. Generalized Kohn-Sham calculations with existing full-range local hybrids provide results consistent with previous non-self-consistent and “localized local hybrid” calculations. These new functionals appear to provide a promising extension of existing local and range-separated hybrids.
Linearized semiclassical initial value time correlation functions with maximum entropy analytic continuation
Authors: Liu Jian , Miller William H.
Published: September 2008

The maximum entropy analytic continuation (MEAC) method is used to extend the range of accuracy of the linearized semiclassical initial value representation (LSC-IVR)/classical Wigner approximation for real time correlation functions. LSC-IVR provides a very effective “prior” for the MEAC procedure since it is very good for short times, exact for all time and temperature for harmonic potentials (even for correlation functions of nonlinear operators), and becomes exact in the classical high temperature limit. This combined MEAC+LSC/IVR approach is applied here to two highly nonlinear dynamical systems, a pure quartic potential in one dimensional and liquid para-hydrogen at two thermal state points (25 and 14 K under nearly zero external pressure). The former example shows the MEAC procedure to be a very significant enhancement of the LSC-IVR for correlation functions of both linear and nonlinear operators, and especially at low temperature where semiclassical approximations are least accurate. For liquid para-hydrogen, the LSC-IVR is seen already to be excellent at T=25 K, but the MEAC procedure produces a significant correction at the lower temperature (T=14 K). Comparisons are also made as to how the MEAC procedure is able to provide corrections for other trajectory-based dynamical approximations when used as priors.
A direct multiple histogram reweighting method for optimal computation of the density of states
Authors: Fenwick Michael K.
Published: September 2008

A simple nonparametric procedure is devised for constructing Boltzmann entropy functions from statistically weighted entropy differences calculated from overlapping histograms. The method is noniterative, avoids numerical problems associated with large state densities, and accommodates variable bin widths for reducing systematic and statistical errors inherent to histogram techniques. Results show that the procedure can yield thermodynamic functions for an Ising spin lattice model that have average errors comparable to ones obtained from a conventional approach. Analysis of thermofunctions computed for a polyalanine peptide simulated by hybrid Monte Carlo replica exchange indicates that method performance can be enhanced through the use of nonuniform state space discretization schemes. An extension of the reweighting procedure for multidimensional applications is presented through calculations of vapor-liquid equilibrium densities of a model fluid simulated by grand canonical replica exchange.
Polarization switching using single-walled carbon nanotubes grown on epitaxial ferroelectric thin films
Authors: Paruch P. , Posadas A.-B. , Dawber M. , Ahn C. H. , McEuen P. L.
Published: September 2008

We have directly grown single-walled carbon nanotubes on epitaxial BaTiO3 thin films, fabricating prototype carbon nanotube-ferroelectric devices. We demonstrate polarization switching using the nanotube as a local electric field source and compare the results to switching with an atomic force microscopy tip. The observed variation of domain growth rates in the two cases agrees with the changes in electric field intensity at the ferroelectric surface.
6:1 aspect ratio silicon pillar based thermal neutron detector filled with B10
Authors: Nikolić R. J. , Conway A. M. , Reinhardt C. E. , Graff R. T. , Wang T. F. , Deo N. , Cheung C. L.
Published: September 2008

Current helium-3 tube based thermal neutron detectors have shortcomings in achieving simultaneously high efficiency and low voltage while maintaining adequate fieldability performance. By using a three-dimensional silicon p-i-n diode pillar array filled with boron-10 these constraints can be overcome. The fabricated pillar structured detector reported here is composed of 2μm diameter silicon pillars with a 4μm pitch and height of 12μm. A thermal neutron detection efficiency of 7.3+∕−0.6% and a neutron-to-gamma discrimination of 105 at 2V reverse bias were measured for this detector. When scaled to larger aspect ratio, a high efficiency device is possible.
An annealing study of an oxygen vacancy related defect in SrTiO3 substrates
Authors: Zvanut M. E. , Jeddy S. , Towett E. , Janowski G. M. , Brooks C. , Schlom D.
Published: September 2008

The study addresses the stability of point defects in SrTiO3 (STO) during thin film processing using electron paramagnetic resonance (EPR) spectroscopy. In particular, the intensity of the Fe3+VO EPR signal is monitored after various steps during the growth of STO films on STO substrates. Controlled O2 and vacuum heat treatments are also performed to clarify the fundamental mechanisms responsible for the effects of different processing steps. Comparison of results from film fabrication with those obtained during exposure to the control ambient shows that the presence of oxygen in the pretreatment growth atmosphere decreases the amount of the Fe3+VO complex, but exposure to the low pressure environment of the growth chamber returns the signal to the original intensity. These results are consistent with accepted theories of oxygen vacancy diffusion. However, an unexpected decrease in the oxygen vacancy related signal is also observed during vacuum treatment of an as-received sample. Furthermore, the decrease occurs over the same temperature range as seen for an O2 anneal. The difference between the O2 and vacuum treatments is revealed in postannealing photoinduced EPR and resistivity measurements, which indicate that vacancy related centers change charge state during the O2 anneal and are not removed by oxygen. The effect of the vacuum treatment, though different from that of oxygen, is not yet clear as no charge state changes were induced after exposure to visible or ultraviolet radiation, but the conductivity of the samples changed.
Insider Perspectives on Institutional Change in Contemporary British Forestry: Identity and Environmental Governance
Authors: Schiellerup Pernille
Published: September 2008

investigate British forestry policy using original primary data from interviews with staff working for the Forestry Commission. Insight is provided into one of Britain's oldest institutions of environmental governance as it sought to redefine its contribution to society at a particularly turbulent period in its recent history. The work is presented in relationship to institutional change in rural areas, environmental governance, and postproductivism. A conceptual framework is employed using ideas from Giddens's structuration theory, Goffman's collaborative production of identities, and Foucault's discourse theory. Particular attention is paid to the implications of transitions for collective and individual work-based identities.
Geopolitics, Ethics, and the Evangelicals' Commitment to Sudan
Authors: Gerhardt Hannes
Published: September 2008

When considering the intersection between geographical knowledge and geopolitical practice, emphasis generally falls on the state and the state's self-serving calculations. This paper, instead, focuses on geopolitical civil society, emphasizing the role that rationalized norms and emotive care-ethics play in molding and facilitating certain forms of geographical knowledge and subsequent foreign interventions. The case to illuminate this theoretical focus centers on American evangelical actors and their specific geopolitical vision, which is largely based on the perceived universal authority of the Bible. The case illustrates how the religious normative imperative to evangelize the world has led to geographically blunt imaginaries that present spaces of alterity as being in urgent need of spiritual and also geopolitical intervention. Opposed to such imaginaries, however, this paper also traces the emergence of an ethics of care that has developed within evangelical circles regarding the people of southern Sudan. This more specific and immediately felt ethical impulse is shown to maintain a more nuanced understanding of heterotopic place. It is argued that there is a frequent clash between such universalist ethical impulses, which tend to code global space according to a particular normative paradigm, and particularist ethical impulses, which are based on a care-ethics that is rooted in an attachment too and an understanding of a particular place. This paper makes the case that, given the right communication channels, these varying ethical impulses can lead to a transformative communication in which universalist geopolitical visions are adapted to place-specific heterotopic geographical realities.
Role of selection in the emergence of lineages and the evolution of virulence in
Neisseria meningitidis
Authors: Buckee Caroline O. , Jolley Keith A. , Recker Mario , Penman Bridget , Kriz Paula , Gupta Sunetra , Maiden Martin C. J.
Published: September 2008

Neisseria meningitis
is a human commensal bacterium that occasionally causes life-threatening disease. As with a number of other bacterial pathogens, meningococcal populations comprise distinct lineages, which persist over many decades and during global spread in the face of high rates of recombination. In addition, the propensity to cause invasive disease is associated with particular “hyperinvasive” lineages that coexist with less invasive lineages despite the fact that disease does not contribute to host-to-host transmission. Here, by combining a modeling approach with molecular epidemiological data from 1,108 meningococci isolated in the Czech Republic over 27 years, we show that interstrain competition, mediated by immune selection, can explain both the persistence of multiple discrete meningococcal lineages and the association of a subset of these with invasive disease. The model indicates that the combinations of allelic variants of housekeeping genes that define these lineages are associated with very small differences in transmission efficiency among hosts. These findings have general implications for the emergence of lineage structure and virulence in recombining bacterial populations.
Drug interactions modulate the potential for evolution of resistance
Authors: Michel Jean-Baptiste , Yeh Pamela J. , Chait Remy , Moellering Robert C. , Kishony Roy
Published: September 2008

Antimicrobial treatments increasingly rely on multidrug combinations, in part because of the emergence and spread of antibiotic resistance. The continued effectiveness of combination treatments depends crucially on the frequency with which multidrug resistance arises. Yet, it is unknown how this propensity for resistance depends on cross-resistance and on epistatic interactions—ranging from synergy to antagonism—between the drugs. Here, we analyzed how interactions between pairs of drugs affect the spontaneous emergence of resistance in the medically important pathogenStaphylococcus aureus. Resistance is selected for within a window of drug concentrations high enough to inhibit wild-type growth but low enough for some resistant mutants to grow. Introducing an experimental method for high-throughput colony imaging, we counted resistant colonies arising across a two-dimensional matrix of drug concentrations for each of three drug pairs. Our data show that these different drug combinations have significantly different impacts on the size of the window of drug concentrations where resistance is selected for. We framed these results in a mathematical model in which the frequencies of resistance to single drugs, cross-resistance, and epistasis combine to determine the propensity for multidrug resistance. The theory suggests that drug pairs which interact synergistically, preferred for their immediate efficacy, may in fact favor the future evolution of resistance. This framework reveals the central role of drug epistasis in the evolution of resistance and points to new strategies for combating the emergence of drug-resistant bacteria.
Analysis and synthesis of high-amplitude
Cis
-elements in the mammalian circadian clock
Authors: Kumaki Yuichi , Ukai-Tadenuma Maki , Uno Ken-ichiro D. , Nishio Junko , Masumoto Koh-hei , Nagano Mamoru , Komori Takashi , Shigeyoshi Yasufumi , Hogenesch John B. , Ueda Hiroki R.
Published: September 2008

Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements. As a step toward system-level understanding of the dynamic transcriptional regulation of the oscillator, we constructed and used a mammalian promoter/enhancer database (
http://promoter.cdb.riken.jp/
) with computational models of the Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements to predict new targets of the clock and subsequently validated these targets at the level of the cell and organism. We further demonstrated the predictive nature of these models by generating and testing synthetic regulatory elements that do not occur in nature and showed that these elements produced high-amplitude circadian gene regulation. Biochemical experiments to characterize these synthetic elements revealed the importance of the affinity balance between transactivators and transrepressors in generating high-amplitude circadian transcriptional output. These results highlight the power of comparative genomics approaches for system-level identification and knowledge-based design of dynamic regulatory circuits.
RNAi screening for kinases and phosphatases identifies FoxO regulators
Authors: Mattila Jaakko , Kallijärvi Jukka , Puig Oscar
Published: September 2008

Forkhead box class O (FoxO) transcription factors are key regulators of growth, metabolism, life span, and stress resistance. FoxOs integrate signals from different pathways and guide the cellular response to varying energy and stress conditions. FoxOs are modulated by several signaling pathways, e.g., the insulin-TOR signaling pathway and the stress induced JNK signaling pathway. Here, we report a genome wide RNAi screen of kinases and phosphatases aiming to find regulators of dFoxO activity in
Drosophila
S2 cells. By using a combination of transcriptional activity and localization assays we identified several enzymes that modulate dFoxO transcriptional activity, intracellular localization and/or protein stability. Importantly, several currently known dFoxO regulators were found in the screening, confirming the validity of our approach. In addition, several interesting new regulators were identified, including protein kinase C and glycogen synthase kinase 3β, two proteins with important roles in insulin signaling. Furthermore, several mammalian orthologs of the proteins identified in
Drosophila
also regulate FOXO activity in mammalian cells. Our results contribute to a comprehensive understanding of FoxO regulatory processes.
Computational prediction of RNA structural motifs involved in posttranscriptional regulatory processes
Authors: Rabani Michal , Kertesz Michael , Segal Eran
Published: September 2008

Messenger RNA molecules are tightly regulated, mostly through interactions with proteins and other RNAs, but the mechanisms that confer the specificity of such interactions are poorly understood. It is clear, however, that this specificity is determined by both the nucleotide sequence and secondary structure of the mRNA. Here, we develop RNApromo, an efficient computational tool for identifying structural elements within mRNAs that are involved in specifying posttranscriptional regulations. By analyzing experimental data on mRNA decay rates, we identify common structural elements in fast-decaying and slow-decaying mRNAs and link them with binding preferences of several RNA binding proteins. We also predict structural elements in sets of mRNAs with common subcellular localization in mouse neurons and fly embryos. Finally, by analyzing pre-microRNA stem–loops, we identify structural differences between pre-microRNAs of animals and plants, which provide insights into the mechanism of microRNA biogenesis. Together, our results reveal unexplored layers of posttranscriptional regulations in groups of RNAs and are therefore an important step toward a better understanding of the regulatory information conveyed within RNA molecules. Our new RNA motif discovery tool is available online.
Control of feeding behavior inC. elegansby human G protein-coupled receptors permits screening for agonist-expressing bacteria
Authors: Teng Michelle S. , Shadbolt Paul , Fraser Andrew G. , Jansen Gert , McCafferty John
Published: September 2008

G protein-coupled receptors (GPCRs) have a key role in many biological processes and are important drug targets for many human diseases. Therefore, understanding the molecular interactions between GPCRs and their ligands would improve drug design. Here, we describe an approach that allows the rapid identification of functional agonists expressed in bacteria. TransgenicCaenorhabditis elegansexpressing the human chemokine receptor 5 (CCR5) in nociceptive neurons show avoidance behavior on encounter with the ligand MIP-1α and avoid feeding onEscherichia coliexpressing MIP-1α compared with control bacteria. This system allows a simple activity screen, based on the distribution of transgenic worms in a binary food-choice assay, without a requirement for protein purification or tagging. By using this approach, a library of 68 MIP-1α variants was screened, and 13 critical agonist residues involved in CCR5 activation were identified, four of which (T8, A9, N22, and A25) have not been described previously, to our knowledge. Identified residues were subsequently validated in receptor binding assays and by calcium flux assays in mammalian cells. This approach serves not only for structure/function studies as demonstrated, but may be used to facilitate the discovery of agonists within bacterial libraries.
Experimental characterization of shear transformation zones for plastic flow of bulk metallic glasses
Authors: Pan D. , Inoue A. , Sakurai T. , Chen M. W.
Published: September 2008

We report experimental characterization of shear transformation zones (STZs) for plastic flow of bulk metallic glasses (BMGs) based on a newly developed cooperative shearing model [Johnson WL, Samwer K (2005) A universal criterion for plastic yielding of metallic glasses with a (T/T
g
)
2/3
temperature dependence.
Phys Rev Lett
95: 195501]. The good agreement between experimental measurements and theoretical predictions in the STZ volumes provides compelling evidence that the plastic flow of metallic glasses occurs through cooperative shearing of unstable STZs activated by shear stresses. Moreover, the ductility of BMGs was found to intrinsically correlate with their STZ volumes. The experiments presented herein pave a way to gain a quantitative insight into the atomic-scale mechanisms of BMG mechanical behavior.
cAMP/PKA signaling and RIM1α mediate presynaptic LTP in the lateral amygdala
Authors: Fourcaudot Elodie , Gambino Frédéric , Humeau Yann , Casassus Guillaume , Shaban Hamdy , Poulain Bernard , Lüthi Andreas
Published: September 2008

NMDA receptor-dependent long-term potentiation (LTP) of glutamatergic synaptic transmission in sensory pathways from auditory thalamus or cortex to the lateral amygdala (LA) underlies the acquisition of auditory fear conditioning. Whereas the mechanisms of postsynaptic LTP at thalamo–LA synapses are well understood, much less is known about the sequence of events mediating presynaptic NMDA receptor-dependent LTP at cortico–LA synapses. Here, we show that presynaptic cortico–LA LTP can be entirely accounted for by a persistent increase in the vesicular release probability. At the molecular level, we found that signaling via the cAMP/PKA pathway is necessary and sufficient for LTP induction. Moreover, by using mice lacking the active-zone protein and PKA target RIM1α (
RIM1
α
−/−
), we demonstrate that RIM1α is required for both chemically and synaptically induced presynaptic LTP. Further analysis of cortico–LA synaptic transmission in
RIM1
α
−/−
mice revealed a deficit in Ca
2+
-release coupling leading to a lower baseline release probability. Our results reveal the molecular mechanisms underlying the induction of presynaptic LTP at cortico–LA synapses and indicate that RIM1α-dependent LTP may involve changes in Ca
2+
-release coupling.
Higher criticism thresholding: Optimal feature selection when useful features are rare and weak
Authors: Donoho David , Jin Jiashun
Published: September 2008

In important application fields today—genomics and proteomics are examples—selecting a small subset of useful features is crucial for success of Linear Classification Analysis. We study feature selection by thresholding of featureZ-scores and introduce a principle of threshold selection, based on the notion ofhigher criticism(HC). Fori= 1, 2, …,p, let πidenote the two-sidedP-value associated with theith featureZ-score and π(i)denote theith order statistic of the collection ofP-values. The HC threshold is the absoluteZ-score corresponding to theP-value maximizing the HC objective (i/p− π(i))/i/p(1−i/p). We consider a rare/weak (RW) feature model, where the fraction of useful features is small and the useful features are each too weak to be of much use on their own. HC thresholding (HCT) has interesting behavior in this setting, with an intimate link between maximizing the HC objective and minimizing the error rate of the designed classifier, and very different behavior from popular threshold selection procedures such as false discovery rate thresholding (FDRT). In the most challenging RW settings, HCT uses an unconventionally low threshold; this keeps the missed-feature detection rate under better control than FDRT and yields a classifier with improved misclassification performance. Replacing cross-validated threshold selection in the popular Shrunken Centroid classifier with the computationally less expensive and simpler HCT reduces the variance of the selected threshold and the error rate of the constructed classifier. Results on standard real datasets and in asymptotic theory confirm the advantages of HCT.
Distinct size distribution of endogenous siRNAs in maize: Evidence from deep sequencing in the
mop1-1
mutant
Authors: Nobuta Kan , Lu Cheng , Shrivastava Roli , Pillay Manoj , De Paoli Emanuele , Accerbi Monica , Arteaga-Vazquez Mario , Sidorenko Lyudmila , Jeong Dong-Hoon , Yen Yang , Green Pamela J. , Chandler Vicki L. , Meyers Blake C.
Published: September 2008

Small RNAs from plants are known to be highly complex and abundant, with this complexity proportional to genome size. Most endogenous siRNAs in
Arabidopsis
are dependent on
RNA-DEPENDENT RNA POLYMERASE 2
(
RDR2
) for their biogenesis. Recent work has demonstrated that the maize
MEDIATOR OF PARAMUTATION1
(
mop1
) gene is a predicted ortholog of
RDR2
. The
mop1
gene is required for establishment of paramutation and maintenance of transcriptional silencing of transposons and transgenes, suggesting the potential involvement of small RNAs. We analyzed small RNAs in wild-type maize and in the isogenic
mop1-1
loss-of-function mutant by using Illumina's sequencing-by-synthesis (SBS) technology, which allowed us to characterize the complement of maize small RNAs to considerable depth. Similar to
rdr2
in
Arabidopsis
, in
mop1-1
, the 24-nucleotide (nt) endogenous heterochromatic short-interfering siRNAs were dramatically reduced, resulting in an enrichment of miRNAs and transacting siRNAs. In contrast to the
Arabidopsis rdr2
mutant, the
mop1-1
plants retained a highly abundant heterochromatic ≈22-nt class of small RNAs, suggesting a second mechanism for heterochromatic siRNA production. The enrichment of miRNAs and loss of 24-nt heterochromatic siRNAs in
mop1-1
should be advantageous for miRNA discovery as the maize genome becomes more fully sequenced.
Opposing functions of IKKβ during acute and chronic intestinal inflammation
Authors: Eckmann Lars , Nebelsiek Tim , Fingerle Alexander A. , Dann Sara M. , Mages Jörg , Lang Roland , Robine Sylvie , Kagnoff Martin F. , Schmid Roland M. , Karin Michael , Arkan Melek C. , Greten Florian R.
Published: September 2008

NF-κB is a key transcriptional regulator of inflammatory responses, but also controls expression of prosurvival genes, whose products protect tissues from damage and may thus act indirectly in an antiinflammatory fashion. The variable importance of these two distinct NF-κB-controlled responses impacts the potential utility of NF-κB inhibition as a treatment strategy for intractable inflammatory conditions, such as inflammatory bowel disease. Here, we show in murine models that inhibition of IKKβ-dependent NF-κB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract. Acute ulcerating inflammation is aggravated because of diminished NF-κB-mediated protection against epithelial cell apoptosis and delayed mucosal regeneration secondary to reduced NF-κB-dependent recruitment of inflammatory cells that secrete cytoprotective factors. In contrast, in IL-10-deficient mice, which serve as a model of chronic T cell-dependent colitis, ablation of IKKβ in the intestinal epithelium has no impact, yet IKKβ deficiency in myeloid cells attenuates inflammation and prolongs survival. These results highlight the striking context and tissue dependence of the proinflammatory and antiapoptotic functions of NF-κB. Our findings caution against the therapeutic use of IKKβ/NF-κB inhibitors in acute inflammatory settings dominated by cell loss and ulceration.
In vivo
enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner
Authors: Albert Heike , Collin Mattias , Dudziak Diana , Ravetch Jeffrey V. , Nimmerjahn Falk
Published: September 2008

IgG antibodies are potent inducers of proinflammatory responses. During autoimmune diseases such as arthritis and systemic lupus erythematosus, IgG autoantibodies are responsible for the chronic inflammation and destruction of healthy tissues by cross-linking Fc receptors on innate immune effector cells. The sugar moiety attached to the asparagine-297 residue in the constant domain of the antibody is critical for the overall structure and function of the molecule. Removal of this sugar domain leads to the loss of the proinflammatory activity, suggesting that
in vivo
modulation of antibody glycosylation might be a strategy to interfere with autoimmune processes. In this work, we investigated whether removal of the majority of the IgG-associated sugar domain by endoglycosidase S (EndoS) from
Streptococcus pyogenes
is able to interfere with autoimmune inflammation. We demonstrate that EndoS injection efficiently removes the IgG-associated sugar domain
in vivo
and interferes with autoantibody-mediated proinflammatory processes in a variety of autoimmune models. Importantly, however, we observed a differential impact of EndoS-mediated sugar side chain hydrolysis on IgG activity depending on the individual IgG subclass.
Energy balance and cancer: the role of sex hormones
Authors: Key Timothy J. , Allen Naomi E. , Verkasalo Pia K. , Banks Emily
Published: September 2008

Energy balance can affect the risk for hormone-related cancers by altering sex hormone levels. Energy intake and expenditure are difficult to measure in epidemiological studies, but a chronic excess of intake relative to expenditure leads to a high BMI, which can be accurately measured. In premenopausal women obesity has little effect on the serum concentration of oestradiol, but causes an increase in the frequency of anovular menstrual cycles and thus a reduction in progesterone levels; these changes lead to a large increase in the risk for endometrial cancer, but little change, or a small decrease, in the risk for breast cancer. In post-menopausal women oestradiol levels are not regulated by negative feedback, and obesity causes an increase in the serum concentration of bioavailable oestradiol; this factor causes increases in the risk for both endometrial cancer and breast cancer. The development of ovarian cancer appears to be related more strongly to the frequency of ovulation than to direct effects of circulating levels of sex hormones, and BMI is not clearly associated with the risk for ovarian cancer. In men, increasing BMI has little effect on bioavailable androgen levels, and any effect of obesity on prostate cancer risk is small.
Microencapsulation: its application in nutrition
Authors: Schrooyen P. M. M. , Meer R. van der , Kruif C. G. De
Published: September 2008

The development of new functional foods requires technologies for incorporating health-promoting ingredients into food without reducing their bioavailability or functionality. In many cases, microencapsulation can provide the necessary protection for these compounds, but in all cases bioavailability should be carefully studied. The present paper gives an overview of the application of various microencapsulation technologies to nutritionally-important compounds, i.e. vitamins, n-3 polyunsaturated fatty acids, Ca, Fe and antioxidants. It also gives a view on future technologies and trends in microencapsulation technology for nutritional applications.
Nutrient partitioning between reproductive and immune functions in animals
Authors: Houdijk Jos G. M. , Jessop Neil S. , Kyriazakis Ilias
Published: September 2008

The physiological processes that underlie the reproductive cycle impose considerable metabolisable protein (MP) demands on a female, especially during the periparturient period. When MP supply falls short of MP demand (i.e. MP becomes scarce), certain, if not all, bodily functions are expected to be penalised. It has been proposed that partitioning of scarce MP is prioritised to reproductive rather than to immune functions. In other words, at times of MP scarcity, the penalty on expression of immunity would be expected to be greater than that on reproduction. This hypothesis forms a nutritional basis for the occurrence of periparturient breakdown of immunity to parasites (BIP), which can be observed in many host–parasite systems. In the present review we explore this nutritional basis, using periparturient sheep infected with the abomasal nematodeTeladorsagia circumcinctaas an example, and attempt to quantify its occurrence. Evidence supporting the nutritional basis of periparturient BIP is reviewed, covering experiments in which nutrient supply (from both exogenous and endogenous sources) and/or nutrient demand were manipulated. Quantitatively, MP requirements for expression of immunity toT. circumcinctawere estimated to be about 1 g/kg metabolic body weight (body weight0·75) per d, approximately 5 % of the maximum MP requirements of periparturient sheep. The major component of this requirement was assumed to be for replenishing irreversible plasma protein losses into the gastrointestinal tract. Although confirmation of this estimate is required, such estimates may be used to improve the known MP requirements of periparturient animals, enabling the extent and the consequences of periparturient BIP to be minimised.
How dietary antigens access the mucosal immune system
Authors: Heyman M.
Published: September 2008

The intestinal epithelium is a selective barrier where incompletely-digested food antigens are transmitted to the immune system. Food antigens are often the starting point of intestinal diseases such as food allergy or coeliac disease. The intestinal epithelial cells (IEC) take up and process food antigens mainly by fluid-phase transcytosis involving two functional pathways, one minor direct pathway without degradation and another major lysosomal degradative pathway. Among the peptidic metabolites generated during transepithelial transport of luminal antigens, some have a molecular mass compatible with a binding to restriction (major histocompatibility complex; MHC) molecules; the latter can be up regulated on enterocytes, especially in inflammatory conditions. Indeed, interferon-γ not only increases the paracellular absorption of antigens, but also their transcytosis across epithelial cells. It has been reported that enterocytes may even directly present peptidic epitopes to underlying T-cells. As a new potential way of transmitting peptidic information to the local or systemic immune system, the secretion by IEC of antigen-presenting vesicles called exosomes and bearing MHC–peptide complexes has recently been proposed. Many other factors such as nutritional or environmental factors can also influence the properties of the epithelial barrier and the outcome of the immune response to lumen antigens.
Mad cows, mad corn and mad communities: the role of socio-cultural factors in the perceived risk of genetically-modified food
Authors: Finucane Melissa L.
Published: September 2008

The rapid globalization of the world economy has increased the need for a knowledge base of reliable socio-cultural differences in perceptions, values and ways of thinking about new food technologies. Awareness of socio-cultural differences is important because collaborative efforts to deal with food hazards presuppose some understanding of where, how and why the viewpoints of various stakeholders may differ. In the present paper factors that influence public perceptions of genetically-modified (GM) food are discussed, with a special focus on the unique circumstances of populations in the USA, Europe and developing countries. It is argued that effective communication and decision making about the risk of GM food depends critically on understanding how socio-cultural groups differ in their values and in the way they deal with the risks and benefits of new technologies. The implications of psychological aspects of perceived risk (including the roles of qualitative dimensions of risk, world views and trust) for public acceptance of new food technologies are highlighted.