bluuebunny/crossref_metadata_2025 huggingface dataset:
Langevin–Bloch equations for a spin bath
Authors: Ghosh Arnab , Sinha Sudarson Sekhar , Ray Deb Shankar
Published: March 2011

We derive the Bloch equations for a two-level system coupled to a spin bath of infinitely many two-level atoms to examine phase and energy relaxation of an optically excited system. We show that increasing temperature assists coherence. This is reflected in a number of anomalous features of relaxation of the system, e.g., decrease of integrated absorption coefficient with temperature, nonlinear variation of linewidth with incident power. We also predict that thermally induced coherence may result in anomalous narrowing of linewidth, reminiscent (but distinct) of “motional narrowing” of spectral line. The theoretical results are discussed in the light of absorption–emission experiments on single quantum dots.
Molecular dynamics simulations for CO2 spectra. II. The far infrared collision-induced absorption band
Authors: Hartmann J.-M. , Boulet C. , Jacquemart D.
Published: March 2011

Classical molecular dynamics simulations have been carried out for gaseous CO2 starting from various anisotropic intermolecular potential energy surfaces. Through calculations for a large number of molecules treated as rigid rotors, the time evolution of the interaction-induced electric dipole vector is obtained and the Laplace transform of its autocorrelation function gives the collision-induced absorption rototranslational spectrum. The results are successfully compared with those of previous similar calculations before studies of the influences of the intermolecular potential and induced-dipole components are made. The calculated spectra show a significant sensitivity to anisotropic forces consistently with previous analyses limited to the spectral moments. The present results also demonstrate the importance of vibrational and back-induction contributions to the induced dipole. Comparisons between measured far infrared (0–250 cm−1) spectra at different temperatures and results calculated without the use of any adjustable parameter are made. When the best and more complete input data are used, the quality of our predictions is similar to that obtained by Gruszka et al. [Mol. Phys. 93, 1007 (1998)] after the introduction of ad hoc short-range overlap contributions. Our results thus largely obviate the need for such contributions the magnitudes of which remain questioned. Nevertheless, problems remain since, whereas good agreements with measurements are obtained above 50 cm−1, the calculations significantly underestimate the absorption below, a problem which is discussed in terms of various possible error sources.
Charge transfer dynamics in Cu-doped ZnO nanowires
Authors: Xing Guozhong , Xing Guichuan , Li Mingjie , Sie Edbert Jarvis , Wang Dandan , Sulistio Arief , Ye Quan-lin , Huan Cheng Hon Alfred , Wu Tom , Sum Tze Chien
Published: March 2011

Time resolved photoluminescence (TRPL) and transient absorption (TA) spectroscopy reveal an ultrafast charge transfer (CT) process, with an electron localization time constant 39±9 ps, between the ZnO host and the Cu dopants in Cu-doped ZnO nanowires. This CT process effectively competes with the ZnO band edge emission, resulting in the quenching of the ZnO UV emission. TRPL measurements show that the UV decay dynamics coincides with the buildup of the Cu-related green emission. TA measurements probing the state-filling of the band edge and defect states provide further support to the CT model where the bleaching dynamics concur with the TRPL lifetimes.
Photoionization of small sodium-doped acetic acid clusters
Authors: Forysinski Piotr W. , Zielke Philipp , Luckhaus David , Corbett Jennifer , Signorell Ruth
Published: March 2011

The uptake of sodium and the fragmentation before and after “soft” photoionization with ultraviolet light are investigated for small acetic acid clusters. The acetic acid clusters are generated in a supersonic expansion and ionized with ultraviolet light after doping with sodium in a pick-up chamber. The composition of the bare acetic acid clusters in the molecular beam is determined independently from complementary photoionization experiments using extreme ultraviolet light. The experimental results are analyzed with the help of density functional calculations for energetics and statistical adiabatic channel calculations for fragmentation kinetics. The study demonstrates that the detected ions originate from fragmentation in the neutral as well as in the ionic state, and in particular that the fragmentation pathway strongly depends on the cluster size.
Effects of the energy spread of secondary electrons in a dc-biased single-surface multipactor
Authors: Hur Min Sup , Kim Jung-Il , Kim Geun-Ju , Jeon Seok-Gy
Published: March 2011

The effects of the energy spread of secondary electrons are theoretically investigated for a dc-biased single-surface multipactor. In our previous publication [S. G. Jeon et al., Phys. Plasmas 16, 073101 (2009)], we obtained the conditions for the phase lock of an electron bunch, assuming zero velocity spread of the secondary electrons. In this work, we extended our previous theory to derive a quadratic map, by which the stability and bifurcation of the electron bunch can be systematically investigated. For the study of the energy spread of the secondary electrons, a randomized term was added to this map. The modified map then showed significant smearing-out of the bifurcated branches. The theoretical results were verified by particle-in-cell simulations, which showed good agreement in wide parameter ranges for both cases of monoenergetic and energy-spread secondary electrons.
Multipactor theory for multicarrier signals
Authors: Anza S. , Mattes M. , Vicente C. , Gil J. , Raboso D. , Boria V. E. , Gimeno B.
Published: March 2011

This work presents a new theory of multipactor under multicarrier signals for parallel-plate geometries, assuming a homogeneous electric field and one-dimensional electron motion. It is the generalization of the nonstationary multipactor theory for single-carrier signals [S. Anza et al.,Phys. Plasmas 17, 062110 (2010)]. It is valid for multicarrier signals with an arbitrary number of carriers with different amplitude, arbitrary frequency, and phase conditions and for any material coating. This new theory is able to model the real dynamics of the electrons during the multipactor discharge for both single and double surface interactions. Among other parameters of the discharge, it calculates the evolution in time of the charge growth, electron absorption, and creation rates as well as the instantaneous secondary emission yield and order. An extensive set of numerical tests with particle-in-cell software has been carried out in order to validate the theory under many different conditions. This theoretical development constitutes the first multipactor theory which completely characterizes the multipactor discharge for arbitrary multicarrier signals, setting the first step for further investigations in the field.
Ion orbit loss and pedestal width of H-mode tokamak plasmas in limiter geometry
Authors: Xiao Xiaotao , Liu Lei , Zhang Xiaodong , Wang Shaojie
Published: March 2011

A simple analytical model is proposed to analyze the effects of ion orbit loss on the edge radial electric field in a tokamak with limiter configuration. The analytically predicted edge radial electric field is consistent with the H-mode experiments, including the width, the magnitude, and the well-like shape. This model provides an explanation to the H-mode pedestal structure. Scaling of the pedestal width based on this model is proposed.
Reshaped Terahertz waveforms from a large-aperture photoconductive antenna with millimeter scale metal hole and grid combination
Authors: Pai Shyh-Shii , Chang Shian-Wen , Wang Tai-Shen
Published: March 2011

Time-domain THz transmission of a metal wire grid is investigated experimentally. The transmission depends on the relative angle (θ) between the polarization of the THz wave and the direction of the wires. When the polarization is parallel to the wires (θ = 0°), the grid works as a high-pass filter with a cutoff frequency at 0.3 THz. Meanwhile, when the polarization is perpendicular to the wires (θ = 90°), the waveform of THz pulses is only slightly altered after passing through the grid. These results are reproduced accurately in computational simulations of the electromagnetic field. Simulation results indicate that strongly excited surface waves between two adjacent metal rods are responsible for the transmission peak at 0.81 THz, while surface waves slightly excited on the front surface of the grid are responsible for the low transmission at 0.3 THz. Transmission spectra of θ = 0° are interpreted qualitatively by applying the concept of effective surface plasmons.
Photocarrier relaxation through the manifold of localized states in a polymer-fullerene bulk heterojunction material
Authors: Coates Nelson E. , Moses Daniel , Heeger Alan J.
Published: March 2011

We investigate the transport and relaxation of photogenerated carriers in a polymer-fullerene bulk-heterojunction (BHJ) material by measuring the transient photoconductivity as a function of the sample temperature. Data in the nanosecond time regime indicate that following the initial trapping (within ∼100 ps), the photogenerated carriers relax into the manifold of disorder-induced localized states near the band edge, and the transport becomes thermally activated. By measuring the temporal dependence of the transport activation energy, we are able to monitor the relaxation of carriers into deeper traps, with a corresponding reduction in carrier mobility. A comparison of BHJs made from different molecular weight poly(3-hexylthiophene) (P3HT) (21 and 95 kDa), indicates that higher molecular weight polymer in the BHJ material yields a consistently higher activation energy. The reduction in the carrier mobility in BHJ materials made with higher molecular weight P3HT is confirmed by steady-state photoconductivity measurements. In contrast to disordered inorganic semiconductors (e.g., amorphous silicon), the activation energies associated with the density of states in the disorder-induced band tails are a small fraction (<10%) of the band gap energy of P3HT.
Cohomology of toric line bundles via simplicial Alexander duality
Authors: Jow Shin-Yao
Published: March 2011

We give a rigorous mathematical proof for the validity of the toric sheaf cohomology algorithm conjectured in the recent paper by Blumenhagen, Jurke, Rahn, and Roschy (arXiv:1003.5217). We actually prove not only the original algorithm but also a speed-up version of it. Our proof is independent from (in fact appeared earlier on the arXiv than) the proof by Roschy and Rahn (arXiv:1006.2392), and has several advantages such as being shorter and cleaner and can also settle the additional conjecture on “Serre duality for Betti numbers” which was raised but unresolved in arXiv:1006.2392.
Plasmon single- and multi-quantum excitation in free metal clusters as seen by photoelectron spectroscopy
Authors: Andersson T. , Zhang C. , Rosso A. , Bradeanu I. , Legendre S. , Canton S. E. , Tchaplyguine M. , Öhrwall G. , Sorensen S. L. , Svensson S. , Mårtensson N. , Björneholm O.
Published: March 2011

Plasmons are investigated in free nanoscale Na, Mg, and K metal clusters using synchrotron radiation-based x-ray photoelectron spectroscopy. The core levels for which the response from bulk and surface atoms can be resolved are probed over an extended binding energy range to include the plasmon loss features. In all species the features due to fundamental plasmons are identified, and in Na and K also those due to either the first order plasmon overtones or sequential plasmon excitation are observed. These features are discussed in view of earlier results for planar macroscopic samples and free clusters of the same materials.
Three-dimensional nonlinear Schrödinger equation in electron-positron-ion magnetoplasmas
Authors: Sabry R. , Moslem W. M. , El-Shamy E. F. , Shukla P. K.
Published: March 2011

Three-dimensional ion-acoustic envelope soliton excitations in electron-positron-ion magnetoplasmas are interpreted. This is accomplished through the derivation of three-dimensional nonlinear Schrödinger equation, where the nonlinearity is balancing with the dispersive terms. The latter contains both an external magnetic field besides the usual plasma parameter effects. Based on the balance between the nonlinearity and the dispersion terms, the regions for possible envelope solitons are investigated indicating that new regimes for modulational instability of envelope ion-acoustic waves could be obtained, which cannot exist in the unmagnetized case. This will allow us to establish additional new regimes, different from the usual unmagnetized plasma, for envelope ion-acoustic waves to propagate in multicomponent plasma that may be observed in space or astrophysics.
Alien Still Life: Distilling the Toxic Logics of the Rocky Flats National Wildlife Refuge
Authors: Krupar Shiloh R
Published: March 2011

“Alien still life” examines the conversion of Rocky Flats, a plutonium factory located near Denver, Colorado, from a nuclear weapons plant to a national wildlife refuge. It argues that the territorial and administrative category of ‘wildlife refuge’ aided an incentives-based cleanup and accelerated turnover of the site to the public as a limited-use recreational space, in the process ‘fixing’ waste to external wilderness. Simultaneously, the technique of ‘legacy management’, a response to the growing number of decommissioned and remediated US Department of Energy nuclear facilities, mobilizes the reduction, containment, and/or denial of Rocky Flats's history and toxicity through discursive and territorial means, such as the portrayal of nature as purity. The resultant ‘alien still life’ marks the voids in the public record, the alienation of the environment from former Rocky Flats workers, and the reconceptualization of ethics necessary to challenge the suspension of politics achieved by the nature refuge fix. The paper tracks subtle shifts in the memory, rhetoric, and politics needed to convert the industrial territory of Rocky Flats to a ‘wild’ space. In an effort to counteract the spectacle of nature as purity, and to reimagine an environmental ethics and political ecology attentive to waste, the layered narrative approach seeks to ‘put waste back into nature’, confronting the radioactive legacies of the Cold War.
Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor α (PPARα) activity
Authors: Gachon Frédéric , Leuenberger Nicolas , Claudel Thierry , Gos Pascal , Jouffe Céline , Fleury Olela Fabienne , de Mollerat du Jeu Xavier , Wahli Walter , Schibler Ueli
Published: March 2011

In mammals, many aspects of metabolism are under circadian control. At least in part, this regulation is achieved by core-clock or clock-controlled transcription factors whose abundance and/or activity oscillate during the day. The clock-controlled proline- and acidic amino acid-rich domain basic leucine zipper proteins D-site-binding protein, thyrotroph embryonic factor, and hepatic leukemia factor have previously been shown to participate in the circadian control of xenobiotic detoxification in liver and other peripheral organs. Here we present genetic and biochemical evidence that the three proline- and acidic amino acid-rich basic leucine zipper proteins also play a key role in circadian lipid metabolism by influencing the rhythmic expression and activity of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). Our results suggest that, in liver, D-site-binding protein, hepatic leukemia factor, and thyrotroph embryonic factor contribute to the circadian transcription of genes specifying acyl-CoA thioesterases, leading to a cyclic release of fatty acids from thioesters. In turn, the fatty acids act as ligands for PPARα, and the activated PPARα receptor then stimulates the transcription of genes encoding proteins involved in the uptake and/or metabolism of lipids, cholesterol, and glucose metabolism.
Discovery and characterization of a unique mycobacterial heme acquisition system
Authors: Tullius Michael V. , Harmston Christine A. , Owens Cedric P. , Chim Nicholas , Morse Robert P. , McMath Lisa M. , Iniguez Angelina , Kimmey Jacqueline M. , Sawaya Michael R. , Whitelegge Julian P. , Horwitz Marcus A. , Goulding Celia W.
Published: March 2011

Mycobacterium tuberculosis
must import iron from its host for survival, and its siderophore-dependent iron acquisition pathways are well established. Here we demonstrate a newly characterized pathway, whereby
M. tuberculosis
can use free heme and heme from hemoglobin as an iron source. Significantly, we identified the genomic region,
Rv0202c
–
Rv0207c
, responsible for the passage of heme iron across the mycobacterial membrane. Key players of this heme uptake system were characterized including a secreted protein and two transmembrane proteins, all three specific to mycobacteria. Furthermore, the crystal structure of the key heme carrier protein Rv0203 was found to have a unique fold. The discovery of a unique mycobacterial heme acquisition pathway opens new avenues of exploration into mycobacterial therapeutics.
Host plant shifts affect a major defense enzyme inChrysomela lapponica
Authors: Kirsch Roy , Vogel Heiko , Muck Alexander , Reichwald Kathrin , Pasteels Jacques M. , Boland Wilhelm
Published: March 2011

Chrysomelid leaf beetles use chemical defenses to overcome predatory attack and microbial infestation. Larvae ofChrysomela lapponicathat feed on willow sequester plant-derived salicin and other leaf alcohol glucosides, which are modified in their defensive glands to bioactive compounds. Salicin is converted into salicylaldehyde by a consecutive action of a β-glucosidase and salicyl alcohol oxidase (SAO). The other leaf alcohol glucosides are not oxidized, but are deglucosylated and esterified with isobutyric- and 2-methylbutyric acid. Like some other closely relatedChrysomelaspecies, certain populations ofC. lapponicashift host plants from willow to salicin-free birch. The only striking difference between willow feeders and birch feeders in terms of chemical defense is the lack of salicylaldehyde formation. To clarify the impact of host plant shifts on SAO activity, we identified and compared this enzyme by cloning, expression, and functional testing in a willow-feeding and birch-feeding population ofC. lapponica. Although the birch feeders still demonstrated defensive gland-specific expression, their SAO mRNA levels were 1,000-fold lower, and the SAO enzyme was nonfunctional. Obviously, the loss of catalytic function of the SAO of birch-adapted larvae is fixed at the transcriptional, translational, and enzyme levels, thus avoiding costly expression of a highly abundant protein that is not required in the birch feeders.
Design principles for self-assembly with short-range interactions
Authors: Hormoz Sahand , Brenner Michael P.
Published: March 2011

Recent experimental advances have opened up the possibility of equilibrium self-assembly of functionalized nanoblocks with a high degree of controllable specific interactions. Here, we propose design principles for selecting the short-range interactions between self-assembling components to maximize yield. We illustrate the approach with an example from colloidal engineering. We construct an optimal set of local interactions for eight colloidal particles (coated, e.g., with DNA strands) to assemble into a particular polytetrahedral cluster. Maximum yield is attained when the interactions between the colloids follow the design rules: All energetically favorable interactions have the same strength, as do all unfavorable ones, and the number of components and energies fall within the proposed range. In general, it might be necessary to use more component than strictly required for enforcing the ground state configuration. The results motivate design strategies for engineering components that can reliably self-assemble.
Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity
Authors: Cruz Daniel , Wang Zhiming , Kibbie Jon , Modlin Robert , Kwon Ohyun
Published: March 2011

The endothelium plays a critical role in promoting inflammation in cardiovascular disease and other chronic inflammatory conditions, and many small-molecule screens have sought to identify agents that prevent endothelial cell activation. Conversely, an augmented immune response can be protective against microbial pathogens and in cancer immunotherapy. Yet, small-molecule screens to identify agents that induce endothelial cell activation have not been reported. In this regard, a bioassay was developed that identifies activated endothelium by its capacity to trigger macrophage inflammatory protein 1 beta from primary monocytes. Subsequently, a 642-compound library of 39 distinctive scaffolds generated by a diversity-oriented synthesis based on the nucleophilic phosphine catalysis was screened for small molecules that activated the endothelium. Among the active compounds identified, the major classes were synthesized through the sequence of phosphine-catalyzed annulation, Tebbe reaction, Diels–Alder reaction, and in some cases, hydrolysis. Ninety-six analogs of one particular class of compounds, octahydro-1,6-naphthyridin-4-ones, were efficiently prepared by a solid-phase split-and-pool technique and by solution phase analog synthesis. Structure-function analysis combined with transcriptional profiling of active and inactive octahydro-1,6-naphthyridin-4-one analogs identified inflammatory gene networks induced exclusively by the active compound. The identification of a family of chemical probes that augment innate immunity through endothelial cell activation provides a framework for understanding gene networks involved in endothelial inflammation as well as the development of novel endothelium-driven immunotherapeutic agents.
Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles
Authors: Comer Eamon , Liu Haibo , Joliton Adrien , Clabaut Alexandre , Johnson Christopher , Akella Lakshmi B. , Marcaurelle Lisa A.
Published: March 2011

Complexity and the presence of stereogenic centers have been correlated with success as compounds transition from discovery through the clinic. Here we describe the synthesis of a library of pyran-containing macrocycles with a high degree of structural complexity and up to five stereogenic centers. A key feature of the design strategy was to use a modular synthetic route with three fragments that can be readily interchanged or “shuffled” to produce subtly different variants with distinct molecular shapes. A total of 352 macrocycles were synthesized ranging in size from 14- to 16-membered rings. In order to facilitate the generation of stereostructure-activity relationships, the complete matrix of stereoisomers was prepared for each macrocycle. Solid-phase assisted parallel solution-phase techniques were employed to allow for rapid analogue generation. An intramolecular nitrile-activated nucleophilic aromatic substitution reaction was used for the key macrocyclization step.
MicroRNA-122 antagonism against hepatitis C virus genotypes 1–6 and reduced efficacy by host RNA insertion or mutations in the HCV 5′ UTR
Authors: Li Yi-Ping , Gottwein Judith M. , Scheel Troels K. , Jensen Tanja B. , Bukh Jens
Published: March 2011

MicroRNA-122 (miR-122) is believed to stimulate hepatitis C virus (HCV) replication through interaction with two adjacent sites downstream of stem loop I (SLI) within the HCV 5′ untranslated region (5′ UTR). Recently, it was demonstrated that locked nucleic acid SPC3649-induced miR-122 antagonism suppressed HCV genotype 1a and 1b infection in vivo. However, virus-producing culture systems with 5′ UTR of different HCV genotypes have not been available for testing 5′ UTR-based treatment approaches. Using JFH1-based Core-NS2 genotype recombinants, we developed 5′ UTR-NS2 recombinants of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a with efficient growth in Huh7.5 cells. Deletion mutagenesis studies demonstrated that the 5′ UTR SLI was essential for genotypes 1–6 infection. However, lack of SLI could be compensated for by insertion of other structured HCV or host RNA sequences, including U3 small nucleolar RNA. We demonstrated that SPC3649-induced miR-122 antagonism had a potent antiviral effect against HCV genotypes 1–6 5′ UTR-NS2 viruses. Strikingly, HCV recombinant virus with substitution of SLI and miR-122 binding site 1 (S1) by the U3 RNA sequence was not affected by miR-122 antagonism; this was attributed to the lack of an intact S1 by reverse genetics studies. Therefore, we engineered the corresponding U3 RNA sequences into S1 and demonstrated that HCV recombinants with wild-type SLI and single or combined mutations at four of eight nucleotides of S1 were viable in Huh7.5 cells. These mutations reduced the efficacy of SPC3649 treatment, indicating that escape variants to miR-122 antagonism-based HCV therapy could potentially occur.
Bacillus anthracis
comparative genome analysis in support of the Amerithrax investigation
Authors: Rasko David A. , Worsham Patricia L. , Abshire Terry G. , Stanley Scott T. , Bannan Jason D. , Wilson Mark R. , Langham Richard J. , Decker R. Scott , Jiang Lingxia , Read Timothy D. , Phillippy Adam M. , Salzberg Steven L. , Pop Mihai , Van Ert Matthew N. , Kenefic Leo J. , Keim Paul S. , Fraser-Liggett Claire M. , Ravel Jacques
Published: March 2011

Before the anthrax letter attacks of 2001, the developing field of microbial forensics relied on microbial genotyping schemes based on a small portion of a genome sequence. Amerithrax, the investigation into the anthrax letter attacks, applied high-resolution whole-genome sequencing and comparative genomics to identify key genetic features of the letters’
Bacillus anthracis
Ames strain. During systematic microbiological analysis of the spore material from the letters, we identified a number of morphological variants based on phenotypic characteristics and the ability to sporulate. The genomes of these morphological variants were sequenced and compared with that of the
B. anthracis
Ames ancestor, the progenitor of all
B. anthracis
Ames strains. Through comparative genomics, we identified four distinct loci with verifiable genetic mutations. Three of the four mutations could be directly linked to sporulation pathways in
B. anthracis
and more specifically to the regulation of the phosphorylation state of Spo0F, a key regulatory protein in the initiation of the sporulation cascade, thus linking phenotype to genotype. None of these variant genotypes were identified in single-colony environmental
B. anthracis
Ames isolates associated with the investigation. These genotypes were identified only in
B. anthracis
morphotypes isolated from the letters, indicating that the variants were not prevalent in the environment, not even the environments associated with the investigation. This study demonstrates the forensic value of systematic microbiological analysis combined with whole-genome sequencing and comparative genomics.
Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome
Authors: Urosevic Jelena , Sauzeau Vincent , Soto-Montenegro María L. , Reig Santiago , Desco Manuel , Wright Emma M. Burkitt , Cañamero Marta , Mulero Francisca , Ortega Sagrario , Bustelo Xosé R. , Barbacid Mariano
Published: March 2011

RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS/RAF/MEK signaling pathway. A well-recognized RASopathy is the cardio-facio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-
RAF
,
MEK1
,
MEK2
, and K-
RAS
. B-
RAF
is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-
Raf
LSLV600E
allele. This targeted allele allows low levels of expression of B-Raf
V600E
, a constitutively active B-Raf kinase first identified in human melanoma. B-Raf
+/LSLV600E
mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf
+/LSLV600E
mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome.
Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice
Authors: Noel Melissa , Norris Erin H. , Strickland Sidney
Published: March 2011

Ethanol exposure during developmental synaptogenesis can lead to brain defects referred to as fetal alcohol syndrome (FAS), which can include mental health problems such as cognitive deficits and mental retardation. In FAS, widespread neuronal death and brain mass loss precedes behavioral and cognitive impairments in adulthood. Because tissue plasminogen activator (tPA) has been implicated in neurodegeneration, we examined whether it mediates FAS. Neonatal WT and tPA
−/−
mice were injected with ethanol to mimic FAS in humans. In WT mice, ethanol elicited caspase-3 activation, significant forebrain neurodegeneration, and decreased contextual fear conditioning in adults. However, tPA-deficient mice were protected from these neurotoxicities, and this protection could be abrogated by exogenous tPA. Selective pharmacological modulators of NMDA and GABA
A
receptor pathways revealed that the effects of tPA were mediated by the NR2B subunit of the NMDA receptor. This study identifies tPA as a critical signaling component in FAS.
Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB
1
) receptors in the regenerating liver
Authors: Mukhopadhyay Bani , Cinar Resat , Yin Shi , Liu Jie , Tam Joseph , Godlewski Grzegorz , Harvey-White Judith , Mordi Isioma , Cravatt Benjamin F. , Lotersztajn Sophie , Gao Bin , Yuan Qiaoping , Schuebel Kornel , Goldman David , Kunos George
Published: March 2011

The mammalian liver regenerates upon tissue loss, which induces quiescent hepatocytes to enter the cell cycle and undergo limited replication under the control of multiple hormones, growth factors, and cytokines. Endocannabinoids acting via cannabinoid type 1 receptors (CB
1
R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB
1
R in the control of liver regeneration. Here we report that mice lacking CB
1
R globally or in hepatocytes only and wild-type mice treated with a CB
1
R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB
1
R and hyperactivation of the biosynthesis of the endocannabinoid anandamide in the liver via an in vivo pathway involving conjugation of arachidonic acid and ethanolamine by fatty-acid amide hydrolase. In wild-type but not CB
1
R
−/−
mice, PHX induces robust up-regulation of key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator forkhead box protein M1 (FoxM1), as revealed by ultrahigh-throughput RNA sequencing and pathway analysis and confirmed by real-time PCR and Western blot analyses. Treatment of wild-type mice with anandamide induces similar changes mediated via activation of the PI3K/Akt pathway. We conclude that activation of hepatic CB
1
R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression.
Graded expression of zinc-responsive genes through two regulatory zinc-binding sites in Zur
Authors: Shin Jung-Ho , Jung Hoi Jong , An Young Jun , Cho Yoo-Bok , Cha Sun-Shin , Roe Jung-Hye
Published: March 2011

Zinc is one of the essential transition metals in cells. Excess or lack of zinc is detrimental, and cells exploit highly sensitive zinc-binding regulators to achieve homeostasis. In this article, we present a crystal structure of active Zur from
Streptomyces coelicolor
with three zinc-binding sites (C-, M-, and D-sites). Mutations of the three sites differentially affected sporulation and transcription of target genes, such that C- and M-site mutations inhibited sporulation and derepressed all target genes examined, whereas D-site mutations did not affect sporulation and derepressed only a sensitive gene. Biochemical and spectroscopic analyses of representative metal site mutants revealed that the C-site serves a structural role, whereas the M- and D-sites regulate DNA-binding activity as an on-off switch and a fine-tuner, respectively. Consistent with differential effect of mutations on target genes, zinc chelation by TPEN derepressed some genes (
znuA, rpmF2
) more sensitively than others (
rpmG2
, SCO7682) in vivo. Similar pattern of TPEN-sensitivity was observed for Zur-DNA complexes formed on different promoters in vitro. The sensitive promoters bound Zur with lower affinity than the less sensitive ones. EDTA-treated apo-Zur gained its DNA binding activity at different concentrations of added zinc for the two promoter groups, corresponding to free zinc concentrations of 4.5 × 10
−16
M and 7.9 × 10
−16
M for the less sensitive and sensitive promoters, respectively. The graded expression of target genes is a clever outcome of subtly modulating Zur-DNA binding affinities in response to zinc availability. It enables bacteria to detect metal depletion with improved sensitivity and optimize gene-expression pattern.
Most fertilizing mouse spermatozoa begin their acrosome reaction before contact with the zona pellucida during in vitro fertilization
Authors: Jin Mayuko , Fujiwara Eiji , Kakiuchi Yasutaka , Okabe Masaru , Satouh Yuhkoh , Baba Shoji A. , Chiba Kazuyoshi , Hirohashi Noritaka
Published: March 2011

To fuse with oocytes, spermatozoa of eutherian mammals must pass through extracellular coats, the cumulus cell layer, and the zona pellucida (ZP). It is generally believed that the acrosome reaction (AR) of spermatozoa, essential for zona penetration and fusion with oocytes, is triggered by sperm contact with the zona pellucida. Therefore, in most previous studies of sperm–oocyte interactions in the mouse, the cumulus has been removed before insemination to facilitate the examination of sperm–zona interactions. We used transgenic mouse spermatozoa, which enabled us to detect the onset of the acrosome reaction using fluorescence microscopy. We found that the spermatozoa that began the acrosome reaction before reaching the zona were able to penetrate the zona and fused with the oocyte's plasma membrane. In fact, most fertilizing spermatozoa underwent the acrosome reaction before reaching the zona pellucida of cumulus-enclosed oocytes, at least under the experimental conditions we used. The incidence of in vitro fertilization of cumulus-free oocytes was increased by coincubating oocytes with cumulus cells, suggesting an important role for cumulus cells and their matrix in natural fertilization.
Adaptive mechanically controlled lubrication mechanism found in articular joints
Authors: Greene George W. , Banquy Xavier , Lee Dong Woog , Lowrey Daniel D. , Yu Jing , Israelachvili Jacob N.
Published: March 2011

Articular cartilage is a highly efficacious water-based tribological system that is optimized to provide low friction and wear protection at both low and high loads (pressures) and sliding velocities that must last over a lifetime. Although many different lubrication mechanisms have been proposed, it is becoming increasingly apparent that the tribological performance of cartilage cannot be attributed to a single mechanism acting alone but on the synergistic action of multiple “modes” of lubrication that are adapted to provide optimum lubrication as the normal loads, shear stresses, and rates change. Hyaluronic acid (HA) is abundant in cartilage and synovial fluid and widely thought to play a principal role in joint lubrication although this role remains unclear. HA is also known to complex readily with the glycoprotein lubricin (LUB) to form a cross-linked network that has also been shown to be critical to the wear prevention mechanism of joints. Friction experiments on porcine cartilage using the surface forces apparatus, and enzymatic digestion, reveal an “adaptive” role for an HA-LUB complex whereby, under compression, nominally free HA diffusing out of the cartilage becomes mechanically, i.e., physically, trapped at the interface by the increasingly constricted collagen pore network. The mechanically trapped HA-LUB complex now acts as an effective (chemically bound) “boundary lubricant”—reducing the friction force slightly but, more importantly, eliminating wear damage to the rubbing/shearing surfaces. This paper focuses on the contribution of HA in cartilage lubrication; however, the system as a whole requires both HA and LUB to function optimally under all conditions.
Missense mutations in the
NF2
gene result in the quantitative loss of merlin protein and minimally affect protein intrinsic function
Authors: Yang Chunzhang , Asthagiri Ashok R. , Iyer Rajiv R. , Lu Jie , Xu David S. , Ksendzovsky Alexander , Brady Roscoe O. , Zhuang Zhengping , Lonser Russell R.
Published: March 2011

Neurofibromatosis type 2 (NF2) is a multiple neoplasia syndrome and is caused by a mutation of the
NF2
tumor suppressor gene that encodes for the tumor suppressor protein merlin. Biallelic
NF2
gene inactivation results in the development of central nervous system tumors, including schwannomas, meningiomas, ependymomas, and astrocytomas. Although a wide variety of missense germline mutations in the coding sequences of the
NF2
gene can cause loss of merlin function, the mechanism of this functional loss is unknown. To gain insight into the mechanisms underlying loss of merlin function in NF2, we investigated mutated merlin homeostasis and function in NF2-associated tumors and cell lines. Quantitative protein and RT-PCR analysis revealed that whereas merlin protein expression was significantly reduced in NF2-associated tumors, mRNA expression levels were unchanged. Transfection of genetic constructs of common
NF2
missense mutations into
NF2
gene-deficient meningioma cell lines revealed that merlin loss of function is due to a reduction in mutant protein half-life and increased protein degradation. Transfection analysis also demonstrated that recovery of tumor suppressor protein function is possible, indicating that these mutants maintain intrinsic functional capacity. Further, increased expression of mutant protein is possible after treatment with specific proteostasis regulators, implicating protein quality control systems in the degradative fate of mutant tumor suppressor proteins. These findings provide direct insight into protein function and tumorigenesis in NF2 and indicate a unique treatment paradigm for this disorder.
T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis
Authors: Angus-Hill Melinda L. , Elbert Kathryn M. , Hidalgo Julio , Capecchi Mario R.
Published: March 2011

The Wnt/β-catenin pathway plays multiple and diverse roles in development by regulating gene expression via T-cell factor/Lymphoid enhancer-binding factor (Tcf/Lef) DNA binding factors. Misregulation of this pathway is thought to initiate colon adenoma formation. It is controversial whetherTcf4(Tcf7L2) functions as an oncogene or tumor suppressor gene in colon carcinogenesis. We show here that Tcf4 haploinsufficiency results in colon tumor formation in a mouse tumor model that normally only develops small intestinal tumors. Further, we show that loss of Tcf4 early in development and in adult colon results in increased cell proliferation. These findings strongly suggest that Tcf4 normally modulates proliferation of the colonic epithelium and that disruption of Tcf4 activity increases proliferation, leading to colon tumorigenesis. Taken together, our in vivo studies favor a tumor suppressor function for Tcf4.
Joan Steitz: RNA is a many-splendored thing
Authors: Sedwick Caitlin
Published: March 2011

Steitz has spent her career uncovering RNA's different cellular avocations.
Collaborative Cohort Study of an Intervention to Reduce Ventilator-Associated Pneumonia in the Intensive Care Unit
Authors: Berenholtz Sean M. , Pham Julius C. , Thompson David A. , Needham Dale M. , Lubomski Lisa H. , Hyzy Robert C. , Welsh Robert , Cosgrove Sara E. , Sexton J. Bryan , Colantuoni Elizabeth , Watson Sam R. , Goeschel Christine A. , Pronovost Peter J.
Published: March 2011

Objective.

To evaluate the impact of a multifaceted intervention on compliance with evidence-based therapies and ventilator-associated pneumonia (VAP) rates.

Design.

Collaborative cohort before-after study.

Setting.

Intensive care units (ICUs) predominantly in Michigan.

Interventions.

We implemented a multifaceted intervention to improve compliance with 5 evidence-based recommendations for mechanically ventilated patients and to prevent VAP. A standardized CDC definition of VAP was used and maintained at each site, and data on the number of VAPs and ventilator-days were obtained from the hospital's infection preventionists. Baseline data were reported and postimplementation data were reported for 30 months. VAP rates (in cases per 1,000 ventilator-days) were calculated as the proportion of ventilator-days per quarter in which patients received all 5 therapies in the ventilator care bundle. Two interventions to improve safety culture and communication were implemented first.

Results.

One hundred twelve ICUs reporting 3,228 ICU-months and 550,800 ventilator-days were included. The overall median VAP rate decreased from 5.5 cases (mean, 6.9 cases) per 1,000 ventilator-days at baseline to 0 cases (mean, 3.4 cases) at 16–18 months after implementation (P < .001) and 0 cases (mean, 2.4 cases) at 28-30 months after implementation (P < .001). Compared to baseline, VAP rates decreased during all observation periods, with incidence rate ratios of 0.51 (95% confidence interval, 0.41–0.64) at 16–18 months after implementation and 0.29 (95% confidence interval, 0.24–0.34) at 28–30 months after implementation. Compliance with evidence-based therapies increased from 32% at baseline to 75% at 16–18 months after implementation (P < .001) and 84% at 28–30 months after implementation (P < .001).

Conclusions.

A multifaceted intervention was associated with an increased use of evidence-based therapies and a substantial (up to 71%) and sustained (up to 2.5 years) decrease in VAP rates.
Serving High-Risk Foods in a High-Risk Setting: Survey of Hospital Food Service Practices after an Outbreak of Listeriosis in a Hospital
Authors: Cokes Carolyn , France Anne Marie , Reddy Vasudha , Hanson Heather , Lee Lillian , Kornstein Laura , Stavinsky Faina , Balter Sharon
Published: March 2011

Background and Objectives.

Prepared ready-to-eat salads and ready-to-eat delicatessen-style meats present a high risk for Listeria contamination. Because no foodborne illness risk management guidelines exist specifically for US hospitals, a survey of New York City (NYC) hospitals was conducted to characterize policies and practices after a listeriosis outbreak occurred in a NYC hospital.

Methods.

From August through October 2008, a listeriosis outbreak in a NYC hospital was investigated. From February through April 2009, NYC's 61 acute-care hospitals were asked to participate in a telephone survey regarding food safety practices and policies, specifically service of high-risk foods to patients at increased risk for listeriosis.

Results.

Five patients with medical conditions that put them at high risk for listeriosis had laboratory-confirmed Listeria monocytogenes infection. The Listeria outbreak strain was isolated from tuna salad prepared in the hospital. Fifty-four (89%) of 61 hospitals responded to the survey. Overall, 81% of respondents reported serving ready-to-eat deli meats to patients, and 100% reported serving prepared ready-to-eat salads. Pregnant women, patients receiving immunosuppressive drugs, and patients undergoing chemotherapy were served ready-to-eat deli meats at 77%, 59%, and 49% of hospitals, respectively, and were served prepared ready-to-eat salads at 94%, 89%, and 73% of hospitals, respectively. Only 4 (25%) of 16 respondents reported having a policy that ready-to-eat deli meats must be heated until steaming hot before serving.

Conclusions.

Despite the potential for severe outcomes of Listeria infection among hospitalized patients, the majority of NYC hospitals had no food preparation policies to minimize risk. Hospitals should implement policies to avoid serving high-risk foods to patients at risk for listeriosis.
Improving Antimicrobial Stewardship The Evolution of Programmatic Strategies and Barriers
Authors: Johannsson Birgir , Beekmann Susan E. , Srinivasan Arjun , Hersh Adam L. , Laxminarayan Ramanan , Polgreen Philip M. ,   on behalf of The Infectious Diseases Society of America Emerging Infections Network
Published: March 2011

Objective.

To describe the prevalence and characteristics of antimicrobial stewardship programs (ASPs) in hospitals across the United States and to describe financial support provided for these programs.

Design.

Electronic and paper 14-question survey of infectious diseases physician members of the Infectious Diseases Society of America Emerging Infections Network (IDSA EIN).

Participants.

All 1,044 IDSA EIN members who care for adult patients were invited to participate.

Results.

Five hundred twenty-two (50%) members responded. Seventy-three percent of respondents reported that their institutions had or were planning an ASP, compared with 50% reporting the same thing in an EIN survey 10 years before. A shift was noted from formulary restriction alone to use of a set of tailored strategies designed to provide information and feedback to prescribers, particularly in community hospitals. Lack of funding and lack of personnel were reported as major barriers to implementing a program. Fifty-two percent of respondents with an ASP reported that infectious diseases physicians do not receive direct compensation for their participation in the ASP, compared with 18% 10 years ago.

Conclusions.

The percentage of institutions reporting ASPs has increased over the last decade, although small community hospitals were least likely to have these programs. In addition, ASP strategies have shifted dramatically. Lack of funding remains a key barrier for ASPs, and administrators need additional cost savings data in order to support ASPs. Interestingly, while guidelines and editorials regard compensated participation by an infectious diseases physician in these programs as critical, we found that more than half of the respondents reported no direct compensation for ASP activities.