bluuebunny/crossref_metadata_2025 huggingface dataset:
United States food policy 1972–1976: reconciling domestic and international objectives
Authors: Destler I. M.
Published: May 2009

US food policy is a product of four legitimate but competing concerns: (1)farm policy; (2)domestic economic policy; (3)foreign policy; and (4)global welfare and development policy. Five major policy episodes in 1972–76 illustrate their interplay: the Soviet grain sales of 1972; the soybean embargo of 1973; the food aid debate of 1974; the food reserves proposal of 1975; and the Soviet grain sales of 1974 and 1975. Competing policy concerns were more explicitly and effectively balanced in 1974 and 1975 than in 1972 and 1973, and policy tended to shift toward protecting domestic food prices in 1973, and meeting world food needs in 1974. But it shifted too late to salvage important policy concerns. The 1972–75 experience suggests that the State Department cannot be the lead international food policy agency because domestic farm and economic concerns are too deeply engaged. But interagency committees based in the Executive Office of the President (EOP) lost their effectiveness as crises waned and their members' attention turned to other things. The best organizational strategy for food would therefore be to accept the day-to-day predominance of the Department of Agriculture and seek to broaden the orientation of the secretary and his staff. Reciprocal State sensitivity to non-foreign policy concerns can help protect international economic and political interests; so can monitoring and intermittent intervention by EOP staffs.
Conflict and cooperation in OPEC: some additional economic considerations
Authors: Willett Thomas D.
Published: May 2009

In a recent article in this journal Paul Jabber presents a cogent analysis of many of the potential conflicts that may face OPEC over the coming years and concludes that a collapse of the cartel is extremely unlikely, even under conditions of severe political dispute among OPEC members. I share Jabber's view that a collapse of the cartel is not probable in the medium-term future. I believe, however, that Jabber has not sufficiently recognized the divergencies as well as the similarities in the economic interests of the oil countries, and that, as a result, his analysis significantly overstates the likelihood that the real level of oil prices, i.e., the nominal price adjusted for the depreciating purchasing power of currencies, is likely to average near if not above the levels initially established with the first full-fledged flexing of OPEC's muscles in 1973–74. After the 1973–74 increases, the real price of oil fell substantially through 1978, although of course nowhere near preembargo levels. Thus Jabber's prediction was that a significant increase in real oil prices will occur over the coming decade.
The Communist States and Western Integration
Authors: Shulman Marshall D.
Published: May 2009

In discussing the process of integration in western Europe, communist writings invariably put the word in quotation marks, and often preface it with “so-called,” to drive home the central point that, while technological progress does create a tendency toward international economic activity, the capitalist system is inherently incapable of an effective response to this necessity. What is involved is not so much the broad, undefined movement toward an Atlantic Community, which Soviet strategists tend to discount, as the specific and practical development of the European Common Market. With or without quotation marks, the movement toward European integration has become a major factor in the evolution of Soviet ideology and policy. Despite its ups and downs, the Common Market has resulted in profound modifications in Soviet ideas concerning contemporary capitalism and the present configuration of power; it has led to a radical revision of the Council of Mutual Economic Assistant (COMECON)—the Soviet counterpart organization for eastern Europe; and it has greatly complicated Moscow's leadership of the world communist movement. Over the long run, if the non-communist nations are able to sustain a movement toward growth and integration, this development gives promise of leading to fundamental transformations in Soviet policies and in the Soviet system itself.
The Establishment of the Far Eastern Commission
Authors: Blakeslee George H.
Published: May 2009

The surrender of Japan led to the problem of determining the kind of administration which should be set up for the occupied country. This problem led in turn to a conflict of view and of policy between the United States and the Soviet Union. The United States was willing, and intended, to consult the other Allied states in regard to the policies to be adopted during the occupation, but wished to have the controlling voice in the determination of these policies, and wished the implementation of these policies and the control of Japan to remain solely with General MacArthur who, as Supreme Commander for the Allied Powers, had already been authorized by the Allied Powers to take such steps as he deemed proper to effectuate the terms of surrender. The Soviet Union, while willing to recognize the leadership of the United States in the occupation of Japan, claimed the right of responsible participation in the control of Japan and in both formulating and implementing the policies for the occupation. During four months the United States and the Soviet Union carried on negotiations in regard to the administration to be established for occupied Japan. Both governments made substantial concessions. They finally reached an agreement, acceptable also to the United Kingdom and China, the two other major Powers chiefly concerned, which was expressed in the Terms of Reference of the Far Eastern Commission and of the Allied Council for Japan.
Endoscopic surgical treatment of posterior glottic stenosis
Authors: Chitose S , Umeno H , Nakashima T
Published: May 2009

A six-year-old girl developed posterior glottic stenosis following surgery for lateral curvature. She was post-operatively intubated for 17 days and had inspiratory stridor after extubation. Laryngoscopy revealed an adhesion at the posterior commissure which severely limited abduction of the bilateral vocal folds and arytenoids. Initially, tracheal fenestration was performed and the scar tissue of the posterior commissure was vaporised using a CO2 laser under endolaryngeal microsurgery. However, despite this procedure the stenosis reformed and an interarytenoid adhesion developed.

Endolaryngeal microsurgery was performed again three months later. Using endoscopic microscissors, the posterior commissure and interarytenoid scar tissue were submucosally separated and the bilateral corniculate cartilages of the superior arytenoids were debulked using CO2 laser. A posteriorly based mucosal flap obtained from the postcricoid region was extended to approximate to the mucosa of the posterior commissure. The mucosal flap was sutured to the inferior subglottic mucosa by two 4–0 polyglactin absorbable sutures. Three months later, the patient's respiratory and phonatory function was satisfactory.

Based on the successful results of the present case, the authors highly recommend the use of a posterior mucosal flap for the treatment of posterior glottic stenosis. This procedure does not require the use of either a laryngofissure or a laryngeal stent.
Tetra-probe, 24-hour pH monitoring for laryngopharyngeal reflux: a technique for simultaneous study of hypopharynx, oesophagus and stomach
Authors: Sato K , Umeno H , Chitose S , Nakashima T
Published: May 2009

Objective:

This study aimed to introduce the technique of tetra-probe, 24-hour pH monitoring for laryngopharyngeal reflux disease.

Methods:

Tetra-probe, 24-hour pH monitoring was performed for 30 suspected cases of laryngopharyngeal reflux. The proximal probe was placed in the hypopharynx, just above the upper oesophageal sphincter, the second probe was placed in the middle oesophagus, the third probe was placed a few centimetres above the lower oesophageal sphincter, and the distal probe was placed in the stomach.

Results:

As the pH at the four sensor sites could be monitored simultaneously, gastric acid levels and gastroesophageal and laryngopharyngeal reflux could be examined. This pH monitoring technique enabled the pH relationship between the four sensor locations to be well documented, enabling gastric acid levels and patterns of reflux to be assessed. This procedure was also able to be used as a functional examination to evaluate anti-reflux medication efficacy.

Conclusions:

Tetra-probe, 24-hour pH monitoring is a reliable functional examination for laryngopharyngeal reflux.
Guest Editorial: The Many Voices of Spanish Bioethics—An Introduction
Authors: RODRÍGUEZ DEL POZO PABLO , FINS JOSEPH J.
Published: May 2009

Edmund Pellegrino noted that contemporary medicine is to a large extent a North American product, and so too is the ethics that accompanies it. This was an accurate observation back in the 1980s when he said it. Even today bioethics is to a considerable extent informed by the seminal works of the Anglo-American model, at least seen from the United States. The dissemination of ideas from the Spanish-speaking world has been nearly invisible to the English-speaking world of bioethics, isolated by language and culture from intellectual currents abroad.
Evaluation of Controlled-Drift Detectors in X-Ray Spectroscopic Imaging Applications
Authors: Castoldi Andrea , Guazzoni Chiara , Ozkan Cigdem , Vedani Giorgio , Hartmann Robert , Bjeoumikhov Aniouar
Published: May 2009

A detector that looks promising for advanced imaging modalities—such as X-ray absorption contrast imaging, X-ray fluorescence imaging, and diffraction-enhanced imaging—is the controlled-drift detector (CDD). The CDD is a novel two-dimensional X-ray imager with energy resolving capability of spectroscopic quality. It is built on a fully depleted silicon wafer and features fast readout while being operated at or near room temperature. The use of CDDs in the aforementioned applications allows translating these techniques from synchrotron-based experiments to laboratory-size experiments using polychromatic X-ray generators. We have built a dedicated and versatile detection module based on a 36 mm2 CDD chip featuring pixels of 180 × 180 μm2, and we evaluated the system performance in different X-ray imaging applications both with synchrotron-based experiments and in the laboratory environment.
The respiratory complexes I from the mitochondria of two Pichia species
Authors: Bridges Hannah R. , Grgic Ljuban , Harbour Michael E. , Hirst Judy
Published: May 2009

NADH:ubiquinone oxidoreductase (complex I) is an entry point for electrons into the respiratory chain in many eukaryotes. It couples NADH oxidation and ubiquinone reduction to proton translocation across the mitochondrial inner membrane. Because complex I deficiencies occur in a wide range of neuromuscular diseases, including Parkinson's disease, there is a clear need for model eukaryotic systems to facilitate structural, functional and mutational studies. In the present study, we describe the purification and characterization of the complexes I from two yeast species, Pichia pastoris and Pichia angusta. They are obligate aerobes which grow to very high cell densities on simple medium, as yeast-like, spheroidal cells. Both Pichia enzymes catalyse inhibitor-sensitive NADH:ubiquinone oxidoreduction, display EPR spectra which match closely to those from other eukaryotic complexes I, and show patterns characteristic of complex I in SDS/PAGE analysis. Mass spectrometry was used to identify several canonical complex I subunits. Purified P. pastoris complex I has a particularly high specific activity, and incorporating it into liposomes demonstrates that NADH oxidation is coupled to the generation of a protonmotive force. Interestingly, the rate of NADH-induced superoxide production by the Pichia enzymes is more than twice as high as that of the Bos taurus enzyme. Our results both resolve previous disagreement about whether Pichia species encode complex I, furthering understanding of the evolution of complex I within dikarya, and they provide two new, robust and highly active model systems for study of the structure and catalytic mechanism of eukaryotic complexes I.
Fast three dimensional migration of He clusters in bcc Fe and Fe–Cr alloys
Authors: Terentyev D. , Juslin N. , Nordlund K. , Sandberg N.
Published: May 2009

In this work, we perform atomistic molecular dynamics simulations to assess the properties of small helium vacancy (He-V) and pure He clusters in body-centered cubic Fe and in Fe90–Cr10 (Fe–10Cr) random alloy. The following two goals are pursued: determining diffusion mechanisms of He-V clusters occurring in dynamic simulations and revealing a possible influence of Cr on the mobility/stability of He-V clusters in the Fe–10Cr alloy. We also present a newly developed set of interatomic potentials for the Fe–Cr–He system, fitted to a set of specially performed density functional theory calculations. The obtained results show that the dissociation energies of the studied He-V clusters, as well as the migration energy of He interstitial, are not significantly affected in the alloy compared to pure Fe. It was found that small pure He clusters with sizes up to four atoms, that were assumed to be immobile in many previous studies devoted to He-release/accumulation kinetics, in fact, exhibit fast three dimensional motion with a migration energy of tens of meV. The presence of 10% Cr in the Fe matrix, however, retards their mobility. We discuss possible reasons for the decreased diffusivity of these He clusters in the Fe–Cr alloy.
Structural paradigm of Se-rich Ge–Se glasses by high-resolution x-ray photoelectron spectroscopy
Authors: Golovchak R. , Shpotyuk O. , Kozyukhin S. , Kovalskiy A. , Miller A. C. , Jain H.
Published: May 2009

The structure of binary GexSe100−x chalcogenide glass family (0≤x≤30) is determined by high-resolution x-ray photoelectron spectroscopy (XPS). On the basis of compositional dependences of fitting parameters for Ge and Se core level XPS spectra, the ratio between edge- and corner-shared tetrahedra is determined. We find that this ratio for glasses with 20≤x≤30 is almost constant with a value same as for the high-temperature crystalline form of GeSe2.
Anomalous temperature dependence of diode saturation currents in polycrystalline silicon thin-film solar cells on glass
Authors: Wong J. , Huang J. L. , Kunz O. , Ouyang Z. , He S. , Widenborg P. I. , Aberle A. G. , Keevers M. , Green M. A.
Published: May 2009

Temperature dependent Suns-Voc measurements are performed on four types of polycrystalline silicon thin-film solar cells on glass substrates, all of which are made by solid phase crystallization∕epitaxy of amorphous silicon from plasma enhanced chemical vapor deposition or e-beam evaporation. Under the two-diode model, the diode saturation currents corresponding to n=1 recombination processes for these polycrystalline silicon p-n junction cells follow an Arrhenius law with activation energies about 0.15–0.18eV lower than that of single-crystal silicon p-n diodes of 1.206eV, regardless of whether the cells have an n- or p-type base. This discrepancy manifests itself unambiguously in a reduced temperature sensitivity of the open-circuit voltage in thin-film polycrystalline silicon solar cells compared to single-crystal silicon cells with similar voltages. The physical origin of the lowered activation energy is attributed to subgap levels acting either as minority carrier traps or shallow recombination centers.
Tetragonal micro/nanotwins in 0.91Pb(Zn1/3Nb2/3)O3−0.09PbTiO3 revealed by reciprocal space mapping
Authors: Chang W. S. , Lim L. C. , Yang P. , Miao H. , Tu C.-S. , Chen Qiming , Soh A. K.
Published: May 2009

Reciprocal space mapping (RSM) of the relaxor ferroelectric 0.91Pb(Zn1/3Nb2/3)O3−0.09PbTiO3 (PZN-9%PT) single crystals has been performed by using high-resolution synchrotron x-ray diffraction as a function of temperature. The PZN–9%PT crystal consists of tetragonal micro/nanotwin domains and undergoes a sequence of rhombohedral+tetragonal→tetragonal→cubic phase transformation upon heating. The rhombohedral-to-tetragonal temperature occurs at ≅70 °C. The observed RSM patterns can be explained by the micro/nanotwin structures and their corresponding diffraction patterns.
Wave propagation and induced steady streaming in viscous fluid contained in a prestressed viscoelastic tube
Authors: Ma Ye , Ng Chiu-On
Published: May 2009

The oscillatory and time-mean motions induced by a propagating wave of small amplitude through a viscous incompressible fluid contained in a prestressed and viscoelastic (modeled as a Voigt material) tube are studied by a perturbation analysis based on equations of motion in the Lagrangian system. The classical problem of oscillatory viscous flow in a flexible tube is re-examined in the contexts of blood flow in arteries or pulmonary gas flow in airways. The wave kinematics and dynamics, including wavenumber, wave attenuation, velocity, and stress fields, are found as analytical functions of the wall and fluid properties, prestress, and the Womersley number for the cases of a free or tethered tube. On extending the analysis to the second order in terms of the small wave steepness, it is shown that the time-mean motion of the viscoelastic tube with sufficient strength is short lived and dies out quickly as a limit of finite deformation is approached. Once the tube has attained its steady deformation, the steady streaming in the fluid can be solved analytically. Results are generated to illustrate the combined effects on the first-order oscillatory flow and the second-order steady streaming due to elasticity, viscosity, and initial stresses of the wall. The present model as applied to blood flow in arteries and gas flow in pulmonary airways during high-frequency ventilation is examined in detail through comparison with models in the literature.
Thermopower-enhanced efficiency of Si/SiGe ballistic rectifiers
Authors: Salloch D. , Wieser U. , Kunze U. , Hackbarth T.
Published: May 2009

Injection-type ballistic rectifiers on Si/SiGe are studied with respect to the influence of gate voltage on the transfer resistance RT (output voltage divided by input current) for different positions of a local gate electrode. The rectifiers are trifurcated quantum wires with straight voltage stem and oblique current-injecting leads. Depending on the gate configuration, thermopower contributions arise from nearly pinched stem regions, which either cancel each other or impose upon the ballistic signal with same or opposite polarity. At best, this enhances RT to a maximum value of 470 Ω close to threshold voltage.
Long-lived blue phosphorescence of oxidized and annealed nanocrystalline silicon
Authors: Gelloz Bernard , Koshida Nobuyoshi
Published: May 2009

It is shown that an appropriate combination of thermal oxidation and high-pressure water vapor annealing for nanosilicon leads to efficient blue-band phosphorescence with a lifetime of several seconds. Based on spectroscopic analyses on both the temperature dependence of decay dynamics and the change in the peak wavelength with the excitation energy, the phosphorescence is related to luminescence centers in nanosilicon network embedded within high-quality oxide. By controlled oxidation, slow blue transitions via triplets are revealed in nanosilicon separately from the conventional fast band.
RSK1 drives p27Kip1phosphorylation at T198 to promote RhoA inhibition and increase cell motility
Authors: Larrea Michelle D. , Hong Feng , Wander Seth A. , da Silva Thiago G. , Helfman David , Lannigan Deborah , Smith Jeffrey A. , Slingerland Joyce M.
Published: May 2009

p90 ribosomal S6 kinase (RSK1) is an effector of both Ras/MEK/MAPK and PI3K/PDK1 pathways. We present evidence that RSK1 drives p27 phosphorylation at T198 to increase RhoA-p27 binding and cell motility. RSK1 activation and p27pT198 both increase in early G1. As for many kinase–substrate pairs, cellular RSK1 coprecipitates with p27. siRNA to RSK1 and RSK1 inhibition both rapidly reduce cellular p27pT198. RSK1 overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, and p27 stability. Moreover, RSK1 transfectants show mislocalization of p27 to cytoplasm, increased motility, and reduced RhoA-GTP, phospho-cofilin, and actin stress fibers, all of which were reversed by shRNA to p27. Phosphorylation by RSK1 increased p27pT198 binding to RhoA in vitro, whereas p27T157A/T198A bound poorly to RhoA compared with WTp27 in cells. Coprecipitation of cellular p27-RhoA was increased in cells with constitutive PI3K activation and increased in early G1. Thus T198 phosphorylation not only stabilizes p27 and mislocalizes p27 to the cytoplasm but also promotes RhoA-p27 interaction and RhoA pathway inhibition. These data link p27 phosphorylation at T198 and cell motility. As for other PI3K effectors, RSK1 phosphorylates p27 at T198. Because RSK1 is also activated by MAPK, the increased cell motility and metastatic potential of cancer cells with PI3K and/or MAPK pathway activation may result in part from RSK1 activation, leading to accumulation of p27T198 in the cytoplasm, p27:RhoA binding, inhibition of RhoA/Rock pathway activation, and loss of actomyosin stability.
Neural correlates of depth of strategic reasoning in medial prefrontal cortex
Authors: Coricelli Giorgio , Nagel Rosemarie
Published: May 2009

We used functional MRI (fMRI) to investigate human mental processes in a competitive interactive setting—the “beauty contest” game. This game is well-suited for investigating whether and how a player's mental processing incorporates the thinking process of others in strategic reasoning. We apply a cognitive hierarchy model to classify subject's choices in the experimental game according to the degree of strategic reasoning so that we can identify the neural substrates of different levels of strategizing. According to this model, high-level reasoners expect the others to behave strategically, whereas low-level reasoners choose based on the expectation that others will choose randomly. The data show that high-level reasoning and a measure of strategic IQ (related to winning in the game) correlate with the neural activity in the medial prefrontal cortex, demonstrating its crucial role in successful mentalizing. This supports a cognitive hierarchy model of human brain and behavior.
Landscape connectivity promotes plant biodiversity spillover into non-target habitats
Authors: Brudvig Lars A. , Damschen Ellen I. , Tewksbury Joshua J. , Haddad Nick M. , Levey Douglas J.
Published: May 2009

Conservation efforts typically focus on maximizing biodiversity in protected areas. The space available for reserves is limited, however, and conservation efforts must increasingly consider how management of protected areas can promote biodiversity beyond reserve borders. Habitat corridors are considered an important feature of reserves because they facilitate movement of organisms between patches, thereby increasing species richness in those patches. Here we demonstrate that by increasing species richness inside target patches, corridors additionally benefit biodiversity in surrounding non-target habitat, a biodiversity “spillover” effect. Working in the world's largest corridor experiment, we show that increased richness extends for approximately 30% of the width of the 1-ha connected patches, resulting in 10–18% more vascular plant species around patches of target habitat connected by corridors than around unconnected but otherwise equivalent patches of habitat. Furthermore, corridor-enhanced spillover into non-target habitat can be predicted by a simple plant life-history trait: seed dispersal mode. Species richness of animal-dispersed plants in non-target habitat increased in response to connectivity provided by corridors, whereas species richness of wind-dispersed plants was unaffected by connectivity and increased in response to changes in patch shape—higher edge-to-interior ratio—created by corridors. Corridors promoted biodiversity spillover for native species of the threatened longleaf pine ecosystem being restored in our experiment, but not for exotic species. By extending economically driven spillover concepts from marine fisheries and crop pollination systems, we show how reconnecting landscapes amplifies biodiversity conservation both within and beyond reserve borders.
Tracing the impact of the Andean uplift on Neotropical plant evolution
Authors: Antonelli Alexandre , Nylander Johan A. A. , Persson Claes , Sanmartín Isabel
Published: May 2009

Recent phylogenetic studies have revealed the major role played by the uplift of the Andes in the extraordinary diversification of the Neotropical flora. These studies, however, have typically considered the Andean uplift as a single, time-limited event fostering the evolution of highland elements. This contrasts with geological reconstructions indicating that the uplift occurred in discrete periods from west to east and that it affected different regions at different times. We introduce an approach for integrating Andean tectonics with biogeographic reconstructions of Neotropical plants, using the coffee family (Rubiaceae) as a model group. The distribution of this family spans highland and montane habitats as well as tropical lowlands of Central and South America, thus offering a unique opportunity to study the influence of the Andean uplift on the entire Neotropical flora. Our results suggest that the Rubiaceae originated in the Paleotropics and used the boreotropical connection to reach South America. The biogeographic patterns found corroborate the existence of a long-lasting dispersal barrier between the Northern and Central Andes, the “Western Andean Portal.” The uplift of the Eastern Cordillera ended this barrier, allowing dispersal of boreotropical lineages to the South, but gave rise to a huge wetland system (“Lake Pebas”) in western Amazonia that prevented in situ speciation and floristic dispersal between the Andes and Amazonia for at least 6 million years. Here, we provide evidence of these events in plants.
The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex
Authors: Yao Xiao Jie , Vélez Ruiz Gisselle , Whorton Matthew R. , Rasmussen Søren G. F. , DeVree Brian T. , Deupi Xavier , Sunahara Roger K. , Kobilka Brian
Published: May 2009

G protein-coupled receptors (GPCRs) mediate the majority of physiologic responses to hormones and neurotransmitters. However, many GPCRs exhibit varying degrees of agonist-independent G protein activation. This phenomenon is referred to as basal or constitutive activity. For many of these GPCRs, drugs classified as inverse agonists can suppress basal activity. There is a growing body of evidence that basal activity is physiologically relevant, and the ability of a drug to inhibit basal activity may influence its therapeutic properties. However, the molecular mechanism for basal activation and inhibition of basal activity by inverse agonists is poorly understood and difficult to study, because the basally active state is short-lived and represents a minor fraction of receptor conformations. Here, we investigate basal activation of the G protein Gs by the β2adrenergic receptor (β2AR) by using purified receptor reconstituted into recombinant HDL particles with a stoichiometric excess of Gs. The β2AR is site-specifically labeled with a small, environmentally sensitive fluorophore enabling direct monitoring of agonist- and Gs-induced conformational changes. In the absence of an agonist, the β2AR and Gs can be trapped in a complex by enzymatic depletion of guanine nucleotides. Formation of the complex is enhanced by the agonist isoproterenol, and it rapidly dissociates on exposure to concentrations of GTP and GDP found in the cytoplasm. The inverse agonist ICI prevents formation of the β2AR-Gs complex, but has little effect on preformed complexes. These results provide insights into G protein-induced conformational changes in the β2AR and the structural basis for ligand efficacy.
JAK mutations in high-risk childhood acute lymphoblastic leukemia
Authors: Mullighan Charles G. , Zhang Jinghui , Harvey Richard C. , Collins-Underwood J. Racquel , Schulman Brenda A. , Phillips Letha A. , Tasian Sarah K. , Loh Mignon L. , Su Xiaoping , Liu Wei , Devidas Meenakshi , Atlas Susan R. , Chen I-Ming , Clifford Robert J. , Gerhard Daniela S. , Carroll William L. , Reaman Gregory H. , Smith Malcolm , Downing James R. , Hunger Stephen P. , Willman Cheryl L.
Published: May 2009

Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(
9
,
22
)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric
BCR-ABL1
-negative ALL patients characterized by deletion of
IKZF1
(encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to
BCR-ABL1
-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases
JAK1
(
n
= 3),
JAK2
(
n
= 16), and
JAK3
(
n
= 1) in 20 (10.7%) of 187
BCR-ABL1
-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of
IKZF1
(70% of all JAK-mutated cases and 87.5% of cases with
JAK2
mutations;
P
= 0.001) and deletion of
CDKN2A
/
B
(70% of all
JAK
-mutated cases and 68.9% of
JAK2
-mutated cases). The JAK-mutated cases had a gene expression signature similar to
BCR-ABL1
pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.
Sulfur cycling and methanogenesis primarily drive microbial colonization of the highly sulfidic Urania deep hypersaline basin
Authors: Borin Sara , Brusetti Lorenzo , Mapelli Francesca , D'Auria Giuseppe , Brusa Tullio , Marzorati Massimo , Rizzi Aurora , Yakimov Michail , Marty Danielle , De Lange Gert J. , Van der Wielen Paul , Bolhuis Henk , McGenity Terry J. , Polymenakou Paraskevi N. , Malinverno Elisa , Giuliano Laura , Corselli Cesare , Daffonchio Daniele
Published: May 2009

Urania basin in the deep Mediterranean Sea houses a lake that is >100 m deep, devoid of oxygen, 6 times more saline than seawater, and has very high levels of methane and particularly sulfide (up to 16 mM), making it among the most sulfidic water bodies on Earth. Along the depth profile there are 2 chemoclines, a steep one with the overlying oxic seawater, and another between anoxic brines of different density, where gradients of salinity, electron donors and acceptors occur. To identify and differentiate the microbes and processes contributing to the turnover of organic matter and sulfide along the water column, these chemoclines were sampled at a high resolution. Bacterial cell numbers increased up to a hundredfold in the chemoclines as a consequence of elevated nutrient availability, with higher numbers in the upper interface where redox gradient was steeper. Bacterial and archaeal communities, analyzed by DNA fingerprinting, 16S rRNA gene libraries, activity measurements, and cultivation, were highly stratified and metabolically more active along the chemoclines compared with seawater or the uniformly hypersaline brines. Detailed analysis of 16S rRNA gene sequences revealed that in both chemoclines δ- and ε-Proteobacteria, predominantly sulfate reducers and sulfur oxidizers, respectively, were the dominant bacteria. In the deepest layers of the basin MSBL1, putatively responsible for methanogenesis, dominated among archaea. The data suggest that the complex microbial community is adapted to the basin's extreme chemistry, and the elevated biomass is driven largely by sulfur cycling and methanogenesis.
Direct functional interaction of initiation factor eIF4G with type 1 internal ribosomal entry sites
Authors: de Breyne Sylvain , Yu Yingpu , Unbehaun Anett , Pestova Tatyana V. , Hellen Christopher U. T.
Published: May 2009

Viral internal ribosomal entry sites (IRESs) mediate end-independent translation initiation. There are 4 major structurally-distinct IRES groups: type 1 (e.g., poliovirus) and type 2 (e.g., encephalomyocarditis virus), which are dissimilar except for a Yn-Xm-AUG motif at their 3′ borders, type 3 (e.g., hepatitis C virus), and type 4 (dicistroviruses). Type 2–4 IRESs mediate initiation by distinct mechanisms that are nevertheless all based on specific noncanonical interactions with canonical components of the translation apparatus, such as eukaryotic initiation factor (eIF) 4G (type 2), 40S ribosomal subunits (types 3 and 4), and eIF3 (type 3). The mechanism of initiation on type 1 IRESs is unknown. We now report that domain V of type 1 IRESs, which is adjacent to the Yn-Xm-AUG motif, specifically interacts with the central domain of eIF4G. The position and orientation of eIF4G relative to the Yn-Xm-AUG motif is analogous in type 1 and 2 IRESs. eIF4G promotes recruitment of eIF4A to type 1 IRESs, and together, eIF4G and eIF4A induce conformational changes at their 3′ borders. The ability of mutant type 1 IRESs to bind eIF4G/eIF4A correlated with their translational activity. These characteristics parallel the mechanism of initiation on type 2 IRESs, in which the key event is binding of eIF4G to the J–K domain adjacent to the Yn-Xm-AUG motif, which is enhanced by eIF4A. These data suggest that fundamental aspects of the mechanisms of initiation on these unrelated classes of IRESs are similar.
A distinct pool of phosphatidylinositol 4,5-bisphosphate in caveolae revealed by a nanoscale labeling technique
Authors: Fujita Akikazu , Cheng Jinglei , Tauchi-Sato Kumi , Takenawa Tadaomi , Fujimoto Toyoshi
Published: May 2009

Multiple functionally independent pools of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P
2
] have been postulated to occur in the cell membrane, but the existing techniques lack sufficient resolution to unequivocally confirm their presence. To analyze the distribution of PI(4,5)P
2
at the nanoscale, we developed an electron microscopic technique that probes the freeze-fractured membrane preparation by the pleckstrin homology domain of phospholipase C-δ1. This method does not require chemical fixation or expression of artificial probes, it is applicable to any cell in vivo and in vitro, and it can define the PI(4,5)P
2
distribution quantitatively. By using this method, we found that PI(4,5)P
2
is highly concentrated at the rim of caveolae both in cultured fibroblasts and mouse smooth muscle cells in vivo. PI(4,5)P
2
was also enriched in the coated pit, but only a low level of clustering was observed in the flat undifferentiated membrane. When cells were treated with angiotensin II, the PI(4,5)P
2
level in the undifferentiated membrane decreased to 37.9% within 10 sec and then returned to the initial level. Notably, the PI(4,5)P
2
level in caveolae showed a slower but more drastic change and decreased to 20.6% at 40 sec, whereas the PI(4,5)P
2
level in the coated pit was relatively constant and decreased only to 70.2% at 10 sec. These results show the presence of distinct PI(4,5)P
2
pools in the cell membrane and suggest a unique role for caveolae in phosphoinositide signaling.
A truncation mutation in
TBC1D4
in a family with acanthosis nigricans and postprandial hyperinsulinemia
Authors: Dash Satya , Sano Hiroyuki , Rochford Justin J. , Semple Robert K. , Yeo Giles , Hyden Caroline S. S. , Soos Maria A. , Clark James , Rodin Andrew , Langenberg Claudia , Druet Celine , Fawcett Katherine A. , Tung Y. C. Loraine , Wareham Nicolas J. , Barroso Inês , Lienhard Gustav E. , O'Rahilly Stephen , Savage David B.
Published: May 2009

Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in
TBC1D4
might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in
TBC1D4
. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (
P
= 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (
P
< 0.05). When coexpressed with wild-type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild-type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.
15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors
Authors: Yan Min , Myung Seung-Jae , Fink Stephen P. , Lawrence Earl , Lutterbaugh James , Yang Peiying , Zhou Xiaohua , Liu Danielle , Rerko Ronald M. , Willis Joseph , Dawson Dawn , Tai Hsin-Hsiung , Barnholtz-Sloan Jill S. , Newman Robert A. , Bertagnolli Monica M. , Markowitz Sanford D.
Published: May 2009

Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE
2
levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.
Ctp1 and Exonuclease 1, alternative nucleases regulated by the MRN complex, are required for efficient meiotic recombination
Authors: Farah Joseph A. , Cromie Gareth A. , Smith Gerald R.
Published: May 2009

Double-strand breaks (DSBs) in DNA are lethal unless repaired. Faithful repair requires processing of the DSB ends and interaction with intact homologous DNA, which can produce genetic recombinants. To determine the role of nucleases in DSB end-processing and joint molecule resolution, we studied recombination at the site of a single DSB, generated by induction of the I-
Sce
I endonuclease, during meiosis of fission yeast lacking Rec12 (Spo11 homolog) and, hence, other DSBs. We find that in the presence of the MRN (Rad32-Rad50-Nbs1) complex efficient recombination requires Ctp1, the ortholog of the nuclease Sae2, but not the nuclease activity of MRN. In the absence of MRN, exonuclease 1 (Exo1) becomes the major nuclease required for efficient recombination. Our data indicate that MRN enables access of Ctp1 to the DSB but blocks access of Exo1. In our assay, the Rad16-Swi10 nuclease, required for nucleotide excision-repair, is required for efficient recombination, presumably to remove heterologous DNA at the end of the I-
Sce
I cut site. Another nuclease, the Mus81-Eme1 Holliday junction resolvase, is required to generate crossovers accompanying gene conversion at the I-
Sce
I cut site. Additional, previously published evidence indicates that these 5 nucleases play similar roles in wild-type fission yeast meiotic recombination and in the repair of spontaneous and damage-induced mitotic DSBs. We propose that in wild-type meiosis MRN, in conjunction with Ctp1, removes the covalently attached Rec12 protein from the DNA end, which is then resected by Ctp1 and other activities to produce the single-stranded DNA necessary for further steps of DSB repair.
Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy
Authors: Dinoso J. B. , Kim S. Y. , Wiegand A. M. , Palmer S. E. , Gange S. J. , Cranmer L. , O'Shea A. , Callender M. , Spivak A. , Brennan T. , Kearney M. F. , Proschan M. A. , Mican J. M. , Rehm C. A. , Coffin J. M. , Mellors J. W. , Siliciano R. F. , Maldarelli F.
Published: May 2009

In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.
Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti
Authors: Yoshikawa Misato , Go Shinji , Takasaki Kotaro , Kakazu Yasuhiro , Ohashi Mitsuru , Nagafuku Masakazu , Kabayama Kazuya , Sekimoto Junji , Suzuki Shun-ichi , Takaiwa Kazutaka , Kimitsuki Takashi , Matsumoto Nozomu , Komune Shizuo , Kamei Daisuke , Saito Masaki , Fujiwara Michihiro , Iwasaki Katsunori , Inokuchi Jin-ichi
Published: May 2009

The ganglioside GM3 synthase (SAT-I), encoded by a single-copy gene, is a primary glycosyltransferase for the synthesis of complex gangliosides. In SAT-I null mice, hearing ability, assessed by brainstem auditory-evoked potentials (BAEP), was impaired at the onset of hearing and had been completely lost by 17 days after birth (P17), showing a deformity in hair cells in the organ of Corti. By 2 months of age, the organ of Corti had selectively and completely disappeared without effect on balance or motor function or in the histology of vestibule. Interestingly, spatiotemporal changes in localization of individual gangliosides, including GM3 and GT1b, were observed during the postnatal development and maturation of the normal inner ear. GM3 expressed in almost all regions of cochlea at P3, but at the onset of hearing it distinctly localized in stria vascularis, spiral ganglion, and the organ of Corti. In addition, SAT-I null mice maintain the function of stria vascularis, because normal potassium concentration and endocochlear potential of endolymph were observed even when they lost the BAEP completely. Thus, the defect of hearing ability of SAT-I null mice could be attributed to the functional disorganization of the organ of Corti, and the expression of gangliosides, especially GM3, during the early part of the functional maturation of the cochlea could be essential for the acquisition and maintenance of hearing function.
NTRC links built-in thioredoxin to light and sucrose in regulating starch synthesis in chloroplasts and amyloplasts
Authors: Michalska Justyna , Zauber Henrik , Buchanan Bob B. , Cejudo Francisco J. , Geigenberger Peter
Published: May 2009

Plants have an unusual plastid-localized NADP-thioredoxin reductase C (NTRC) containing both an NADP-thioredoxin reductase (NTR) and a thioredoxin (Trx) domain in a single polypeptide. Although NTRC is known to supply reductant for detoxifying hydrogen peroxide in the dark, its other functions are unknown. We now report that NTRC plays a previously unrecognized role in the redox regulation of ADP-glucose pyrophosphorylase (AGPase), a central enzyme of starch synthesis. When supplied NADPH, NTRC activated AGPase in vitro in a redox reaction that required the active site cysteines of both domains of the enzyme. In leaves, AGPase was activated in planta either by light or external feeding of sucrose in the dark. Leaves of an
Arabidopsis
NTRC KO mutant showed a decrease both in the extent of redox activation of AGPase and in the enhancement of starch synthesis either in the light (by 40–60%) or in the dark after treatment with external sucrose (by almost 100%). The light-dependent activation of AGPase in isolated chloroplasts, by contrast, was unaffected. In nonphotosynthetic tissue (roots), KO of NTRC decreased redox activation of AGPase and starch synthesis in response to light or external sucrose by almost 90%. The results provide biochemical and genetic evidence for a role of NTRC in regulating starch synthesis in response to either light or sucrose. The data also suggest that the Trx domain of NTRC and, to a lesser extent, free Trxs linked to ferredoxin enable amyloplasts of distant sink tissues to sense light used in photosynthesis by leaf chloroplasts and adjust heterotrophic starch synthesis accordingly.
Long-lived Indy and calorie restriction interact to extend life span
Authors: Wang Pei-Yu , Neretti Nicola , Whitaker Rachel , Hosier Suzanne , Chang Chengyi , Lu Daniel , Rogina Blanka , Helfand Stephen L.
Published: May 2009

Calorie restriction (CR) improves health and extends life span in a variety of species. Despite many downstream molecules and physiological systems having been identified as being regulated by CR, the mechanism by which CR extends life span remains unclear. The
Drosophila
gene
Indy
(for I'm not dead yet), involved in the transport and storage of Krebs cycle intermediates in tissues important in fly metabolism, was proposed to regulate life span via an effect on metabolism that could overlap with CR. In this study, we report that CR down regulates
Indy
mRNA expression, and that CR and the level of
Indy
expression interact to affect longevity. Optimal life span extension is seen when
Indy
expression is decreased between 25 and 75% of normal.
Indy
long-lived flies show several phenotypes that are shared by long-lived CR flies, including decreased insulin-like signaling, lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity. We conclude that
Indy
and CR interact to affect longevity and that a decrease in
Indy
may induce a CR-like status that confers life span extension.