bluuebunny/crossref_metadata_2025 huggingface dataset:
Laser wavelength effects on ionic and atomic emission from tin plasmas
Authors: Campos D. , Harilal S. S. , Hassanein A.
Published: April 2010

We investigated the effects of laser wavelength on atomic and ionic emission from Sn plasmas. Plasmas were produced using planar Sn targets excited with 10.6 μm carbon dioxide (CO2) and 1.06 μm neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers. Two-dimensional spectral imaging of visible emission showed that continuum emission was significantly more intense in the CO2 laser produced plasma (LPP) whereas line emission was considerably more extensive in the Nd:YAG LPP. Faraday cup analysis showed that ion profiles were narrower with CO2 LPPs although they possessed higher kinetic energies.
Remote plasma assisted growth of graphene films
Authors: Nandamuri Gopichand , Roumimov Sergei , Solanki Raj
Published: April 2010

Single and multiple layers of graphene films were grown on (111) oriented single crystals of nickel and polycrystalline nickel films using remote plasma assisted chemical vapor deposition. Remote plasma was employed to eliminate the effect of the plasma electrical field on the orientation of the grown graphene films, as well as to reduce the growth temperature compared to conventional chemical vapor deposition. The electrical and optical properties, including high resolution transmission electron microscopy of these films, suggest that this approach is both versatile and scalable for potential large area optoelectronic applications.
Natural fueling of a tokamak fusion reactor
Authors: Wan Weigang , Parker Scott E. , Chen Yang , Perkins Francis W.
Published: April 2010

A natural fueling mechanism that helps to maintain the main core deuterium and tritium (DT) density profiles in a tokamak fusion reactor is presented. In H-mode plasmas dominated by ion-temperature gradient (ITG) driven turbulence, cold DT ions near the edge will naturally pinch radially inward toward the core. This mechanism is due to the quasineutral heat flux dominated nature of ITG turbulence and still applies when trapped and passing kinetic electron effects are included. Fueling using shallow pellet injection is augmented by an inward pinch of cold DT fuel. The natural fueling mechanism is investigated using the gyrokinetic turbulence code GEM [Y. Chen and S. E. Parker, J. Comput. Phys. 220, 839 (2007)] and is analyzed using quasilinear theory. Profiles similar to those used for conservative International Thermonuclear Experimental Reactor [R. Aymar et al., Nucl. Fusion 41, 1301 (2001)] transport modeling that have a completely flat density profile are examined and it is found that natural fueling actually reduces the linear growth rate and energy transport. Natural fueling requires a two-component plasma and ion-ion and charge-exchange collisions set limits on this favorable effect.
Nature of deep center emissions in GaN
Authors: Sedhain A. , Li J. , Lin J. Y. , Jiang H. X.
Published: April 2010

Photoluminescence (PL) emission spectroscopy was employed to probe the nature of deep center emissions in GaN. The room temperature PL spectrum measured in the infrared (IR) region revealed an emission band centered around 1.23 eV. Based on detailed analysis of both the IR and visible emission spectra, we suggest that this emission band is a band-to-impurity transition involving a deep level complex consisting of a gallium vacancy and an oxygen atom sitting on one of the neighboring nitrogen sites; the (VGa–ON)2− charge state of (VGa–ON)2−/1−. Two electronic structures, which arise due to two different configurations of (VGa–ON)2−/1−, with ON either along the c-axis (axial configuration) or in one of the three equivalent tetrahedral positions (basal configuration), were observed. Our result also provides explicit evidence that both the yellow luminescence band and the 1.23 eV emission line in GaN are related to a common deep center, which is believed to be (VGa–ON)2−/1−.
Quantum efficiency and oscillator strength of site-controlled InAs quantum dots
Authors: Albert F. , Stobbe S. , Schneider C. , Heindel T. , Reitzenstein S. , Höfling S. , Lodahl P. , Worschech L. , Forchel A.
Published: April 2010

We report on time-resolved photoluminescence spectroscopy to determine the oscillator strength (OS) and the quantum efficiency (QE) of site-controlled InAs quantum dots nucleating on patterned nanoholes. These two quantities are determined by measurements on site-controlled quantum dot (SCQD) samples with varying thickness of the capping layer. We determine radiative and nonradiative decay rates, from which we calculate an OS of 10.1±2.6 and an encouragingly high QE of (47±14)% for the SCQDs. The nonideal QE is attributed to nonradiative recombination at the etched nanohole interface.
Polarization-independent multiple selective reflections from bichiral liquid crystal films
Authors: Ha Na Young , Jeong Soon Moon , Nishimura Suzushi , Takezoe Hideo
Published: April 2010

We have demonstrated polarization-independent multiple reflections covering overall visible region from a bichiral liquid crystal (LC) film with both chiral structures. The bichiral LC film was fabricated by an all-solution process using left-handed and right-handed polymeric cholesteric liquid crystal (CLC) films with a single pitch and an isotropic polymer film. The multiple reflections exceeding 50% reflectance were clearly observed at various polarizations of normally incident light. This characteristic can extend practical applications of CLCs to polarization-independent devices over broad-band regions.
Significant enhancement of magnetoelectric output in multiferroic heterostructural films modulated by electric polarization cycles
Authors: Wu Yujie , Wan Jian-guo , Liu Jun-ming , Wang Guanghou
Published: April 2010

The Pb(Zr,Ti)O3/CoFe2O4/Pb(Zr,Ti)O3 heterostructural film was prepared and the variation in its magnetoelectric output with the cycling electric polarization was investigated. The giant magnetoelectric output, which was about one order enhancement in magnitude compared with the original film, was observed after the film was subjected to the cycling electric polarization with the strength of 45 MV/m and cycling number of ∼2.2×108. We consider that both oxygen vacancy migration in the heterostructure and the polarized electric charges in the CoFe2O4 layer play important roles in such significant magnetoelectric enhancement.
Photoluminescence spectroscopy and positron annihilation spectroscopy probe of alloying and annealing effects in nonpolar m-plane ZnMgO thin films
Authors: Yang A. L. , Song H. P. , Liang D. C. , Wei H. Y. , Liu X. L. , Jin P. , Qin X. B. , Yang S. Y. , Zhu Q. S. , Wang Z. G.
Published: April 2010

Temperature-dependent photoluminescence characteristics of non-polar m-plane ZnO and ZnMgO alloy films grown by metal organic chemical vapor deposition have been studied. The enhancement in emission intensity caused by localized excitons in m-plane ZnMgO alloy films was directly observed and it can be further improved after annealing in nitrogen. The concentration of Zn vacancies in the films was increased by alloying with Mg, which was detected by positron annihilation spectroscopy. This result is very important to directly explain why undoped Zn1−xMgxO thin films can show p-type conduction by controlling Mg content, as discussed by Li et al. [Appl. Phys. Lett. 91, 232115 (2007)].
Thermal conductivity and dynamic heat capacity across the metal-insulator transition in thin film VO2
Authors: Oh Dong-Wook , Ko Changhyun , Ramanathan Shriram , Cahill David G.
Published: April 2010

The thermal properties of VO2 thin films, 90–440 nm thick, are measured by time-domain thermoreflectance (TDTR) across the metal-insulator transition (MIT). The thermal conductivity increases by as much as 60% in the metallic phase; this increase in conductivity is in good agreement with the expected electronic contribution to the thermal conductivity. For relatively thick layers, TDTR data are sensitive to the dynamic heat capacity and show a pronounced peak near the MIT temperature created by a contribution to the enthalpy from periodic transformations at the 10 MHz frequency of the thermal waves used in the experiment. The dynamic heat capacity increases as the amplitude ΔT of the thermal waves becomes comparable to the width of the MIT and reaches ≈30% of the bulk latent heat for ΔT≈1.6 K.
Dual carrier traps related hysteresis in organic inverters with polyimide-modified gate-dielectrics
Authors: Chou Wei-Yang , Yeh Bo-Liang
Published: April 2010

We integrated pentacene- and NN′-diheptyl-3,4,9,10-perylenebiscarboximide-based transistors into an organic complementary metal oxide semiconductor (O-CMOS) whose gate-dielectric surface was modified by polyimide (PI). The hysteresis behaviors in metal-oxide-semiconductors, field-effect transistors, and O-CMOS were reported clearly. Measurements of hysteresis showed that the PI exhibited high trapping and detrapping speeds for charge carriers, including holes and electrons, to result in high performance transistors and O-CMOSs; moreover, the trapping and detrapping speeds were matched. Finally, a PI-modified organic inverter with little hysteresis, low static power dissipation, high noise margins, and switching voltage near VDD/2 was achieved simultaneously.
De novo mutations in the gene encoding the synaptic scaffolding proteinSHANK3in patients ascertained for schizophrenia
Authors: Gauthier Julie , Champagne Nathalie , Lafrenière Ronald G. , Xiong Lan , Spiegelman Dan , Brustein Edna , Lapointe Mathieu , Peng Huashan , Côté Mélanie , Noreau Anne , Hamdan Fadi F. , Addington Anjené M. , Rapoport Judith L. , DeLisi Lynn E. , Krebs Marie-Odile , Joober Ridha , Fathalli Ferid , Mouaffak Fayçal , Haghighi Ali P. , Néri Christian , Dubé Marie-Pierre , Samuels Mark E. , Marineau Claude , Stone Eric A. , Awadalla Philip , Barker Philip A. , Carbonetto Salvatore , Drapeau Pierre , Rouleau Guy A. ,   the S2D Team, Daignault Kathleen , Diallo Ousmane , Duguay Joannie , Drits Marina , Henrion Edouard , Jolivet Philippe , Kuku Frédéric , Lachapelle Karine , Laliberté Guy , Laurent Sandra , Liao Meijiang , Marino Carlos , Piton Amélie , Raymond Annie , Reynolds Annie , Rochefort Daniel , St-Onge Judith , Thibodeau Pascale , Tsurudome Kazuya , Yang Yan , Leroy Sophie , Ossian Katia , Chayet Mélanie , Gourion David
Published: April 2010

Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations inSHANK3were previously reported in autism, the occurrence ofSHANK3mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.
High-risk myeloma is associated with global elevation of miRNAs and overexpression of
EIF2C2/AGO2
Authors: Zhou Yiming , Chen Lijuan , Barlogie Bart , Stephens Owen , Wu Xiaosong , Williams David R. , Cartron Marie-Astrid , van Rhee Frits , Nair Bijay , Waheed Sarah , Pineda-Roman Mauricio , Alsayed Yazan , Anaissie Elias , Shaughnessy John D.
Published: April 2010

MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (
P
< 0.01) and proliferation index (
P
< 0.05). Increased expression of
EIF2C2/AGO2
, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of
AGO2
dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of
AGO2
and the enzyme complexes that regulate miRNA maturation and function.
Conservation of recombination hotspots in yeast
Authors: Tsai Isheng J. , Burt Austin , Koufopanou Vassiliki
Published: April 2010

Meiotic recombination does not occur randomly along a chromosome, but instead tends to be concentrated in small regions, known as “recombination hotspots.” Recombination hotspots are thought to be short-lived in evolutionary time due to their self-destructive nature, as gene conversion favors recombination-suppressing alleles over recombination-promoting alleles during double-strand repair. Consistent with this expectation, hotspots in humans are highly dynamic, with little correspondence in location between humans and chimpanzees. Here, we identify recombination hotspots in two lineages of the yeast
Saccharomyces paradoxus,
and compare their locations to those found previously in
Saccharomyces cerevisiae
. Surprisingly, we find considerable overlap between the two species, despite the fact that they are at least 10 times more divergent than humans and chimpanzees. We attribute this unexpected result to the low frequency of sex and outcrossing in these yeasts, acting to reduce the population genetic effect of biased gene conversion. Traces from two other signatures of recombination, namely high mutagenicity and GC-biased gene conversion, are consistent with this interpretation. Thus, recombination hotspots are not inevitably short-lived, but rather their persistence through evolutionary time will be determined by the frequency of outcrossing events in the life cycle.
Bovine cytochrome
c
oxidase structures enable O
2
reduction with minimization of reactive oxygens and provide a proton-pumping gate
Authors: Muramoto Kazumasa , Ohta Kazuhiro , Shinzawa-Itoh Kyoko , Kanda Katsumasa , Taniguchi Maki , Nabekura Hiroyuki , Yamashita Eiki , Tsukihara Tomitake , Yoshikawa Shinya
Published: April 2010

The O
2
reduction site of cytochrome
c
oxidase (CcO), comprising iron (Fe

a
3

) and copper (Cu
B
) ions, is probed by x-ray structural analyses of CO, NO, and CN
-
derivatives to investigate the mechanism of the complete reduction of O
2
. Formation of the

derivative contributes to the trigonal planar coordination of

and displaces one of its three coordinated imidazole groups while a water molecule becomes hydrogen bonded to both the CN
-
ligand and the hydroxyl group of Tyr244. When O
2
is bound to

, it is negatively polarized (

), and expected to induce the same structural change induced by CN
-
. This structural change allows

to receive three electron equivalents nonsequentially from

,

, and Tyr-OH, providing complete reduction of O
2
with minimization of production of active oxygen species. The proton-pumping pathway of bovine CcO comprises a hydrogen-bond network and a water channel which extend to the positive and negative side surfaces, respectively. Protons transferred through the water channel are pumped through the hydrogen-bond network electrostatically with positive charge created at the Fe

a

center by electron donation to the O
2
reduction site. Binding of CO or NO to

induces significant narrowing of a section of the water channel near the hydrogen-bond network junction, which prevents access of water molecules to the network. In a similar manner, O
2
binding to

is expected to prevent access of water molecules to the hydrogen-bond network. This blocks proton back-leak from the network and provides an efficient gate for proton-pumping.
EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity
Authors: Bieschke Jan , Russ Jenny , Friedrich Ralf P. , Ehrnhoefer Dagmar E. , Wobst Heike , Neugebauer Katja , Wanker Erich E.
Published: April 2010

Protein misfolding and formation of β-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer’s and Parkinson’s disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits α-synuclein and amyloid-β fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.
Contrasts between adaptive coding and noncoding changes during human evolution
Authors: Haygood Ralph , Babbitt Courtney C. , Fedrigo Olivier , Wray Gregory A.
Published: April 2010

Changes in non–protein-coding regulatory DNA sequences have been proposed to play distinctive roles in adaptive evolution. We analyzed correlations between gene functions and evidence for positive selection in a common statistical framework across several large surveys of coding and noncoding sequences throughout the human genome. Strong correlations with both classifications in gene ontologies and measurements of gene expression indicate that neural development and function have adapted mainly through noncoding changes. In contrast, adaptation via coding changes is dominated by immunity, olfaction, and male reproduction. Genes with highly tissue-specific expression have undergone more adaptive coding changes, suggesting that pleiotropic constraints inhibit such changes in broadly expressed genes. In contrast, adaptive noncoding changes do not exhibit this pattern. Our findings underscore the probable importance of noncoding changes in the evolution of human traits, particularly cognitive traits.
Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (
LIPC
)
Authors: Neale Benjamin M. , Fagerness Jesen , Reynolds Robyn , Sobrin Lucia , Parker Margaret , Raychaudhuri Soumya , Tan Perciliz L. , Oh Edwin C. , Merriam Joanna E. , Souied Eric , Bernstein Paul S. , Li Binxing , Frederick Jeanne M. , Zhang Kang , Brantley Milam A. , Lee Aaron Y. , Zack Donald J. , Campochiaro Betsy , Campochiaro Peter , Ripke Stephan , Smith R. Theodore , Barile Gaetano R. , Katsanis Nicholas , Allikmets Rando , Daly Mark J. , Seddon Johanna M.
Published: April 2010

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (
LIPC
) in the high-density lipoprotein cholesterol (HDL) pathway (discovery
P
= 4.53e-05 for rs493258). Our
LIPC
association was strongest for a functional promoter variant, rs10468017, (
P
= 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with
LIPC
was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with
P
= 3.71e-09. We observed weaker associations with other HDL loci (
ABCA1
,
P
= 9.73e-04; cholesterylester transfer protein,
P
= 1.41e-03;
FADS1-3
,
P
= 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the
LIPC
association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.
Guard cell anion channel SLAC1 is regulated by CDPK protein kinases with distinct Ca
2+
affinities
Authors: Geiger D. , Scherzer S. , Mumm P. , Marten I. , Ache P. , Matschi S. , Liese A. , Wellmann C. , Al-Rasheid K. A. S. , Grill E. , Romeis T. , Hedrich R.
Published: April 2010

In response to drought stress, the phytohormone abscisic acid (ABA) induces stomatal closure. Thereby the stress hormone activates guard cell anion channels in a calcium-dependent, as well as –independent, manner.
O
pen
st
omata
1
protein kinase (OST1) and ABI1 protein phosphatase (
ABA
i
nsensitive
1
) represent key components of calcium-independent ABA signaling. Recently, the guard cell anion channel SLAC1 was identified. When expressed heterologously SLAC1 remained electrically silent. Upon coexpression with Ca
2+
-independent OST1, however, SLAC1 anion channels appear activated in an ABI1-dependent manner. Mutants lacking distinct calcium-dependent protein kinases (CPKs) appeared impaired in ABA stimulation of guard cell ion channels, too. To study SLAC1 activation via the calcium-dependent ABA pathway, we studied the SLAC1 response to CPKs in the
Xenopus laevis
oocyte system. Split YFP-based protein–protein interaction assays, using SLAC1 as the bait, identified guard cell expressed CPK21 and 23 as major interacting partners. Upon coexpression of SLAC1 with CPK21 and 23, anion currents document SLAC1 stimulation by these guard cell protein kinases. Ca
2+
-sensitive activation of SLAC1, however, could be assigned to the CPK21 pathway only because CPK23 turned out to be rather Ca
2+
-insensitive. In line with activation by OST1, CPK activation of the guard cell anion channel was suppressed by ABI1. Thus the CPK and OST1 branch of ABA signal transduction in guard cells seem to converge on the level of SLAC1 under the control of the ABI1/ABA-receptor complex.
Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis
Authors: Pastorelli Luca , Garg Rekha R. , Hoang Sharon B. , Spina Luisa , Mattioli Benedetta , Scarpa Melania , Fiocchi Claudio , Vecchi Maurizio , Pizarro Theresa T.
Published: April 2010

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn’s disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.
Entropic mechanism of large fluctuation in allosteric transition
Authors: Itoh Kazuhito , Sasai Masaki
Published: April 2010

A statistical mechanical model of allosteric transitions in proteins is developed by extending the structure-based model of protein folding to cases of multiple native conformations. The partition function is calculated exactly within the model and the free-energy surface reflecting allostery is derived. This approach is applied to an example protein, the receiver domain of the bacterial enhancer-binding protein NtrC. The model predicts the large entropy associated with a combinatorial number of preexisting transition routes. This large entropy lowers the free-energy barrier of the allosteric transition, which explains the large structural fluctuation observed in the NMR data of NtrC. The global allosteric transformation of NtrC is explained by the shift of preexisting distribution of conformations upon phosphorylation, but the local structural adjustment around the phosphorylation site is explained by the complementary induced-fit mechanism. Structural disordering accompanied by fluctuating interactions specific to two allosteric conformations underlies a large number of routes of allosteric transition.
Internally mixed sulfate and organic particles as potential ice nuclei in the tropical tropopause region
Authors: Wise Matthew E. , Baustian Kelly J. , Tolbert Margaret A.
Published: April 2010

Cirrus clouds are ubiquitous in the tropical tropopause region and play a major role in the Earth’s climate. Any changes to cirrus abundance due to natural or anthropogenic influences must be considered to evaluate future climate change. The detailed impact of cirrus clouds on climate depends on ice particle number, size, morphology, and composition. These properties depend in turn on the nucleation mechanism of the ice particles. Although it is often assumed that ice nucleates via a homogeneous mechanism, recent work points to the possibility that heterogeneous ice nucleation is important in the tropical tropopause region. However, there are very few studies of depositional ice nucleation on the complex types of particles likely to be found in this region of the atmosphere. Here, we use a unique method to probe depositional ice nucleation on internally mixed ammonium sulfate/palmitic acid particles, namely optical microscopy coupled with Raman microscopy. The deliquescence and efflorescence phase transitions of the mixed particles were first studied to gain insight into whether the particles are likely to be liquid or solid in the tropical tropopause region. The ice nucleating ability of the particles was then measured under typical upper tropospheric conditions. It was found that coating the particles with insoluble palmitic acid had little effect on the deliquescence, efflorescence, or ice nucleating ability of ammonium sulfate. Additional experiments involving Raman mapping provide new insights into how the composition and morphology of mixed particles impact their ability to nucleate ice.
Steric confinement of proteins on lipid membranes can drive curvature and tubulation
Authors: Stachowiak Jeanne C. , Hayden Carl C. , Sasaki Darryl Y.
Published: April 2010

Deformation of lipid membranes into curved structures such as buds and tubules is essential to many cellular structures including endocytic pits and filopodia. Binding of specific proteins to lipid membranes has been shown to promote membrane bending during endocytosis and transport vesicle formation. Additionally, specific lipid species are found to colocalize with many curved membrane structures, inspiring ongoing exploration of a variety of roles for lipid domains in membrane bending. However, the specific mechanisms by which lipids and proteins collaborate to induce curvature remain unknown. Here we demonstrate a new mechanism for induction and amplification of lipid membrane curvature that relies on steric confinement of protein binding on membrane surfaces. Using giant lipid vesicles that contain domains with high affinity for his-tagged proteins, we show that protein crowding on lipid domain surfaces creates a protein layer that buckles outward, spontaneously bending the domain into stable buds and tubules. In contrast to previously described bending mechanisms relying on local steric interactions between proteins and lipids (i.e. helix insertion into membranes), this mechanism produces tubules whose dimensions are defined by global parameters: domain size and membrane tension. Our results suggest the intriguing possibility that confining structures, such as lipid domains and protein lattices, can amplify membrane bending by concentrating the steric interactions between bound proteins. This observation highlights a fundamental physical mechanism for initiation and control of membrane bending that may help explain how lipids and proteins collaborate to create the highly curved structures observed in vivo.
A high-resolution assessment on global nitrogen flows in cropland
Authors: Liu Junguo , You Liangzhi , Amini Manouchehr , Obersteiner Michael , Herrero Mario , Zehnder Alexander J. B. , Yang Hong
Published: April 2010

Crop production is the single largest cause of human alteration of the global nitrogen cycle. We present a comprehensive assessment of global nitrogen flows in cropland for the year 2000 with a spatial resolution of 5 arc-minutes. We calculated a total nitrogen input (IN) of 136.60 trillion grams (Tg) of N per year, of which almost half is contributed by mineral nitrogen fertilizers, and a total nitrogen output (OUT) of 148.14 Tg of N per year, of which 55% is uptake by harvested crops and crop residues. We present high-resolution maps quantifying the spatial distribution of nitrogen IN and OUT flows, soil nitrogen balance, and surface nitrogen balance. The high-resolution data are aggregated at the national level on a per capita basis to assess nitrogen stress levels. The results show that almost 80% of African countries are confronted with nitrogen scarcity or nitrogen stress problems, which, along with poverty, cause food insecurity and malnutrition. The assessment also shows a global average nitrogen recovery rate of 59%, indicating that nearly two-fifths of nitrogen inputs are lost in ecosystems. More effective management of nitrogen is essential to reduce the deleterious environmental consequences.
Nucleotide-dependent conformational change governs specificity and analog discrimination by HIV reverse transcriptase
Authors: Kellinger Matthew W. , Johnson Kenneth A.
Published: April 2010

Single turnover studies on HIV reverse transcriptase suggest that nucleoside analogs bind more tightly to the enzyme than normal substrates, contrary to rational structural predictions. Here we resolve these controversies by monitoring the kinetics of nucleotide-induced changes in enzyme structure. We show that the specificity constant for incorporation of a normal nucleotide (dCTP) is determined solely by the rate of binding (including isomerization) because isomerization to the closed complex commits the substrate to react. In contrast, a nucleoside analog (3TC-TP, triphosphate form of lamivudine) is incorporated slowly, allowing the conformational change to come to equilibrium and revealing tight nucleotide binding. Our data reconcile previously conflicting reports suggesting that nucleotide analogs bind tighter than normal nucleotides. Rather, dCTP and 3TC-TP bind with nearly equal affinities, but the binding of dCTP never reaches equilibrium. Discrimination against 3TC-TP is based on the slower rate of incorporation due to misalignment of the substrate and/or catalytic residues.
Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors
Authors: Rodriguez Gustavo J. , Yao Rong , Lichtarge Olivier , Wensel Theodore G.
Published: April 2010

G protein-coupled receptors for dopamine and serotonin control signaling pathways targeted by many psychoactive drugs. A puzzle is how receptors with similar functions and nearly identical binding site structures, such as D2 dopamine receptors and 5-HT2A serotonin receptors, could evolve a mechanism that discriminates stringently in their cellular responses between endogenous neurotransmitters. We used the Difference Evolutionary Trace (Difference-ET) and residue-swapping to uncover two distinct sets of specificity-determining sequence positions. One at the ligand-binding pocket determines the relative affinities for these two ligands, and a distinct, surprising set of positions outside the binding site determines whether a bound ligand can trigger the conformational rearrangement leading to G protein activation. Thus one site specifies affinity while the other encodes a filter for efficacy. These findings demonstrate that allosteric pathways linking distant interactions via alternate conformational states enforce specificity independently of the ligand-binding site, such that either one may be rationally rekeyed to different ligands. The conversion of a dopamine receptor effectively into a serotonin receptor illustrates the plasticity of GPCR signaling during evolution, or in pathological states, and suggests new approaches to drug discovery, targeting both classes of sites.
A defunctioning polymorphism in
FCGR2B
is associated with protection against malaria but susceptibility to systemic lupus erythematosus
Authors: Willcocks Lisa C. , Carr Edward J. , Niederer Heather A. , Rayner Tim F. , Williams Thomas N. , Yang Wanling , Scott J. Anthony G. , Urban Britta C. , Peshu Norbert , Vyse Timothy J. , Lau Yu Lung , Lyons Paul A. , Smith Kenneth G. C.
Published: April 2010

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcγRIIb is an inhibitory Fc receptor with a critical role in immune regulation. Mouse data suggest that FcγRIIb deficiency increases susceptibility to autoimmune disease but protects against infection. We show that a SNP in human
FCGR2B
that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians. The minor allele of this SNP is more common in Southeast Asians and Africans, populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56;
P
= 7.1 × 10
−5
). This protective effect against malaria may contribute to the higher frequency of this SNP and hence, SLE in Africans and Southeast Asians.
Imprints of the genetic code in the ribosome
Authors: Johnson David B. F. , Wang Lei
Published: April 2010

The establishment of the genetic code remains elusive nearly five decades after the code was elucidated. The stereochemical hypothesis postulates that the code developed from interactions between nucleotides and amino acids, yet supporting evidence in a biological context is lacking. We show here that anticodons are selectively enriched near their respective amino acids in the ribosome, and that such enrichment is significantly correlated with the canonical code over random codes. Ribosomal anticodon-amino acid enrichment further reveals that specific codons were reassigned during code evolution, and that the code evolved through a two-stage transition from ancient amino acids without anticodon interaction to newer additions with anticodon interaction. The ribosome thus serves as a molecular fossil, preserving biological evidence that anticodon-amino acid interactions shaped the evolution of the genetic code.
Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease
Authors: Coomaraswamy Janaky , Kilger Ellen , Wölfing Heidrun , Schäfer Claudia , Kaeser Stephan A. , Wegenast-Braun Bettina M. , Hefendehl Jasmin K. , Wolburg Hartwig , Mazzella Matthew , Ghiso Jorge , Goedert Michel , Akiyama Haruhiko , Garcia-Sierra Francisco , Wolfer David P. , Mathews Paul M. , Jucker Mathias
Published: April 2010

Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuroinflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neuritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP301S tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between β-amyloid (Aβ)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Aβ peptides, the lack of codeposition of the two peptides in crosses between ADan- and Aβ-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain.
Disruption of an intersubunit electrostatic bond is a critical step in glycine receptor activation
Authors: Todorovic Jelena , Welsh Brian T. , Bertaccini Edward J. , Trudell James R. , Mihic S. John
Published: April 2010

Proper regulation of neurotransmission requires that ligand-activated ion channels remain closed until agonist binds. How channels then open remains poorly understood. Glycine receptor (GlyR) gating is initiated by agonist binding at interfaces between adjacent subunits in the extracellular domain. Aspartate-97, located at the α1 GlyR interface, is a conserved residue in the cys-loop receptor superfamily. The mutation of D97 to arginine (D97R) causes spontaneous channel opening, with open and closed dwell times similar to those of maximally activated WT GlyR. Using a model of theN-terminal domain of the α1 GlyR, we hypothesized that an arginine-119 residue was forming intersubunit electrostatic bonds with D97. The D97R/R119E charge reversal restored this interaction, stabilizing channels in their closed states. Cysteine substitution shows that this link occurs between adjacent subunits. This intersubunit electrostatic interaction among GlyR subunits thus contributes to the stabilization of the closed channel state, and its disruption represents a critical step in GlyR activation.
Induced pluripotent stem cells derived from mouse models of lysosomal storage disorders
Authors: Meng Xing-Li , Shen Jin-Song , Kawagoe Shiho , Ohashi Toya , Brady Roscoe O. , Eto Yoshikatsu
Published: April 2010

Most lysosomal storage diseases (LSDs) are life-threatening genetic diseases. The pathogenesis of these diseases is poorly understood. Induced pluripotent stem (iPS) cell technology offers new opportunities for both mechanistic studies and development of stem cell– based therapies. Here we report the generation of disease-specific iPS cells from mouse models of Fabry disease, globoid cell leukodystrophy (GLD), and mucopolysaccharidosis VII (MPSVII). These mouse model–derived iPS cells showed defects in disease-specific enzyme activities and significant accumulation of substrates for these enzymes. In the lineage-directed differentiation studies, Fabry-iPS and GLD-iPS cells were efficiently differentiated into disease-relevant cell types, such as cardiomyocytes and neural stem cells, which might be useful in mechanistic and therapeutic studies. Notably, MPSVII-iPS cells demonstrated a markedly impaired ability to form embryoid bodies (EBs) in vitro. MPSVII-EBs exibited elevated levels of hyaluronan and its receptor CD44, and markedly reduced expression levels of E-cadherin and cell-proliferating marker. Partial correction of enzyme deficiency in MSPVII-iPS cells led to improved EB formation and reversal of aberrant protein expression. These data indicate a potential mechanism for the partial lethality of MPSVII mice in utero, and suggest a possible abnormality of embryonic development in MPSVII patients. Thus, our study demonstrates the unique promise of iPS cells for studying the pathogenesis and treatment of LSDs.
Compound haploinsufficiencies ofEbf1andRunx1genes impede B cell lineage progression
Authors: Lukin Kara , Fields Scott , Lopez Desiree , Cherrier Marie , Ternyak Kristina , Ramírez Julita , Feeney Ann J. , Hagman James
Published: April 2010

Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation ofCd79a(mb-1) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences ofEbf1haploinsufficiency together with haploinsufficiency ofRunx1genes in mice. Although numbers of “committed” pro-B cells were maintained inEbf1+/−Runx1+/−(ERhet) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, κ0sterile transcripts, CD2 and CD25 were reduced and delayed inERhetpro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells inERhetmice. Late pre-B and immature and mature B cells were decreased in the bone marrow ofEbf1+/−(Ehet) mice and were nearly absent inERhetmice. Although we did not observe significant effects of haploinsuficiencies onIgHorIgκ rearrangements, a relative lack ofIgλ rearrangements was detected inEhetandERhetpre-B cells. Together, these observations suggest that B cell lineage progression is impaired at multiple stages in the bone marrow ofEhetandERhetmice. Furthermore, enforced expression of EBF1 and RUNX1 in terminally differentiated plasmacytoma cells activated multiple early B cell-specific genes synergistically. Collectively, these studies illuminate the effects of reducedEbf1dosage and the compounding effects of reducedRunx1dosage. Our data confirm and extend the importance of EBF1 in regulating target genes andIggene rearrangements necessary for B cell lineage specification, developmental progression, and homeostasis.
RGS4 is a negative regulator of insulin release from pancreatic β-cells in vitro and in vivo
Authors: Ruiz de Azua Inigo , Scarselli Marco , Rosemond Erica , Gautam Dinesh , Jou William , Gavrilova Oksana , Ebert Philip J. , Levitt Pat , Wess Jürgen
Published: April 2010

Therapeutic strategies that augment insulin release from pancreatic β-cells are considered beneficial in the treatment of type 2 diabetes. We previously demonstrated that activation of β-cell M
3
muscarinic receptors (M3Rs) greatly promotes glucose-stimulated insulin secretion (GSIS), suggesting that strategies aimed at enhancing signaling through β-cell M3Rs may become therapeutically useful. M3R activation leads to the stimulation of G proteins of the G
q
family, which are under the inhibitory control of proteins known as regulators of G protein signaling (RGS proteins). At present, it remains unknown whether RGS proteins play a role in regulating insulin release. To address this issue, we initially demonstrated that MIN6 insulinoma cells express functional M3Rs and that RGS4 was by far the most abundant RGS protein expressed by these cells. Strikingly, siRNA-mediated knockdown of RGS4 expression in MIN6 cells greatly enhanced M3R-mediated augmentation of GSIS and calcium release. We obtained similar findings using pancreatic islets prepared from RGS4-deficient mice. Interestingly, RGS4 deficiency had little effect on insulin release caused by activation of other β-cell GPCRs. Finally, treatment of mutant mice selectively lacking RGS4 in pancreatic β-cells with a muscarinic agonist (bethanechol) led to significantly increased plasma insulin and reduced blood glucose levels, as compared to control littermates. Studies with β-cell-specific M3R knockout mice showed that these responses were mediated by β-cell M3Rs. These findings indicate that RGS4 is a potent negative regulator of M3R function in pancreatic β-cells, suggesting that RGS4 may represent a potential target to promote insulin release for therapeutic purposes.
Deciding what to eat
Authors: Short Ben
Published: April 2010

A signaling pathway directs cells to degrade peroxisomes while leaving other organelles untouched.
LGN regulates mitotic spindle orientation during epithelial morphogenesis
Authors: Zheng Zhen , Zhu Huabin , Wan Qingwen , Liu Jing , Xiao Zhuoni , Siderovski David P. , Du Quansheng
Published: April 2010

Coordinated cell polarization and mitotic spindle orientation are thought to be important for epithelial morphogenesis. Whether spindle orientation is indeed linked to epithelial morphogenesis and how it is controlled at the molecular level is still unknown. Here, we show that the NuMA- and Gα-binding protein LGN is required for directing spindle orientation during cystogenesis of MDCK cells. LGN localizes to the lateral cell cortex, and is excluded from the apical cell cortex of dividing cells. Depleting LGN, preventing its cortical localization, or disrupting its interaction with endogenous NuMA or Gα proteins all lead to spindle misorientation and abnormal cystogenesis. Moreover, artificial mistargeting of endogenous LGN to the apical membrane results in a near 90° rotation of the spindle axis and profound cystogenesis defects that are dependent on cell division. The normal apical exclusion of LGN during mitosis appears to be mediated by atypical PKC. Thus, cell polarization–mediated spatial restriction of spindle orientation determinants is critical for epithelial morphogenesis.
Transfer of ion binding site from ether-à-go-go to Shaker: Mg2+ binds to resting state to modulate channel opening
Authors: Lin Meng-chin A. , Abramson Jeff , Papazian Diane M.
Published: April 2010

In ether-à-go-go (eag) K+ channels, extracellular divalent cations bind to the resting voltage sensor and thereby slow activation. Two eag-specific acidic residues in S2 and S3b coordinate the bound ion. Residues located at analogous positions are ∼4 Å apart in the x-ray structure of a Kv1.2/Kv2.1 chimera crystallized in the absence of a membrane potential. It is unknown whether these residues remain in proximity in Kv1 channels at negative voltages when the voltage sensor domain is in its resting conformation. To address this issue, we mutated Shaker residues I287 and F324, which correspond to the binding site residues in eag, to aspartate and recorded ionic and gating currents in the presence and absence of extracellular Mg2+. In I287D+F324D, Mg2+ significantly increased the delay before ionic current activation and slowed channel opening with no readily detectable effect on closing. Because the delay before Shaker opening reflects the initial phase of voltage-dependent activation, the results indicate that Mg2+ binds to the voltage sensor in the resting conformation. Supporting this conclusion, Mg2+ shifted the voltage dependence and slowed the kinetics of gating charge movement. Both the I287D and F324D mutations were required to modulate channel function. In contrast, E283, a highly conserved residue in S2, was not required for Mg2+ binding. Ion binding affected activation by shielding the negatively charged side chains of I287D and F324D. These results show that the engineered divalent cation binding site in Shaker strongly resembles the naturally occurring site in eag. Our data provide a novel, short-range structural constraint for the resting conformation of the Shaker voltage sensor and are valuable for evaluating existing models for the resting state and voltage-dependent conformational changes that occur during activation. Comparing our data to the chimera x-ray structure, we conclude that residues in S2 and S3b remain in proximity throughout voltage-dependent activation.