bluuebunny/crossref_metadata_2025 huggingface dataset:
Rupture directivity of small earthquakes at Parkfield
Authors: Kane Deborah L. , Shearer Peter M. , Goertz‐Allmann Bettina P. , Vernon Frank L.
Published: November 2012

Theoretical modeling of strike‐slip ruptures along a bimaterial interface suggests that earthquakes initiating on the interface will have a preferred rupture direction. We test this model with 450 small earthquakes (2 < M < 5) from Parkfield, California, to look for evidence of consistent rupture directivity along the San Andreas Fault. We analyze azimuthal variations in earthquake source spectra after applying an iterative correction for wave propagation effects. Our approach avoids directly modeling source spectra because these models generally assume symmetric rupture; instead, we look for azimuthal variations in the amplitudes of the source spectra over specified frequency bands. Our overall results show similar proportions of events exhibiting characteristics of rupture directivity toward either the southeast or northwest. However, the proportion of events with southeast rupture directivity increases as we limit the data set to larger magnitudes, with 70% of the 46 events M > 3 exhibiting southeast rupture characteristics. Some spatial and temporal variability in rupture directivity is also apparent. We observe a higher proportion of northwest directivity ruptures following the 2004 M 6 Parkfield earthquake, which ruptured toward the northwest. Our results are generally consistent with the preferred southeast rupture directivity model but suggest that directivity is likely due to several contributing factors.
Stratospheric ozone and the morphology of the northern hemisphere planetary waveguide
Authors: Albers John R. , McCormack John P. , Nathan Terrence R.
Published: November 2012

A middle atmosphere general circulation model is used to examine the effects of zonally asymmetric ozone (ZAO) on the Northern Hemisphere planetary waveguide (PWG) during winter (December–February). The morphology of the PWG is measured by a refractive index, Eliassen‐Palm flux vectors, the latitude of the subtropical zero wind line, and the latitude of the subtropical jet. ZAO causes the PWG to contract meridionally in the upper stratosphere, expand meridionally in the lower stratosphere, and expand vertically in the upper stratosphere and lower mesosphere. The ZAO‐induced changes in the PWG are the result of increased upward and poleward flux of planetary wave activity into the extratropical stratosphere and lower mesosphere. These changes cause an increase in the Eliassen‐Palm flux convergence at high latitudes, which produces a warmer and weaker stratospheric polar vortex and an increase in the frequency of stratospheric sudden warmings. The ability of ZAO to alter the flux of planetary wave activity into the polar vortex has important implications for accurately modeling wave‐modulated and wave‐driven phenomena in the middle atmosphere, including the 11‐year solar cycle, stratospheric sudden warmings, and the phase of the Northern Hemisphere annular mode.
Why does radar reflectivity tend to increase downward toward the ocean surface, but decrease downward toward the land surface?
Authors: Liu Chuntao , Zipser Edward J.
Published: November 2012

Both ground and space borne radars have shown that radar reflectivity profiles below the freezing level have different slopes over land and ocean in general. This is critical in correctly estimating the surface precipitation rate in the usual situation in which the radar reflectivity cannot be measured as close to the surface as one would like. Using 14 years of Tropical Rainfall Measuring Mission precipitation radar observations, the variations of slopes of the radar reflectivity in the low troposphere are examined over the stratiform and convective precipitation regions. Radar reflectivity below the freezing level usually decreases toward the surface over land, but increases toward the surface over the ocean. Increasing reflectivity toward the surface is hypothesized to occur mainly when raindrops grow while falling through low clouds, which is favored by high humidity at low levels, and by updraft speeds lower than the fall speed of raindrops, both more likely over oceans. Other things being equal, proxy evidence is presented that the more intense the convection, the more likely reflectivity is to decrease toward the surface, and that this is at least as important as low‐level relative humidity. Over monsoon regions with more moderate convection but higher humidity, such as southeast China and the Amazon, there are more profiles with reflectivity increasing toward the surface than over other continental regions such as Africa. Radar reflectivity tends to increase toward the surface in shallow warm rain systems in trade cumulus regions, but tends to decrease toward the surface when high reflectivity values are present at or above the freezing level.
Spatial‐temporal variations of evapotranspiration and runoff/precipitation ratios responding to the changing climate in the Pacific Northwest during 1921‐2006
Authors: Liu Mingliang , Adam Jennifer C. , Hamlet Alan F.
Published: November 2012

Water resources in the Pacific Northwest (PNW) are very sensitive to climate change. There are still big knowledge gaps on how evapotranspiration (ET) varies in responding to changing temperature (T) and precipitation (P) over different zones in terms of supply and demand regime for ET. Here, we employ the Variable Infiltration Capacity (VIC) hydrologic model and a high‐resolution meteorological data set to quantify spatial and seasonal variations of ET and the runoff (R)/precipitation (P) ratio over the PNW and attribute effects of T and P. We evaluate modeled ET and R with eddy covariance measurements, upscaled regional ET, and reconstructed natural streamflow. Simulation results indicate that water‐limited (annual potential ET (PET) ≥ P) and energy‐limited zones (annual PET < P) have different responses to changing climate. In general, water‐limited zones tend to be more associated with increasing ET and decreasing R/P than do energy‐limited regions. With controlled simulation experiments, we document that trends in annual and warm‐season ET and R/P are dominantly controlled by P, while in the cool season they are mainly controlled by T. During an entire cycle of the Pacific Decadal Oscillation (1947‐2006), the PNW experienced a substantial increase in ET and a decrease in R and R/P under the trends of warming and drying. In this snowmelt‐dominated region where warming‐induced changes to the snowpack are impacting seasonal freshwater availability, decreases in R/P could further aggravate water scarcity. To reduce uncertainties, high‐resolution meteorological data sets and intensive model calibrations and evaluations against ET are required.
Microbial diversity and impact on carbonate geochemistry across a changing geochemical gradient in a karst aquifer
Authors: Gray Cassie J , Engel Annette S
Published: November 2012

Although microbes are known to influence karst (carbonate) aquifer ecosystem-level processes, comparatively little information is available regarding the diversity of microbial activities that could influence water quality and geological modification. To assess microbial diversity in the context of aquifer geochemistry, we coupled 16S rRNA Sanger sequencing and 454 tag pyrosequencing to in situ microcosm experiments from wells that cross the transition from fresh to saline and sulfidic water in the Edwards Aquifer of central Texas, one of the largest karst aquifers in the United States. The distribution of microbial groups across the transition zone correlated with dissolved oxygen and sulfide concentration, and significant variations in community composition were explained by local carbonate geochemistry, specifically calcium concentration and alkalinity. The waters were supersaturated with respect to prevalent aquifer minerals, calcite and dolomite, but in situ microcosm experiments containing these minerals revealed significant mass loss from dissolution when colonized by microbes. Despite differences in cell density on the experimental surfaces, carbonate loss was greater from freshwater wells than saline, sulfidic wells. However, as cell density increased, which was correlated to and controlled by local geochemistry, dissolution rates decreased. Surface colonization by metabolically active cells promotes dissolution by creating local disequilibria between bulk aquifer fluids and mineral surfaces, but this also controls rates of karst aquifer modification. These results expand our understanding of microbial diversity in karst aquifers and emphasize the importance of evaluating active microbial processes that could affect carbonate weathering in the subsurface.
Are we missing half of the viruses in the ocean?
Authors: Steward Grieg F , Culley Alexander I , Mueller Jaclyn A , Wood-Charlson Elisha M , Belcaid Mahdi , Poisson Guylaine
Published: November 2012

Viruses are abundant in the ocean and a major driving force in plankton ecology and evolution. It has been assumed that most of the viruses in seawater contain DNA and infect bacteria, but RNA-containing viruses in the ocean, which almost exclusively infect eukaryotes, have never been quantified. We compared the total mass of RNA and DNA in the viral fraction harvested from seawater and using data on the mass of nucleic acid per RNA- or DNA-containing virion, estimated the abundances of each. Our data suggest that the abundance of RNA viruses rivaled or exceeded that of DNA viruses in samples of coastal seawater. The dominant RNA viruses in the samples were marine picorna-like viruses, which have small genomes and are at or below the detection limit of common fluorescence-based counting methods. If our results are typical, this means that counts of viruses and the rate measurements that depend on them, such as viral production, are significantly underestimated by current practices. As these RNA viruses infect eukaryotes, our data imply that protists contribute more to marine viral dynamics than one might expect based on their relatively low abundance. This conclusion is a departure from the prevailing view of viruses in the ocean, but is consistent with earlier theoretical predictions.
Environmental distribution of coral-associated relatives of apicomplexan parasites
Authors: Janouškovec Jan , Horák Aleš , Barott Katie L , Rohwer Forest L , Keeling Patrick J
Published: November 2012

A lineage of plastid-bearing eukaryotic microbes that is closely related to apicomplexan parasites was recently found in a specific association with coral reefs (apicomplexan-related lineage-V, or ARL-V). Here, we address the possible nature of this association using plastid ‘contamination’ in fine-scale bacterial sequence surveys. In a transect between corals and associated macroalgae, ARL-V is specifically associated with the coral, in contrast to all microalgal types (including diatoms, haptophytes, pelagophytes and photosynthetic apicomplexan relatives, Chromera and Vitrella), which are associated with macroalgae. ARL-V is associated with at least 20 species of symbiotic corals through extended time periods and large geographic distances. It is significantly enriched in healthy coral tissue and shallow reef depths. Altogether, the evidence points to a specific relationship between ARL-V and corals, and is suggestive of symbiosis, perhaps based on photosynthesis.
The response of entire male and female pigs from 20 to 100-kg liveweight to dietary available lysine
Authors: Moore K. L. , Mullan B. P. , Campbell R. G. , Kim J. C.
Published: November 2012

Two experiments were conducted to determine the responses of entire male and female pigs of the Australian Pig Improvement Co. genotype to dietary lysine. In Experiment 1, a total of 350 [Large White × (Landrace × Duroc)] entire male and female pigs weighing 22.3 ± 0.16 kg (mean ± s.e.m.) were used in a 2 by 5 factorial design with the main treatments being sex (entire males and females) and five levels of standardised ileal digestible (SID) lysine to digestible energy ratio (0.6, 0.7, 0.8, 0.9 and 1.0 g SID lysine/MJ DE). In Experiment 2, a total of 420 [Large White × (Landrace × Duroc)] entire male and female pigs weighing 49.6 ± 0.34 kg (mean ± s.e.m.) were used in a 2 by 5 factorial design with the main treatments being sex (entire males and females) and five levels of SID lysine to MJ DE ratio (0.4, 0.5, 0.6, 0.7 and 0.8 g). From 20 to 50 kg liveweight (LW), entire males had a similar average daily gain (ADG), lower feed intake (FI, P < 0.001) and better feed to gain ratio (F : G, P < 0.001) compared with females. From 50 to 100 kg LW, entire males had a higher ADG (P < 0.001), similar FI and improved F : G ratio (P < 0.001) compared with females. Data were subjected to the quadratic response model to determine optimum SID lysine requirement for maximum ADG and minimum F : G for the weight ranges 20–35, 35–50, 50–65, 65–80, and 80 to 95 kg LW. For male pigs, maximum ADG was achieved at SID lysine levels of 1.00, 0.87, 0.72, 0.67 and 0.63 g/MJ DE, respectively. Minimum F : G was achieved at SID lysine levels of 1.00, 0.87, 0.80, 0.69 and 0.63 g/MJ DE for the respective weight ranges. For female pigs, maximum ADG was achieved at SID lysine levels of 0.90, 0.84, 0.67, 0.63 and 0.58 g/MJ DE. Minimum F : G for females was achieved at SID lysine levels of 0.86, 0.85, 0.64, 0.66 and 0.40 g/MJ DE for the respective weight ranges. The results suggest that this Australian genotype requires greater dietary SID lysine in the growing and finishing phase than the levels currently used by the Australian industry.
Solvent-Dependent Access to Two Different Ni4II Core Topologies from the First Use of Pyridine-2,6-dimethanol in Nickel(II) Cluster Chemistry
Authors: Alexopoulou Konstantina I. , Raptopoulou Catherine P. , Psycharis Vassilis , Terzis Aris , Tangoulis Vassilis , Stamatatos Theocharis C. , Perlepes Spyros P.
Published: November 2012

The use of pyridine-2,6-dimethanol, pdmH2, in reactions with nickel(ii) acetate has led to two Ni4 clusters, depending on the solvent. [Ni4(O2CMe)4(pdmH)4]·MeCN (1·MeCN) can be obtained from MeCN and [Ni4(O2CMe)6(pdmH)2(EtOH)2]·1.2EtOH (2·1.2EtOH) from EtOH. Each cluster can be converted into the other in the appropriate solvent. The tetranuclear cluster molecule 1 possesses a distorted cubane {Ni4(μ3-OR)4}4+ core (RO– = pdmH–) with the NiII atoms and the alkoxide-type oxygen atoms from the η3 : η1 : μ3 pdmH– ligands occupying alternate vertices of the cube; four η1 : η1 : μ MeCO2– groups cap four faces of the cube. The four NiII atoms in molecule 2 are located at four vertices of a defective dicubane and are bridged by six oxygen atoms, two μ3 from the η3 : η1 : η1 : μ3 pdmH– ligands and four from four monoatomically bridging MeCO2– groups; peripheral ligation is provided by two η1 : η1 : μ MeCO2– groups and two terminal EtOH ligands. IR data are discussed in terms of the coordination modes of the ligands. Variable-temperature direct-current magnetic susceptibility data of 1 and 2 were modelled with two and three J values respectively, indicating diamagnetic ground states (S = 0). The sign and the magnitude of the J values are discussed in terms of structural features of the complexes.
A model system for mitochondrial biogenesis reveals evolutionary rewiring of protein import and membrane assembly pathways
Authors: Hewitt Victoria L. , Heinz Eva , Shingu-Vazquez Miguel , Qu Yue , Jelicic Branka , Lo Tricia L. , Beilharz Traude H. , Dumsday Geoff , Gabriel Kipros , Traven Ana , Lithgow Trevor
Published: November 2012

The controlled biogenesis of mitochondria is a key cellular system coordinated with the cell division cycle, and major efforts in systems biology currently are directed toward understanding of the control points at which this coordination is achieved. Here we present insights into the function, evolution, and regulation of mitochondrial biogenesis through the study of the protein import machinery in the human fungal pathogen,
Candida albicans
. Features that distinguish
C
.
albicans
from baker’s yeast (
Saccharomyces cerevisiae
) include the stringency of metabolic control at the level of oxygen consumption, the potential for ATP exchange through the porin in the outer membrane, and components and domains in the sorting and assembling machinery complex, a molecular machine that drives the assembly of proteins in the outer mitochondrial membrane. Analysis of targeting sequences and assays of mitochondrial protein import show that components of the electron transport chain are imported by distinct pathways in
C. albicans
and
S. cerevisiae
, representing an evolutionary rewiring of mitochondrial import pathways. We suggest that studies using this pathogen as a model system for mitochondrial biogenesis will greatly enhance our knowledge of how mitochondria are made and controlled through the course of the cell-division cycle.
p10, the N-terminal domain of p35, protects against CDK5/p25-induced neurotoxicity
Authors: Zhang Lingyan , Liu Wen , Szumlinski Karen K. , Lew John
Published: November 2012

Cyclin-dependent kinase 5(CDK5) in complex with its activator, p35 (protein of 35 kDa), is essential for early neurodevelopment in mammals. However, endogenous cleavage of p35 to p25 is associated with neuron death and neurodegenerative disease. Here we show that a peptide (p10′) encoding the N-terminal domain of p35 protects against CDK5/p25-induced toxicity in neurons. p10′ also prevented the death of neurons treated with the neurotoxin, 1-methyl-4-phenylpyridinium (MPP
+
), which induces conversion of endogenous p35 to p25, and Parkinson disease (PD)-like symptoms in animals. MPP
+
induces CDK5/p25-dependent phosphorylation of peroxiredoxin 2 (Prx2), resulting in inhibition of its peroxireductase activity and accumulation of reactive oxygen species (ROS). We found that p10′ expression inhibited both Prx2 phosphorylation and ROS accumulation in neurons. In addition, p10′ inhibited the p25-induced appearance of antigen of the Ki67 antibody (Ki67) and phosphohistone H2AX (γH2AX), classic markers of cell cycle activity and DNA double-strand breakage, respectively, associated with neuron death. Our results suggest that p10 (protein of 10 kDa) is a unique prosurvival domain in p35, essential for normal CDK5/p35 function in neurons. Loss of the p10 domain results in CDK5/p25 toxicity and neurodegeneration in vivo.
The correlates of psychological health among the Turkish unemployed: Psychological burden of financial help during unemployment
Authors: Bilgiç Reyhan , Yılmaz Nilgün
Published: November 2012

The purpose of this study is to examine the major determinants of psychological health during unemployment. With this in mind, 438 (17% female and 83% male) unemployed individuals were contacted through Turkey's State Employment Office. It was expected that the relationship between duration of unemployment and psychological wellbeing would be nonlinear. Additionally it was hypothesized that perceived social support would moderate the relationship between length of unemployment and psychological health. Further, we suggested that self‐esteem would be related to psychological health and moderate the relationship between length of unemployment and psychological health. The results supported the curvilinearity hypothesis of the relationship between unemployment duration and psychological health as measured by General Health Questionnaire. However, social support was not found to moderate the relationship between unemployment duration and psychological health. The hypothesis that self‐esteem would moderate the relationship between length of unemployment and psychological distress was not supported, although self‐esteem was a strong negative determinant of psychological distress during unemployment. Regression analysis showed that the best predictors of psychological health were self‐esteem, perceived social support and perceived adequacy of financial aid received from relatives. Interestingly, perceived adequacy of the financial aid was negatively related to psychological health. This result was contradictory with the previous literature pointing out that financial aid reduces the effects of poverty due to unemployment. The findings of this study are important since the relationship between unemployment duration and psychological health was nonlinear, indicating that relevant services should be especially careful to intervene to increase social support and self‐esteem during these critical times. The other results and limitations are discussed.
The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments
Authors: Cortese Katia , Howes Mark T. , Lundmark Richard , Tagliatti Erica , Bagnato Paola , Petrelli Annalisa , Bono Maria , McMahon Harvey T. , Parton Robert G. , Tacchetti Carlo
Published: November 2012

The ErbB2 receptor is a clinically validated cancer target whose internalization and trafficking mechanisms remain poorly understood. HSP90 inhibitors, such as geldanamycin (GA), have been developed to target the receptor to degradation or to modulate downstream signaling. Despite intense investigations, the entry route and postendocytic sorting of ErbB2 upon GA stimulation have remained controversial. We report that ErbB2 levels inversely impact cell clathrin-mediated endocytosis (CME) capacity. Indeed, the high levels of the receptor are responsible for its own low internalization rate. GA treatment does not directly modulate ErbB2 CME rate but it affects ErbB2 recycling fate, routing the receptor to modified multivesicular endosomes (MVBs) and lysosomal compartments, by perturbing early/recycling endosome structure and sorting capacity. This activity occurs irrespective of the cargo interaction with HSP90, as both ErbB2 and the constitutively recycled, HSP90-independent, transferrin receptor are found within modified endosomes, and within aberrant, elongated recycling tubules, leading to modified MVBs/lysosomes. We propose that GA, as part of its anticancer activity, perturbs early/recycling endosome sorting, routing recycling cargoes toward mixed endosomal compartments.
Numerical inverse scattering for the focusing and defocusing nonlinear Schrödinger equations
Authors: Trogdon Thomas , Olver Sheehan
Published: November 2012

We solve the focusing and defocusing nonlinear Schrödinger (NLS) equations numerically by implementing the inverse scattering transform. The computation of the scattering data and of the NLS solution are both spectrally convergent. Initial conditions in a suitable space are treated. Using the approach of Biondini & Bui, we numerically solve homogeneous Robin boundary-value problems on the half line. Finally, using recent theoretical developments in the numerical approximation of Riemann–Hilbert problems, we prove that, under mild assumptions, our method of approximating solutions to the NLS equations is uniformly accurate in their domain of definition.
Spectral gaps for water waves above a corrugated bottom
Authors: Chiadò Piat V. , Nazarov S. A. , Ruotsalainen K.
Published: November 2012

In this paper, the essential spectrum of the linear problem on water waves in a water layer and in a channel with a gently corrugated bottom is studied. We show that, under a certain geometric condition, the essential spectrum has spectral gaps. In other words, there exist intervals in the positive real semi-axis that are free of the spectrum but have their endpoints in it. The position and the length of the gaps are found out by applying an asymptotic analysis to the model problem in the periodicity cell.
Upregulation of TRIM5α gene expression after live-attenuated simian immunodeficiency virus vaccination in Mauritian cynomolgus macaques, but TRIM5α genotype has no impact on virus acquisition or vaccination outcome
Authors: Mattiuzzo Giada , Rose Nicola J. , Almond Neil , Towers Greg J. , Berry Neil
Published: November 2012

Polymorphism in the TRIM5α/TRIMcyp gene, which interacts with the lentiviral capsid, has been shown to impact on simian immunodeficiency virus (SIV) replication in certain macaque species. Here, in the context of a live-attenuated SIV vaccine study conducted in Mauritian-origin cynomolgus macaques (MCM), we demonstrate upregulation of TRIM5α expression in multiple lymphoid tissues immediately following vaccination. Despite this, the restricted range of TRIM5α genotypes and lack of TRIMcyp variants had no or only limited impact on the replication kinetics in vivo of either the SIVmac viral vaccine or wild-type SIVsmE660 challenge. Additionally, there appeared to be no impact of TRIM5α genotype on the outcome of homologous or heterologous vaccination/challenge studies. The limited spectrum of TRIM5α polymorphism in MCM appears to minimize host bias to provide consistency of replication for SIVmac/SIVsm viruses in vivo, and therefore on vaccination and pathogenesis studies conducted in this species.
Full-length genome sequences of five hepatitis C virus isolates representing subtypes 3g, 3h, 3i and 3k, and a unique genotype 3 variant
Authors: Lu Ling , Li Chunhua , Yuan Jie , Lu Teng , Okamoto Hiroaki , Murphy Donald G.
Published: November 2012

We characterized the full-length genomes of five distinct hepatitis C virus (HCV)-3 isolates. These represent the first complete genomes for subtypes 3g and 3h, the second such genomes for 3k and 3i, and of one novel variant presently not assigned to a subtype. Each genome was determined from 18–25 overlapping fragments. They had lengths of 9579–9660 nt and each contained a single ORF encoding 3020–3025 aa. They were isolated from five patients residing in Canada; four were of Asian origin and one was of Somali origin. Phylogenetic analysis using 64 partial NS5B sequences differentiated 10 assigned subtypes, 3a–3i and 3k, and two additional lineages within genotype 3. From the data of this study, HCV-3 full-length sequences are now available for six of the assigned subtypes and one unassigned. Our findings should add insights to HCV evolutionary studies and clinical applications.
The role of PR-Set7 in replication licensing depends on Suv4-20h
Authors: Beck David B. , Burton Adam , Oda Hisanobu , Ziegler-Birling Céline , Torres-Padilla Maria-Elena , Reinberg Danny
Published: November 2012

PR-Set7 is the sole monomethyltransferase responsible for H4K20 monomethylation (H4K20me1) that is the substrate for further methylation by Suv4-20h1/h2. PR-Set7 is required for proper cell cycle progression and is subject to degradation by the CRL4Cdt2 ubiquitin ligase complex as a function of the cell cycle and DNA damage. This report demonstrates that PR-Set7 is an important downstream effector of CRL4Cdt2 function during origin of DNA replication licensing, dependent on Suv4-20h1/2 activity. Aberrant rereplication correlates with decreased levels of H4K20me1 and increased levels of H4K20 trimethylation (H4K20me3). Expression of a degradation-resistant PR-Set7 mutant in the mouse embryo that is normally devoid of Suv4-20 does not compromise development or cell cycle progression unless Suv4-20h is coexpressed. PR-Set7 targeting to an artificial locus results in recruitment of the origin recognition complex (ORC) in a manner dependent on Suv4-20h and H4K20me3. Consistent with this, H4K20 methylation status plays a direct role in recruiting ORC through the binding properties of ORC1 and ORCA/LRWD1. Thus, coordinating the status of H4K20 methylation is pivotal for the proper selection of DNA replication origins in higher eukaryotes.
Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis
Authors: Colas Alexandre R. , McKeithan Wesley L. , Cunningham Thomas J. , Bushway Paul J. , Garmire Lana X. , Duester Gregg , Subramaniam Shankar , Mercola Mark
Published: November 2012

Tight control over the segregation of endoderm, mesoderm, and ectoderm is essential for normal embryonic development of all species, yet how neighboring embryonic blastomeres can contribute to different germ layers has never been fully explained. We postulated that microRNAs, which fine-tune many biological processes, might modulate the response of embryonic blastomeres to growth factors and other signals that govern germ layer fate. A systematic screen of a whole-genome microRNA library revealed that the let-7 and miR-18 families increase mesoderm at the expense of endoderm in mouse embryonic stem cells. Both families are expressed in ectoderm and mesoderm, but not endoderm, as these tissues become distinct during mouse and frog embryogenesis. Blocking let-7 function in vivo dramatically affected cell fate, diverting presumptive mesoderm and ectoderm into endoderm. siRNA knockdown of computationally predicted targets followed by mutational analyses revealed that let-7 and miR-18 down-regulate Acvr1b and Smad2, respectively, to attenuate Nodal responsiveness and bias blastomeres to ectoderm and mesoderm fates. These findings suggest a crucial role for the let-7 and miR-18 families in germ layer specification and reveal a remarkable conservation of function from amphibians to mammals.
Spliceosome activation: U4 is the path, stem I is the goal, and Prp8 is the keeper. Let's cheer for the ATPase Brr2!
Authors: Nielsen Klaus H. , Staley Jonathan P.
Published: November 2012

During pre-mRNA splicing, the spliceosome is activated for catalysis by unwinding base-paired U4/U6 small nuclear RNAs, a step that must be precisely timed. We know that unwinding requires the ATPase Brr2, but the mechanism and regulation of unwinding have been understood poorly. In the November 1, 2012, issue of Genes & Development, Hahn and colleagues (pp. 2408–2421) and Mozaffari-Jovin and colleagues (pp. 2422–2434) defined a pathway for U4/U6 unwinding. Moreover, Mozaffari-Jovin and colleagues suggested a mechanism for regulating Brr2.
Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome
Authors: McCord Rachel Patton , Nazario-Toole Ashley , Zhang Haoyue , Chines Peter S. , Zhan Ye , Erdos Michael R. , Collins Francis S. , Dekker Job , Cao Kan
Published: November 2012

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin–lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.
Obligate Ligation-Gated Recombination (ObLiGaRe): Custom-designed nuclease-mediated targeted integration through nonhomologous end joining
Authors: Maresca Marcello , Lin Victor Guosheng , Guo Ning , Yang Yi
Published: November 2012

Custom-designed nucleases (CDNs) greatly facilitate genetic engineering by generating a targeted DNA double-strand break (DSB) in the genome. Once a DSB is created, specific modifications can be introduced around the breakage site during its repair by two major DNA damage repair (DDR) mechanisms: the dominant but error-prone nonhomologous end joining (NHEJ) pathway, and the less-frequent but precise homologous recombination (HR) pathway. Here we describe ObLiGaRe, a new method for site-specific gene insertions that uses the efficient NHEJ pathway and acts independently of HR. This method is applicable with both zinc finger nucleases (ZFNs) and Tale nucleases (TALENs), and has enabled us to insert a 15-kb inducible gene expression cassette at a defined locus in human cell lines. In addition, our experiments have revealed the previously underestimated error-free nature of NHEJ and provided new tools to further characterize this pathway under physiological and pathological conditions.
Gaussian deconvolution: a useful method for a form-free modeling of scattering data from mono- and multilayered planar systems
Authors: Oliveira Cristiano L. P. , Gerbelli Barbara B. , Silva Emerson R. T. , Nallet Frédéric , Navailles Laurence , Oliveira Elisabeth A. , Pedersen Jan Skov
Published: November 2012

A new method for analysis of scattering data from lamellar bilayer systems is presented. The method employs a form-free description of the cross-section structure of the bilayer and the fit is performed directly to the scattering data, introducing also a structure factor when required. The cross-section structure (electron density profile in the case of X-ray scattering) is described by a set of Gaussian functions and the technique is termed Gaussian deconvolution. The coefficients of the Gaussians are optimized using a constrained least-squares routine that induces smoothness of the electron density profile. The optimization is coupled with the point-of-inflection method for determining the optimal weight of the smoothness. With the new approach, it is possible to optimize simultaneously the form factor, structure factor and several other parameters in the model. The applicability of this method is demonstrated by using it in a study of a multilamellar system composed of lecithin bilayers, where the form factor and structure factor are obtained simultaneously, and the obtained results provided new insight into this very well known system.
The AMPIX electrochemical cell: a versatile apparatus forin situX-ray scattering and spectroscopic measurements
Authors: Borkiewicz Olaf J. , Shyam Badri , Wiaderek Kamila M. , Kurtz Charles , Chupas Peter J. , Chapman Karena W.
Published: November 2012

This article presents a versatile easy-to-use electrochemical cell suitable forin operando,in situmeasurements of battery materials during electrochemical cycling using a variety of X-ray techniques. Argonne's multi-purposein situX-ray (AMPIX) cell provides reliable electrochemical cycling over extended periods owing to the uniform stack pressure applied by rigid X-ray windows and the formation of a high-fidelity hermetic seal. The suitability of the AMPIX cell for a broad range of synchrotron-based X-ray scattering and spectroscopic measurements has been demonstrated with studies at eight Advanced Photon Source beamlines to date. Compatible techniques include pair distribution function analysis, high-resolution powder diffraction, small-angle scattering and X-ray absorption spectroscopy. These techniques probe a broad range of electronic, structural and morphological features relevant to battery materials. The AMPIX cell enables experiments providing greater insight into the complex processes that occur in operating batteries by allowing the electrochemical reactions to be probed at fine reaction intervals with greater consistency (within the charge–discharge cycle and between different methodologies) with potential for new time-dependent kinetic studies or studies of transient species. Representative X-ray and electrochemical data to demonstrate the functionality of the AMPIX cell are presented.
Rietveld refinement and structure verification using `Morse' restraints
Authors: Bushmarinov Ivan S. , Dmitrienko Artem O. , Korlyukov Alexander A. , Antipin Mikhail Yu.
Published: November 2012

A new restraint scheme for Rietveld refinement based on Morse bond energy potential is introduced, in which the asymmetry of the Morse potential allows the refinement to `break' the incorrectly placed bonds. The analysis of bond-length distributions at different values of restraint strength reveals a visible difference in behavior of wrong and correct structures, which can be detected using robust statistical methods. This fact is employed as a basis for a novel structure verification criterion. The approach is demonstrated on known difficult cases of acetolone and γ-quinacridone and used for the Rietveld refinement ofN-(6-phenylhexanoyl)glycyl-L-tryptophanamide, an organic molecule of a potential anxiolytic containing 32 non-H atoms and 14 single bonds. The results are verified using density functional theory calculations with periodic boundary conditions.
Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population‐based study of 327 patients
Authors: Bonicelli Gilles , Abdulkarim Khadija , Mounier Morgane , Johansson Peter , Rossi Cédric , Jooste Valérie , Andreasson Björn , Maynadié Marc , Girodon François
Published: November 2012

Three hundred and twenty‐seven patients from two population‐based cohorts with an established diagnosis of polycythaemia vera were studied for prognostic risk factors for survival and leukaemia in a long‐term survey. The relative survival (RS) was 72% and 46% at 10 and 20 years respectively, from the time of diagnosis. Multivariate analysis identified age >70 years, white blood cell count >13 × 109/l and thrombo‐embolism at diagnosis as independent risk factors. Patients with two or three of these factors had a 10 year RS of 26%, compared with 59% and 84% in patients with one and no risk factors, respectively. Age and leucocyte count are the main predicting factors for survival in polycythaemia vera.
Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long‐term follow‐up study
Authors: Sahebi Firoozeh , Shen Yan , Thomas Sandra H. , Rincon Amalia , Murata‐Collins Joyce , Palmer Joycelynne , Krishnan Amrita Y. , Karanes Chatchada , Htut Myo , Somlo George , Forman Stephen J.
Published: November 2012

We analysed the long‐term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu‐mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high‐dose melphalan conditioning for autograft followed by low‐dose total body irradiation conditioning for allogeneic HCT (auto‐allo regimen). Donors included human‐leucocyte‐antigen‐matched siblings (n = 55) or matched unrelated donors (n = 5). With a median follow‐up of 9·8 years, 7‐year overall survival (OS) and progression‐free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft‐versus‐host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post‐transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, five had normal karyotypes, and five were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.
Hypersensitivity reactions to the Sabin vaccine in children with cow's milk allergy
Authors: Parisi C. A. S. , Smaldini P. L. , Gervasoni M. E. , Maspero J. F. , Docena G. H.
Published: November 2012

Background

The Sabin vaccine is used world‐wide, and most children with food allergies receive it without incident. However, in the 2009 vaccination campaign conducted in Argentina, four children experienced immediate‐type hypersensitivity reactions following vaccination.

Objective

We aimed to review the medical history of the affected children, study their allergic condition after the episodes and analyse the presence of allergenic vaccine components.

Methods

Patients were selected based on their immediate allergic reactions following vaccination. They were assessed for allergies to cow's milk and hen's egg. The presence of cow's milk proteins in the vaccine was tested by various immunoassays involving cow's milk‐ or α‐lactalbumin‐specific polyclonal rabbit antiserum and patient sera.

Results

All of the patients had a history of milk allergy, and no history or current evidence of egg hypersensitivity was found. Levels of cow's milk‐ and Sabin vaccine‐specific IgE were increased, and the result of a skin prick test with cow's milk proteins or the Sabin vaccine was positive in each patient. In addition, an ELISA using specific rabbit antiserum detected α‐lactalbumin in the Sabin vaccine. When α‐lactalbumin was employed as a soluble inhibitor in a competitive ELISA, binding to vaccine‐coated plates by cow's milk‐ or α‐lactalbumin‐specific rabbit antiserum or by patient serum containing IgE was inhibited.

Conclusions

We have demonstrated that these patients were allergic to cow's milk, and had circulating and mast cell‐bound IgE antibodies specific to cow's milk proteins. We found that the Sabin vaccine contained α‐lactalbumin, which may have been responsible for the reactions elicited following vaccination with the Sabin and dual viral vaccines in combination.
Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility
Authors: Rogers A. J. , Chu J.‐H. , Darvishi K. , Ionita‐Laza I. , Lehmann H. , Mills R. , Lee C. , Raby B. A.
Published: November 2012

Background

Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focussed almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs).

Objective

To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma‐susceptibility variants at these loci.

Methods

We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20 092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT‐CNV.

Results

Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In six instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried six asthma‐candidate CNVs (range 1–29). However, the vast majority of identified CNVs were of rare frequency (< 5%) and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma.

Conclusions and Clinical Relevance

Although a substantial proportion of asthma‐susceptibility genes harbour polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma‐associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.
Land use causes genetic differentiation of life‐history traits in Bromus hordeaceus
Authors: Völler Eva , Auge Harald , Bossdorf Oliver , Prati Daniel
Published: November 2012

There is increasing evidence that species can evolve rapidly in response to environmental change. However, although land use is one of the key drivers of current environmental change, studies of its evolutionary consequences are still fairly scarce, in particular studies that examine land‐use effects across large numbers of populations, and discriminate between different aspects of land use. Here, we investigated genetic differentiation in relation to land use in the annual grass Bromus hordeaceus. A common garden study with offspring from 51 populations from three regions and a broad range of land‐use types and intensities showed that there was indeed systematic population differentiation of ecologically important plant traits in relation to land use, in particular due to increasing mowing and grazing intensities. We also found strong land‐use‐related genetic differentiation in plant phenology, where the onset of flowering consistently shifted away from the typical time of management. In addition, increased grazing intensity significantly increased the genetic variability within populations. Our study suggests that land use can cause considerable genetic differentiation among plant populations, and that the timing of land use may select for phenological escape strategies, particularly in monocarpic plant species.
Hydrogen Ion Balance in Dialysis Therapy
Authors: Gotch Frank A. , Sargent John A. , Keen Marcia L.
Published: November 2012

A model to describe hydrogen ion balance (H+B) in acetate and bicarbonate dialysis therapy was developed based on measurement of metabolic addition of hydrogen ion (H+) to the body between and during dialyses and measurement of net buffer repletion during dialysis. Metabolic H+ generation was shown to be equal to 0.77 times the protein catabolic rate plus the total net removal of lactate and β‐hydroxybutyrate ions during dialysis. Buffer repletion was calculated from total net flux of acetate and bicarbonate during dialysis. The model was used for eight paired studies of H+B on one week each of acetate and bicarbonate dialysis and showed that cumulative H+B with acetate was ‐7 ± 28 (M ± SEM) mmol/ week compared to ‐175 ± 45 mmol/week with bicarbonate (P < 0.001). It is concluded that there is an initial, strongly negative H+B when patients on acetate dialysis are converted to bicarbonate. The possible physiologic significance of this is discussed.
Pathogenesis of Dialysis‐Induced Hypoxemia
Authors: Davidson Warren D. , Dolan Martin J. , Whipp Brian J. , Weitzman Richard E. , Wasserman Karlmann
Published: November 2012

Patients undergoing hemodialysis with acetate‐containing dialysis solutions develop hypoxemia. To determine the cause of the hypoxemia, we studied and compared the ventilatory, gas‐exchange and blood‐gas responses in chronic renal failure patients undergoing hemodialysis with acetate and bicarbonate dialysis solutions. Seven stable chronic dialysis patients were dialyzed against acetate and bicarbonate solutions in a random order. Dialysis was carried out using a 1.5 m2 hollow fiber dialyzer at a blood flow rate of 200 ml/min and a dialysate flow rate of 500 ml/min. During acetate dialysis, Pao2 fell within 15 minutes from a mean control predialysis concentration of 84 = 6 (SEM) mmHg to a mean of 70 ± 7.5 mmHg (P < 0.05), and remained low throughout the study. Pao2 did not change significantly during bicarbonate dialysis. Total ventilation fell from a predialysis level of 7.2 ± 0.7 L/ min to 5.7 ± 0.6 L/min within 15 minutes (P < 0.05). Paco2 was not significantly changed from predialysis levels with either acetate or bicarbonate dialysis. Measurement of blood concentration of CO2 and bicarbonate across the dialyzer indicated that the total CO2 loss (as CO2 and bicarbonate) through the dialyzer was 3 millimoles per minute or the equivalent of approximately 60 ml of CO2 per minute, i.e., about one third of the patient's metabolic production of CO2.